Population Pharmacokinetic and Pharmacodynamic Analysis of Belimumab Administered Subcutaneously in Healthy Volunteers and Patients with Systemic Lupus Erythematosus

Population Pharmacokinetic and Pharmacodynamic Analysis of Belimumab Administered Subcutaneously... Clin Pharmacokinet (2018) 57:717–728 https://doi.org/10.1007/s40262-017-0586-5 ORIGINAL RESEARCH ARTICLE Population Pharmacokinetic and Pharmacodynamic Analysis of Belimumab Administered Subcutaneously in Healthy Volunteers and Patients with Systemic Lupus Erythematosus 1 2 3 • • Herbert Struemper Mita Thapar David Roth Published online: 8 September 2017 The Author(s) 2017. This article is an open access publication Abstract Methods Non-linear mixed-effects modeling (NON- Background Intravenous belimumab 10 mg/kg every MEM) was used to develop a population pharmacoki- 4 weeks is indicated in patients with active, autoantibody- netic model and perform a covariate analysis. positive systemic lupus erythematosus receiving standard Subsequently, exploratory exposure-response analysis and systemic lupus erythematosus care. Subcutaneous 200-mg logistic regression modeling was performed based on the weekly administration, which may prove more convenient individual parameter estimates of the population pharma- for patients and improve adherence, is currently under cokinetic model. investigation. Results Population-pharmacokinetic parameters for sub- Objective The objective of this study was to characterize cutaneous belimumab were consistent with those for the population pharmacokinetics and exposure-efficacy intravenous belimumab and other immunoglobulin G1 response of subcutaneous belimumab in a pooled analysis monoclonal antibodies. Pharmacokinetic parameters and of pharmacokinetic data [phase I: BEL114448 subcutaneous belimumab exposure were consistent (NCT01583530) and BEL116119 (NCT01516450) in between healthy subjects and patients with systemic lupus healthy subjects (n = 134); phase III: BEL112341 erythematosus, and no evidence for target-mediated dis- (NCT01484496) in adults with systemic lupus erythe- position of belimumab was found. Subcutaneous matosus (n = 554)] and pharmacodynamic data belimumab steady-state exposure was achieved after [BEL112341 in adults with systemic lupus erythematosus *11 weeks; subcutaneous belimumab steady-state mini- (n = 833)]. mum concentration exceeded that of intravenous belimumab after \4 weeks, and average steady-state con- centration was similar to that achieved following intra- venous administration. In patients with moderate-to-severe systemic lupus erythematosus, subcutaneous belimumab 200 mg once weekly plus standard of care significantly improved the systemic lupus erythematosus responder index. However, at this dose, the systemic lupus erythe- Electronic supplementary material The online version of this matosus responder index response was not significantly article (doi:10.1007/s40262-017-0586-5) contains supplementary material, which is available to authorized users. associated with belimumab exposure concentrations. Conclusion The analysis demonstrates that a 200-mg once- & Herbert Struemper weekly dose of belimumab is appropriate for subcutaneous herbert.x.struemper@gsk.com administration in patients with systemic lupus erythe- Quantitative Clinical Development, PAREXEL International matosus and that no dose adjustments are required for adult on behalf of GlaxoSmithKline, 2520 Meridian Parkway, patients to maintain efficacy and safety. Suite 200, Durham, NC 27713, USA ICON, Marlow, Buckinghamshire, UK GlaxoSmithKline, Collegeville, PA, USA 718 H. Struemper et al. patient convenience and independence, and reduce the overall healthcare burden of belimumab treatment [10–14]. Key Points The ability to administer treatments away from the clinic can largely eliminate substantial time and financial costs Population-pharmacokinetic parameters for associated with travel to/from the drug-administering site, subcutaneous belimumab were consistent with those for the infusion itself, and for post-infusion monitoring. In for intravenous belimumab and other a study of patients with rheumatoid arthritis, more patients immunoglobulin G1 monoclonal antibodies. chose SC treatment than IV treatment, with the reduced In patients with moderate-to-severe systemic lupus need to travel to receive an infusion being an influential erythematosus, subcutaneous belimumab (200 mg, factor [15]. A popPK model comparing IV with SC weekly) plus standard systemic lupus erythematosus belimumab has previously been developed using pooled care significantly improved the systemic lupus data from two phase I studies (BEL114448 erythematosus responder index. However, at this [NCT01583530] and BEL116119 [NCT01516450]) in dose, the systemic lupus erythematosus responder healthy subjects [12–14]. This present analysis character- index response was not significantly associated with izes the popPK and exposure-efficacy response of belimumab exposure concentrations. belimumab following SC administration in a pooled anal- No dose adjustments are required for subcutaneous ysis of PK data from these aforementioned phase I studies in belimumab in adult patients with systemic lupus healthy subjects [12, 14], combined with PK and pharma- erythematosus to maintain efficacy and safety. codynamics (PD) data from a large phase III study in adult patients with SLE [BEL112341 (NCT01484496)] [10]. 2 Methods 1 Introduction 2.1 Objectives Systemic lupus erythematosus (SLE) is a chronic multi- The objectives of the popPK analysis were to develop a system autoimmune disease presenting a broad spectrum of model that characterizes the PK disposition of SC clinical manifestations [1]. B-lymphocyte stimulator belimumab following 200-mg weekly (QW) administration (BLyS) is a member of the tumor necrosis factor family, in healthy subjects and patients with SLE, to evaluate the and plays an integral role in the selection and survival of B potential effect of selected covariates on key PK parame- cells [2]. Although the definitive role of BLyS in SLE has ters, and to estimate individual subject PK parameters such not yet been fully elucidated, B cells and BLyS have been as steady-state area under the curve, average steady-state identified as playing critical roles in SLE pathogenesis [2]. concentration (C ), steady-state maximum concentration, avg Belimumab is a recombinant, human, immunoglobulin steady-state minimum concentration (C ), elimination min G1 (IgG1) monoclonal antibody that targets BLyS, half-life for the first phase, elimination half-life for the inhibiting B-cell survival and differentiation without terminal phase, and steady-state volume of distribution. In directly causing B-cell death [2, 3]. Two phase III, ran- addition, an exploratory exposure-response analysis was domized, double-blind, placebo-controlled studies [BLISS- proposed, plotting exposure (C ) vs. the selected avg 52 (NCT00424476) and BLISS-76 (NCT00410384)] have PD/efficacy/safety endpoints at week 52, alongside a demonstrated that intravenous (IV) belimumab plus stan- popPK/PD analysis on a selected PD/efficacy/safety end- dard SLE care is associated with a significant reduction in point(s) of special interest (phase III study only). disease activity in active autoantibody-positive SLE [4, 5]. The IV formulation of belimumab is indicated for the 2.2 Study Design treatment of active autoantibody-positive SLE in patients receiving standard SLE care, at a dose of 10 mg/kg at In this popPK/PD analysis, PK data from 688 individuals 2-week intervals for the first three doses and every 4 weeks from three studies [phase I: BEL116119 and BEL114448 thereafter [6]. A population-pharmacokinetic (popPK) (n = 134); phase III: BEL112341 [10] (NCT01484496; model for IV belimumab was developed [7] using pooled n = 554)] and PD data from BEL112341, for which the data from phase I and II studies [8, 9] and the two pivotal methods and results have been described previously phase III studies, BLISS-52 and BLISS-76 [4, 5]. [10, 12, 14], were analyzed using a popPK/PD approach A subcutaneous (SC) formulation of belimumab is cur- (Table 1). The primary efficacy endpoint for Study rently under investigation, the use of which may improve BEL112341 was the SLE responder index 4 (SRI4), a Population Pharmacokinetics/Pharmacodynamics of Subcutaneous Belimumab 719 Table 1 Studies included in the belimumab population pharmacokinetic/pharmacodynamic (PK/PD) analysis Study Population Dose and administration Planned PK data PD/efficacy/safety endpoints Phase I n = 16 Two single-dose groups Not available (BEL116119 Healthy IV group: 200-mg single- IV group: pre-dose (day 0), 5 min, 1 h, 6 h, days 1, [12]) volunteers dose IV infusion over 1 h 2, 4, 7, 14, 21, 28, 42, 56, and 70 post-dose (Japan) (n = 8) SC group: 200-mg SC SC group: pre-dose (day 0), 6 h, days 1, 2, 3, 4, 5, 6, single dose 7, 10, 14, 21, 28, 42, 56, and 70 post-dose over 10–15 s (n = 8) Phase I n = 118 Four single-dose groups Not available (BEL114448) Healthy Group 1: SC, 2 sequential Groups 1, 2, 3 (SC dosing): pre-dose (day 0), 6 h, volunteers injections (0.6 mL/ days 1, 2, 3, 4, 5, 6, 7, 10, 14, 21, 28, 42, 56, and (USA) injection; 200 mg/mL) 70 post-dose Group 2: SC, 1 injection (1.2 mL/injection; 200 mg/mL) Group 3: SC, 1 injection (1.2 mL/injection; 200 mg/mL) Group 4: IV control Group 4 (IV dosing): pre-dose (day 0), 5 min, 1 h, (240 mg lyophilized 3 h, 6 h, days 1, 2, 4, 7, 14, 21, 28, 42, 56, and 70 formulation) post-dose Two groups with 4-weekly SC doses Group 5: weekly 9 4; SC, Groups 5 and 6: pre-dose (day 0), 6 h, days 1, 2, 3, 2 sequential injections 4, 5, 6, 7 (prior to second dosing), 14 (prior to (0.6 mL/injection; third dosing), 21 (prior to fourth dosing), 6 h post- 200 mg/mL) fourth dose, days 22, 23, 24, 25, 26, 27, 28, 31, 35, 42, 49, 63, 77, 91, and 119 post-dose Group 6: weekly 9 4; SC, 1 injection (1.2 mL/ injection; 200 mg/mL) Phase III n = 833 (554 on SC 200 mg, weekly for Pre-dose (day 0), weeks 4, 8, 16, 24, and 52, SRI response (BEL112341) belimumab; 51 weeks 1–4 weeks after the last dose (for patients exiting Change in SELENA- 279 on before week 52), 8 weeks after the last dose (for SLEDAI score placebo) patients not entering the extension phase or Change in naı¨ve withdrawing from the study at any time) Patients with peripheral B-cell SLE (global) subset (CD20?/ CD27-) Change in complement (C3, C4) level Change in anti- dsDNA antibody level Change in total serum IgG level Frequency of SAEs Frequency of serious/severe infections CD cluster of differentiation, dsDNA double-stranded DNA, IgG immunoglobulin G, IV intravenous, SAEs serious adverse events, SC subcu- taneous, SELENA-SLEDAI Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus, SLE systemic lupus erythematosus, SRI systemic lupus erythematosus responder index 720 H. Struemper et al. composite index that includes a C4-point reduction in parametric bootstrap analysis (500 datasets, random the Safety of Estrogens in Lupus Erythematosus sampling with replacement with subjects as the sampling National Assessment-SLE Disease Activity Index unit). Following popPK model development, PK profiles (SELENA-SLEDAI) [10]. were simulated using population parameters from this All subjects with evaluable dosing, actual sampling analysis for the SC curves (Table 3) and from the IV time, and belimumab concentration data were included in popPK model [7] for the IV curves. Steady-state param- the popPK dataset and analysis. All subjects and placebo eters were derived from profiles following 24 weeks of subjects with evaluable PD efficacy/safety data were dosing. included in the popPK/PD dataset and analysis. 2.3.3 Population Pharmacokinetic/Pharmacodynamic 2.2.1 Assay Methods Model Development Serum concentrations of belimumab were determined by a Following a graphical exposure-response analysis for validated electrochemiluminescence-based immunoassay selected PD/efficacy/safety endpoints, a logistic regression with a lower limit of quantitation of 100 ng/mL of model was developed to characterize SRI4 response in belimumab in human serum. relation to C (generally considered relevant for both avg efficacy and safety dose response) and other subject char- acteristics as potential predictors of efficacy. The proba- 2.3 Modeling bility of being a SRI responder was obtained by the equation: 2.3.1 Software and Estimation Methods P ¼ expðLPÞ=ð1 þ expðLPÞÞ: When the observed response is 0, the variable to be fitted Models were developed with a non-linear mixed-effects is Y = 1 - P and when the observation is 1, Y = P. modeling approach using NONMEM Version VII level The main logistic regression analysis was applied to the 3.0 (ICON Development Solutions, Ellicott City, MD, combined placebo and belimumab-treated SRI data set. USA) and PDx-Pop (Version 5.1). Population pharma- Consistent with covariate model development of the cokinetic parameters were estimated using the first-order popPK model, this model was developed using a hybrid conditional estimation method with interaction; popPK/PD full model/backward elimination approach to identify sig- (logistic regression) parameters were estimated using the nificant predictors (a = 0.05). The full covariate model Laplace estimation method. included the effects of 18 predictors including demo- graphic variables, baseline disease characteristics, presence of co-medications, and belimumab exposure (difference of 2.3.2 Population Pharmacokinetic Model Development C to median C in the belimumab-treated population). avg avg To characterize the SRI response in belimumab-treated A linear two-compartment model (ADVAN3, TRANS4 patients, these covariate effects were only applied to subroutine) was chosen as the structural PK model, based belimumab-treated patients; the response for placebo on the previously characterized IV popPK model [7], and patients being represented by the intercept parameter. The two-compartment behavior was confirmed via exploratory final model was derived by stepwise backwards elimination data analysis of the serially sampled IV/SC PK data. First- of effects not meeting the significance criterion for the log- order absorption into the central compartment with rate likelihood ratio test. constant and a lag time was added to model the SC data. In a sensitivity analysis to explore any impact of Inter-individual variability was tested and included with placebo data on the effects retained in the final model of lognormal random-effect distributions. A hybrid full the main analysis, an alternate analysis was conducted by model/backward elimination approach was used to develop restricting the exposure-response data to belimumab- the covariate model. The full model was determined by a treated patients only, i.e., removing data for placebo selection of 26 covariate effects guided by the covariate patients. The final model of the sensitivity analysis was analysis for the IV popPK analysis. The full model was derived by constructing a full model with the same reduced to the final model by step-wise removal (backward covariate effects (except for the treatment effect) as in elimination) of effects not meeting the statistical signifi- the main analysis and applying the same stepwise cance criterion (a = 0.001, as for IV popPK analysis). backwards elimination procedure to arrive at an alternate The model was qualified with diagnostic plots, visual final model. predictive checks (500 data sets), and with a non- Population Pharmacokinetics/Pharmacodynamics of Subcutaneous Belimumab 721 Table 2 Subject demographics and baseline characteristics (popula- concentrations from six subjects were excluded from the tion-pharmacokinetic analyses: N = 688) analysis. Study-specific median values were imputed for missing continuous covariate values in the dataset. Demographics Sex: female, n (%) 584 (85) 3.1.2 Population Pharmacokinetic Modeling Race, n (%) White 422 (61) The pharmacokinetics of SC belimumab was best descri- Asian 137 (23.5) bed by a linear two-compartment base model with an African American 76 (11) absorption lag time followed by first-order absorption into American Indian or Alaska Native 41 (6) the central compartment and elimination from the central Other 12 (1.7) compartment. No evidence for substantial target-mediated Mean (SD) age, years 37.6 (11.8) disposition of belimumab was found. The random-effects Median (range) 37 (18–77) structure of the model included inter-individual variability Mean (SD) weight, kg 70.0 (17.6) on central clearance (CL), inter-compartmental clearance Median (range) 67.0 (34.1–138) (Q), central (V ) and peripheral (V ) volumes of distribu- c p Mean (SD) BMI, kg/m 26.1 (6.18) tion, as well as a combined proportional and additional Median (range) 24.7 (14.8–72.7) residual error model. Significant covariate effects (a = 0.001) retained in the Characteristics Mean (SD) Median (range) final model after backward elimination included body mass IgG, g/L 14.9 (5.43) 13.7 (4.70–53.5) index (BMI) on V (power coefficient of -0.6110) and Proteinuria, mg/mg 0.340 (0.651) 0.118 (0.0210–6.23) body weight on CL and V (power coefficients of 0.75 and Albumin levels, g/L 40.7 (4.47) 41.0 (18.0–55.0) 1.00, respectively), and albumin (Fig. 1a) and IgG Creatinine clearance, mL/min 115 (38.3) 109 (35.0–353) (Fig. 1b) on CL. In general, belimumab CL increased with Hemoglobin, g/L 126 (15.8) 126 (73.0–173) increasing levels of baseline IgG (power coefficient of WBC count, Gi/L 6.09 (2.41) 5.70 (1.30–13.9) 0.347). An inverse relationship was seen between baseline albumin levels and belimumab CL, whereby CL decreased BMI body mass index, IgG immunoglobulin G, SD standard devia- with albumin (power coefficient of -0.736). The only tion, WBC white blood cell pharmacokinetically relevant covariates (defined as a Study BEL112341 determined proteinuria by measuring the spot urine protein:creatinine ratio (mg/mg). In the BEL112341 clinical change relative to the population median beyond the -20 study report and other submission documents, these values are to ?25% range in CL or V for the 5th to 95th percentile reported as g/24-h equivalent proteinuria values. In Study range of the patient covariate distribution) were BMI and BEL112341, 99 subjects (18% of subjects in Study BEL112341) had body weight. The predicted effects of age, sex, race, dis- proteinuria [0.5 g/24 h and 19 subjects (3% of subjects in Study ease activity, concomitantly administered medications BEL112341) had proteinuria C2 g/24 h (corticosteroids, angiotensin-converting enzyme inhibitors, azathioprine, methotrexate, mycophenolate mofetil, anti- malarial medications, statins, non-steroidal anti-inflamma- 3 Results tory drugs, and aspirin), baseline characteristics, or other tested factors were neither statistically significant nor 3.1 Population-Pharmacokinetic Model pharmacokinetically relevant (the exposure-response anal- ysis demonstrated that the SRI response was at the 200-mg 3.1.1 Subject Disposition QW dose level, which is not significantly correlated with exposure variability). Pharmacokinetic parameters and SC A total of 4958 belimumab concentrations (on average, belimumab exposure were consistent between healthy seven per subject) from 688 healthy volunteers and patients subjects and patients with SLE. with SLE were included in the popPK analysis (Table 2). The parameters of the final SC belimumab popPK model Of these 4958 concentrations, 2298 were contributed by were estimated with good precision (relative standard error 134 subjects who were serially sampled [17 concentrations % 0.3–28%) and agreement between model and bootstrap per subject on average, from healthy volunteers in two parameters (Table 3). Goodness-of-fit plots for the final phase I studies (BEL116119 [12] and BEL114448 [14])] model indicate that the model provided an appropriate and 2660 concentrations were contributed by 554 patients description of the data (Fig. 2). Visual predictive checks who were sparsely sampled [five concentrations per patient indicated that the final model represented both central on average, from patients with SLE in one phase III study tendency and variability of belimumab pharmacokinetics (BLISS SC BEL112341 [10])]. Quantifiable pre-first dose well for both routes of administration (Fig. 3) and for each 722 H. Struemper et al. A B 800 800 600 600 400 400 200 200 20 30 40 50 60 10 20 30 40 50 60 Baseline albumin (g/L) Baseline IgG (g/L) Fig. 1 Covariate effect of baseline albumin (a) and immunoglobulin indicates the predicted relationship; the light gray rectangle indicates G [IgG] (b) on clearance. Margin box plots: black bar median; box the 5th to 95th percentiles; and the dark gray rectangle indicates the interquartile range; circles outliers. The red line indicates the locally interquartile range weighted scatterplot smoothing fit of observed data; the black line of the three studies [Fig. 2 of the Electronic Supplementary and fixed SC dosing, two additional PK profiles for a low- Material (ESM)], the latter indicating that the model weight and heavy subject were simulated by setting both appropriately represents both healthy subjects and patients body weight and BMI to the 5th and 95th percentiles, with SLE. respectively, in Study BEL112341 (Fig. 4, dotted and Based on the popPK parameters, belimumab is absorbed dashed lines, respectively, other covariates were kept at following SC administration with a lag time of 0.18 days, median values). As expected, increased body size resulted absorption half-life of 3 days, and bioavailability of 74%. in a smaller exposure for SC belimumab and a larger Key structural popPK parameters included total systemic exposure for IV belimumab (and vice versa), while the CL of 204 mL/day; V and volume of distribution of the range of deviation from the prototypical popPK profile was peripheral compartment (2300 and 2650 mL, respectively); comparable for both routes of administration. Figure 3 of and inter-compartmental CL of 698 mL/day (Table 3). A the ESM illustrates this relationship by comparing indi- terminal half-life of 18 days, distribution half-life of vidual C estimates for this and the IV popPK analysis avg 1.1 days, and steady-state volume of distribution of [7]: geometric means and ranges of C are well matched avg 4950 mL were derived from the structural parameters. between SC 200-mg QW dosing and IV 10-mg/kg every To compare chronic exposures resulting from the IV 4 weeks dosing with reversed trends in relation to body dosing regimen approved for SLE with the SC phase III weight. dosing regimen, PK profiles based on the popPK parame- ters of the IV [7] and SC models were simulated (Fig. 4, 3.2 Exposure-Response Analysis solid line). First-dose and steady-state time to maximum concentration for SC belimumab were shown to be 5.5 and 3.2.1 Patient Disposition 2.6 days, respectively. Steady-state exposure for SC belimumab was reached after approximately 11 weeks of A total of 833 patients (554 on belimumab and 279 on 200-mg QW dosing (at C11 weeks C exceeds 95% of placebo; all from Study BEL112341) had SRI response min steady state C ). Steady-state area under the curve from values that were included in the popPK/PD analysis. In the min pre-dose to the end of the dosing interval for SC belimumab arm, 340/554 (61%) patients were responders belimumab 200-mg QW dosing was 726 day 9 lg/mL, and 214/554 (39%) were non-responders; in the placebo and steady-state maximum concentration, C , and C arm, 135/279 (48%) patients were responders and 144/279 min avg were 108, 97, and 104 lg/mL, respectively (Fig. 4). Sub- (52%) were non-responders. cutaneous belimumab C exceeded that of IV belimumab min steady-state C after \4 weeks, and C of SC 3.2.2 Graphical Exposure-Response Analysis min avg belimumab was similar to that achieved following IV administration (Fig. 4). Selected efficacy (SRI, change from baseline in SELENA- To illustrate how the impact of body weight and BMI on SLEDAI at week 52), safety (presence of serious adverse chronic exposure differs between weight-proportional IV events, presence of serious infections), and PD data CL (mL/day) Population Pharmacokinetics/Pharmacodynamics of Subcutaneous Belimumab 723 Table 3 Parameter estimates of the final population-pharmacokinetic model Parameter Implementation Point estimate (%RSE , 95% CI) Bootstrap estimates, median (%RSE, 95% CI) Fixed effects F [fraction] THETA (6) 0.742 (6.75, 0.644–0.840) 0.742 (5.1, 0.673–0.824) ALAG [day] THETA (7) 0.179 (1.99, 0.172–0.186) 0.179 (3.2, 0.168–0.189) Kabs [1/day] THETA (5) 0.235 (5.74, 0.209–0.261) 0.232 (9, 0.198–0.282) CL [mL/day] THETA (1) 204 (6.76, 177–231) 204 (5.0, 186–226) 0.75 Effect of BWT [kg] 9 (BWT/67)–– Effect of BALB [g/L] 9 (BALB/41) -0.736 (14.1, -0.940 to -0.532) -0.737 (14.6, -0.953 to -0.533) Effect of BIGG [g/L] 9 (BIGG/13.7) 0.347 (10.4, 0.276–0.418) 0.352 (11.7, 0.272–0.436) V [mL] THETA (2) 2300 (9.83, 1860–2740) 2290 (8.9, 1890–2705) Effect of BWT 9 (BWT/67) – – 2 h Effect of BBMI [kg/m ] 9 (BBMI/24.7) -0.610 (28.2, -0.947 to -0.273) -0.608 (36.7, –0.997 to -0.16) Q [mL/day] THETA (3) 698 (13.3, 517–879) 683 (22.1, 494–1115) 0.75 Effect of BWT 9 (BWT/67)–– V [mL] 0.8 THETA (4) 2650 (7.09, 2280–3020) 2650 (6.8, 2360–3045) Effect of BWT 9 (BWT/67) – – Inter-individual variability x OMEGA (1,1) 0.0910 (6.11, 0.0801–0.102) 0.0901 (8.1, 0.077–0.105) CL x OMEGA (2,2) 0.497 (9.94, 0.400–0.594) 0.488 (16.9, 0.316–0.650) V1 x OMEGA (2,1) 0.0630 (19.7, 0.0387–0.0873) 0.0632 (749.5, 0.013–0.103) CL/V1 x OMEGA (3,3) 1.07 (21.1, 0.627–1.51) 1.03 (46.4, 0.206–1.892) x OMEGA (4,4) 0.110 (16.5, 0.0743–0.146) 0.111 (19.9, 0.076–0.166) V2 Residual variability r SIGMA (1) 0.0327 (2.63, 0.0310–0.0344) 0.0328 (6.6, 0.029–0.0375) proportional r SIGMA (2) 0.134 (23.7, 0.0717–0.196) 0.138 (39.1, 0.056–0.291) additive ALAG absorption lag time, BALB baseline albumin level, BBMI baseline body mass index, BIGG baseline immunoglobulin G level, BWT baseline body weight, CI confidence interval, CL systemic clearance, F bioavailability for SC dosing, Kabs absorption rate constant, Q inter- compartmental clearance, RSE relative standard error, SC subcutaneous, THETA or h corresponding structural model parameter, Vc central volume of distribution, V peripheral volume of distribution Calculated as (standard error/mean) 9 100% (change from baseline of naı¨ve peripheral B cells, com- applied to belimumab-treated patients: sex, age, race cat- plement C3, complement C4, anti-double-stranded DNA egories, body weight quartiles, SELENA-SLEDAI score, antibody level, and IgG at week 52) were graphically anti-double-stranded DNA antibody presence, low com- examined for a relationship with SC belimumab exposure plement, proteinuria, belimumab treatment, difference to (C ). For the safety endpoints, the C interquartile median belimumab steady-state C , corticosteroid treat- avg avg avg ranges of subjects with serious adverse events or infections ment, antimalarial treatment, and immunosuppressant contained the interquartile ranges of subjects without such treatment. events (Fig. 1 of the ESM). Similarly, none of the other After reducing the full model to statistically significant endpoints showed a strong consistent correlation with SC predictors (a = 0.05), only the following effects remained belimumab exposure (data not shown). in the final model (Table 4). A baseline SELENA-SLEDAI score C10 or American Indian/Alaska Native ethnicity was 3.2.3 Systemic Lupus Erythematosus Responder Index found to increase the probability of being an SRI responder Logistic Regression Modeling for patients treated with belimumab; baseline proteinuria [0.5 g/24 h or African American ethnicity decreased the To identify any predictors of efficacy and to further explore probability of being an SRI responder for these patients (the lack of) exposure effects on efficacy, a logistic (Fig. 5). For patients with SLE receiving belimumab regression analysis of the SRI, the primary efficacy end- 200 mg QW, exposure variations were not a significant point, was conducted. The starting point was a logistic predictor of SRI response, whether the exposure effect was regression model with the following candidate predictors implemented linearly (change in objective function 724 H. Struemper et al. Fig. 2 Goodness-of-fit plots for the final population- pharmacokinetic model. Blue 100 100 circles indicate the observed/ predicted belimumab concentrations; black lines 10 10 indicate the identity or zero lines; and red lines indicated the locally weighted scatterplot smoothing line 1 1 0.1 0.1 1 10 100 1 10 100 Population pr edictions (µg/mL) Individual predictions (µg/mL) 4 4 2 2 0 0 -2 -2 -4 -4 1 10 100 0 100 200 300 400 Population pr edictions (µg/mL) Time after first dose (days ) Fig. 3 Visual predictive check for IV SC final population-pharmacokinetic 500.0 model stratified by route of administration. Open circle observed concentrations; solid line 100.0 median of observed concentrations; dashed lines 5th 50.0 and 95th percentile of observed 50.0 concentration. The red shaded region indicates the 95% prediction interval for the median 10.0 10.0 of predicted concentrations and the blue shaded regions indicated the 5.0 5.0 95% prediction interval for the 5th and 95th percentiles of predicted concentrations. IV intravenous, SC subcutaneous 1.0 1.0 0.5 0.5 0 20 40 60 80 100 0 20 40 60 80 100 Time after dose (days) Time after dose (days) Serum belimumab concentration (µg/mL) Observations (µg/mL) Conditional weighted r esiduals Serum belimumab concentration (µg/mL) Observations (µg/mL) Conditional weighted r esiduals Population Pharmacokinetics/Pharmacodynamics of Subcutaneous Belimumab 725 C (µg/mL) C (µg/mL) C (µg/mL) max min avg IV 10 mg/kg 313 56 110 SC 200 mg 108 97 104 0 2 4 6 8 10 12 14 16 Time (weeks) Fig. 4 Comparison of pharmacokinetic (PK) profiles and steady-state represent PK profiles based on identical popPK parameters except for PK parameters for intravenous (IV) belimumab 10 mg/kg 3 9 every setting body weight and body mass index (BMI) parameters to the 5th 2 weeks (Q2W) then every 4 weeks (Q4W) vs. subcutaneous (SC) and 95th percentiles of body weight (46.6 and 105.1 kg) and BMI belimumab 200 mg once weekly (QW) based on simulations with (18.4 and 38.5 kg/m ) in Study BEL112341; and the black dashed population-PK (popPK) parameters. Red or blue solid lines represent line represents steady-state minimum (trough) concentration (C ) min deterministic simulations based on popPK parameters from IV [7] and for chronic IV dosing. C average steady-state concentration, C avg max SC (Table 3) popPK analyses; red or blue dotted/dashed lines maximum concentration Table 4 Parameter estimates of Parameter NONMEM estimates the final logistic regression model Point estimate %RSE 95% CI Intercept -0.0190 494 -0.203 to 0.165 Effect of SS on SRI 0.922 16.8 0.618–1.23 Effect of proteinuria on SRI -0.468 49.1 -0.919 to -0.0172 Effect of RACE3 on SRI -0.840 34.9 -1.41 to -0.266 Effect of RACE4 on SRI 1.10 41.7 0.200–2.00 CI confidence interval, RACE3 African American, RACE4 American Indian or Alaska Native, RSE relative standard error, SRI systemic lupus erythematosus responder index, SS SELENA-SLEDAI All the covariate effects were evaluated on subjects receiving belimumab Calculated as (standard error/parameter estimate) 9 100% value =-1.25) or with a power model (change in objec- response (removal of which resulted in a change in tive function value =-2.10). objective function value =-4.53, i.e., the effect was sig- The effects retained in the final model of the main nificant at the a = 0.05, but not at the a = 0.01 level). analysis were also significant, with qualitatively similar parameter values in the final model of the sensitivity analysis, which was restricted to belimumab-treated 4 Discussion patients. Furthermore, in the sensitivity analysis, the exposure effect was not statistically significant. The sen- Population-pharmacokinetic model parameters for SC sitivity analysis retained one additional predictor, namely belimumab in this analysis were consistent with outcomes baseline corticosteroid use increasing the likelihood of SRI from the IV belimumab popPK analysis [7] and with Serum belimumab concentrations (µg/mL) 726 H. Struemper et al. Fig. 5 Systemic lupus erythematosus responder index odds ratios in the final logistic 2.51 regression model. All covariate SELENA SLEDAI >10 effects were added as a linear function. SELENA-SLEDAI Safety of Estrogens in Lupus Erythematosus National 0.63 Assessment-Systemic Lupus Proteinuria >0.5 g/24h Erythematosus 0.43 African American 3.00 American Indian or Alaska Native 0 2 4 6 results reported for other IgG1 monoclonal antibodies contradictory as albumin and IgG bind to different sites on without substantial target-mediated disposition [16]. The FcRn and do not compete for binding with FcRn [17]. bioavailability of SC belimumab was estimated to be 74%. Therefore, albumin might be an indicator of the total Subcutaneous belimumab 200 mg QW in patients with capacity of FcRn-mediated recycling, while endogenous SLE resulted in steady-state belimumab C ; similar to the IgG levels indicate how much of that capacity can be used avg C seen for IV 10-mg/kg dosing [7]. The efficacy of SC by exogenous IgG, such as belimumab. These effects of avg belimumab [10] is at least equivalent to that observed in albumin and IgG on belimumab CL are consistent with the IV belimumab pivotal trials [4, 5], with a similar safety similar size effects identified in the earlier IV belimumab profile. These results indicate that SC belimumab 200-mg popPK analysis [7], and have also been previously QW dosing is suitable for SC administration in patients observed for other monoclonal antibodies [16]. with SLE. As expected, with BLyS (the target of belimumab) The derivation and analysis of the popPK model largely levels (median 1.31 ng/mL) being several orders of mag- reflect phase III study data, which constitute the majority of nitude lower than steady-state belimumab concentrations, the data analyzed. These data provide the primary evidence no evidence for substantial target-mediated disposition of for the safety and efficacy of belimumab in patients with belimumab was found. The serially sampled PK profiles of SLE, and consequently the model can be considered to the IV and SC phase I studies [7, 12, 14] reflect linear reasonably predict the serum drug concentrations of SC elimination kinetics and no substantial contribution of belimumab expected in clinical practice. target-mediated clearance at the observed exposure con- No effects of patient age, sex, race, disease activity, co- centrations. This was confirmed during the covariate medications, or baseline characteristics were found to alter analysis by the fact that neither BLyS levels nor other SC belimumab exposure in a manner to suggest that dose disease characteristics had a significant impact on adjustments are required for maintenance of efficacy and belimumab clearance. However, target-mediated clearance safety in adults with SLE. Higher levels of baseline albu- at very low belimumab exposures only relevant in the late min were shown to decrease belimumab CL. A high wash-out phase cannot be excluded. albumin level may be an indicator of a high degree of The logistic regression analysis demonstrated that neonatal Fc receptor (FcRn) expression, leading to a high among the candidate effects, only baseline disease char- degree of protection of IgG and albumin from lysosomal acteristics (high SLE disease activity, proteinuria) and two degradation [17] and therefore also to reduced belimumab of the race categories were significant predictors of SRI CL. By comparison, higher baseline IgG levels increased response. These predictors are consistent with the results the CL of belimumab, likely owing to increased competi- the subgroup analysis carried out as part of the statistical tion between endogenous IgG and belimumab for binding analysis for Study BEL112341 [10]; however, their clinical to saturable levels of FcRn. These two effects are not significance is not known. Population Pharmacokinetics/Pharmacodynamics of Subcutaneous Belimumab 727 with the 1964 Helsinki Declaration and its later amendments or The analysis further demonstrated that SC belimumab comparable ethical standards. exposure did not have a statistically significant impact on the SRI response or on the incidence of serious adverse Consent to Participate Informed consent was obtained from all events. This was consistent with a graphical exposure-re- individual participants included in the study. sponse analysis for key biomarkers (naı¨ve B cells, IgG, Open Access This article is distributed under the terms of the anti-double-stranded DNA antibodies, and complement) in Creative Commons Attribution-NonCommercial 4.0 International Study BEL112341, which did not reveal a dependence of License (http://creativecommons.org/licenses/by-nc/4.0/), which per- the biomarkers response at week 52 on C (data not avg mits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) shown). Moreover, these exposure response results for SC and the source, provide a link to the Creative Commons license, and belimumab results are consistent with the dose response indicate if changes were made. seen in the phase III IV belimumab studies [5, 7]. The 10-mg/kg dose groups were consistently superior across multiple efficacy endpoints compared with the 1-mg/kg dosing groups in the IV phase III studies, which led to the References choice of the 200-mg weekly SC belimumab dose as the SC dose approximating the C for IV 10-mg/kg every avg 1. Adinolfi A, Valentini E, Calabresi E, Tesei G, Signorini V, Barsotti S, et al. One year in review 2016: systemic lupus ery- 4 weeks dosing. However, the increase in efficacy for the thematosus. Clin Exp Rheumatol. 2016;34(4):569–74. 10-mg/kg IV dose was relatively moderate given the ten- 2. Cancro MP, D’Cruz DP, Khamashta MA. The role of B lym- fold difference in dose, which is consistent with the phocyte stimulator (BLyS) in systemic lupus erythematosus. interpretation that the 200-mg dose results in a range of J Clin Invest. 2009;119(5):1066–73. 3. Baker KP, Edwards BM, Main SH, Choi GH, Wager RE, Halpern exposures located in the shallow upper domain of a satu- WG, et al. Generation and characterization of LymphoStat-B, a rating exposure-efficacy response curve. Surprisingly, in human monoclonal antibody that antagonizes the bioactivities of the combined belimumab/placebo population of the B lymphocyte stimulator. Arthritis Rheumatol. BLISS-SC study, the odds ratio of SRI response was 2003;48(11):3253–65. 4. Furie R, Petri M, Zamani O, Cervera R, Wallace DJ, Tegzova D, numerically improved for patients with SLE in the heavier et al. A phase III, randomized, placebo-controlled study of beli- body weight quartiles [10]. The SC belimumab popPK/PD mumab, a monoclonal antibody that inhibits B lymphocyte analysis demonstrated that no dose adjustment is required stimulator, in patients with systemic lupus erythematosus. based on body weight or other analyzed patient Arthritis Rheum. 2011;63(12):3918–30. 5. Navarra SV, Guzman RM, Gallacher AE, Hall S, Levy RA, characteristics. Jimenez RE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, pla- cebo-controlled, phase 3 trial. Lancet. 2011;377(9767):721–31. 6. GlaxoSmithKline. Benlysta prescribing information. http://www. 5 Conclusion gsksource.com/gskprm/htdocs/documents/BENLYSTA-PI-MG. PDF. Accessed 3 Aug 2017. 7. Struemper H, Chen C, Cai W. Population pharmacokinetics of This analysis indicates that belimumab 200 mg QW is belimumab following intravenous administration in patients with appropriate for SC administration in patients with SLE and systemic lupus erythematosus. J Clin Pharmacol. 2013;53(7):711–20. that no dose adjustments are required for adult patients to 8. Furie R, Stohl W, Ginzler EM, Becker M, Mishra N, Chatham W, maintain efficacy and safety. et al. Biologic activity and safety of belimumab, a neutralizing anti-B-lymphocyte stimulator (BLyS) monoclonal antibody: a Acknowledgements Medical writing assistance was provided by phase I trial in patients with systemic lupus erythematosus. Louisa Pettinger, PhD, and Jennie McLean, PhD, of Fishawack Arthritis Res Ther. 2008;10(5):R109. Indicia Ltd, and was funded by GlaxoSmithKline. The authors wish to 9. Wallace DJ, Stohl W, Furie RA, Lisse JR, McKay JD, Merrill JT, thank the patients and trial investigators involved in this study. et al. A phase II, randomized, double-blind, placebo-controlled, dose-ranging study of belimumab in patients with active systemic Compliance with Ethical Standards lupus erythematosus. Arthritis Rheumatol. 2009;61(9):1168–78. 10. Stohl W, Schwarting A, Okada M, Scheinberg M, Doria A, Funding This study was funded by GlaxoSmithKline. Hammer AE, et al. Efficacy and safety of subcutaneous beli- mumab in systemic lupus erythematosus: a fifty-two-week ran- Conflict of Interest Herbert Struemper is a former employee of and domized, double-blind, placebo-controlled study. Arthritis owns stock in GlaxoSmithKline. David Roth is an employee of and Rheumatol. 2017;69(5):1016–27. owns stock in GlaxoSmithKline. Mita Thapar has no conflicts of 11. Sheikh SZ, Hammer AE, Fox NL, Groark J, Struemper H, Roth interest directly relevant to the contents of this study. D, et al. Evaluation of a novel autoinjector for subcutaneous self- administration of belimumab in systemic lupus erythematosus. Ethics Approval All procedures performed in studies involving Int J Clin Pharmacol Ther. 2016;54(11):914. human participants were in accordance with the ethical standards of 12. Shida Y, Takahashi N, Sakamoto T, Ino H, Endo A, Hirama T. the investigational review board or human subjects committee and The pharmacokinetics and safety profiles of belimumab after 728 H. Struemper et al. single subcutaneous and intravenous doses in healthy Japanese 15. Chilton F, Collett RA. Treatment choices, preferences and deci- volunteers. J Clin Pharm Ther. 2014;39(1):97–101. sion-making by patients with rheumatoid arthritis. Musculoskelet 13. Yapa SW, Roth D, Gordon D, Struemper H. Comparison of Care. 2008;6(1):1–14. intravenous and subcutaneous exposure supporting dose selection 16. Dirks NL, Meibohm B. Population pharmacokinetics of thera- of subcutaneous belimumab systemic lupus erythematosus phase peutic monoclonal antibodies. Clin Pharmacokinet. 3 program. Lupus. 2016;25(13):1448–55. 2010;49(10):633–59. 14. Cai WW, Fiscella M, Chen C, Zhong ZJ, Freimuth WW, Subich 17. Chaudhury C, Mehnaz S, Robinson JM, Hayton WL, Pearl DK, DC. Bioavailability, pharmacokinetics, and safety of belimumab Roopenian DC, et al. The major histocompatibility complex-re- administered subcutaneously in healthy subjects. Clin Pharmacol lated Fc receptor for IgG (FcRn) binds albumin and prolongs its Drug Dev. 2013;2(4):349–57. lifespan. J Exp Med. 2003;197(3):315–22. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Pharmacokinetics Springer Journals

Population Pharmacokinetic and Pharmacodynamic Analysis of Belimumab Administered Subcutaneously in Healthy Volunteers and Patients with Systemic Lupus Erythematosus

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Abstract

Clin Pharmacokinet (2018) 57:717–728 https://doi.org/10.1007/s40262-017-0586-5 ORIGINAL RESEARCH ARTICLE Population Pharmacokinetic and Pharmacodynamic Analysis of Belimumab Administered Subcutaneously in Healthy Volunteers and Patients with Systemic Lupus Erythematosus 1 2 3 • • Herbert Struemper Mita Thapar David Roth Published online: 8 September 2017 The Author(s) 2017. This article is an open access publication Abstract Methods Non-linear mixed-effects modeling (NON- Background Intravenous belimumab 10 mg/kg every MEM) was used to develop a population pharmacoki- 4 weeks is indicated in patients with active, autoantibody- netic model and perform a covariate analysis. positive systemic lupus erythematosus receiving standard Subsequently, exploratory exposure-response analysis and systemic lupus erythematosus care. Subcutaneous 200-mg logistic regression modeling was performed based on the weekly administration, which may prove more convenient individual parameter estimates of the population pharma- for patients and improve adherence, is currently under cokinetic model. investigation. Results Population-pharmacokinetic parameters for sub- Objective The objective of this study was to characterize cutaneous belimumab were consistent with those for the population pharmacokinetics and exposure-efficacy intravenous belimumab and other immunoglobulin G1 response of subcutaneous belimumab in a pooled analysis monoclonal antibodies. Pharmacokinetic parameters and of pharmacokinetic data [phase I: BEL114448 subcutaneous belimumab exposure were consistent (NCT01583530) and BEL116119 (NCT01516450) in between healthy subjects and patients with systemic lupus healthy subjects (n = 134); phase III: BEL112341 erythematosus, and no evidence for target-mediated dis- (NCT01484496) in adults with systemic lupus erythe- position of belimumab was found. Subcutaneous matosus (n = 554)] and pharmacodynamic data belimumab steady-state exposure was achieved after [BEL112341 in adults with systemic lupus erythematosus *11 weeks; subcutaneous belimumab steady-state mini- (n = 833)]. mum concentration exceeded that of intravenous belimumab after \4 weeks, and average steady-state con- centration was similar to that achieved following intra- venous administration. In patients with moderate-to-severe systemic lupus erythematosus, subcutaneous belimumab 200 mg once weekly plus standard of care significantly improved the systemic lupus erythematosus responder index. However, at this dose, the systemic lupus erythe- Electronic supplementary material The online version of this matosus responder index response was not significantly article (doi:10.1007/s40262-017-0586-5) contains supplementary material, which is available to authorized users. associated with belimumab exposure concentrations. Conclusion The analysis demonstrates that a 200-mg once- & Herbert Struemper weekly dose of belimumab is appropriate for subcutaneous herbert.x.struemper@gsk.com administration in patients with systemic lupus erythe- Quantitative Clinical Development, PAREXEL International matosus and that no dose adjustments are required for adult on behalf of GlaxoSmithKline, 2520 Meridian Parkway, patients to maintain efficacy and safety. Suite 200, Durham, NC 27713, USA ICON, Marlow, Buckinghamshire, UK GlaxoSmithKline, Collegeville, PA, USA 718 H. Struemper et al. patient convenience and independence, and reduce the overall healthcare burden of belimumab treatment [10–14]. Key Points The ability to administer treatments away from the clinic can largely eliminate substantial time and financial costs Population-pharmacokinetic parameters for associated with travel to/from the drug-administering site, subcutaneous belimumab were consistent with those for the infusion itself, and for post-infusion monitoring. In for intravenous belimumab and other a study of patients with rheumatoid arthritis, more patients immunoglobulin G1 monoclonal antibodies. chose SC treatment than IV treatment, with the reduced In patients with moderate-to-severe systemic lupus need to travel to receive an infusion being an influential erythematosus, subcutaneous belimumab (200 mg, factor [15]. A popPK model comparing IV with SC weekly) plus standard systemic lupus erythematosus belimumab has previously been developed using pooled care significantly improved the systemic lupus data from two phase I studies (BEL114448 erythematosus responder index. However, at this [NCT01583530] and BEL116119 [NCT01516450]) in dose, the systemic lupus erythematosus responder healthy subjects [12–14]. This present analysis character- index response was not significantly associated with izes the popPK and exposure-efficacy response of belimumab exposure concentrations. belimumab following SC administration in a pooled anal- No dose adjustments are required for subcutaneous ysis of PK data from these aforementioned phase I studies in belimumab in adult patients with systemic lupus healthy subjects [12, 14], combined with PK and pharma- erythematosus to maintain efficacy and safety. codynamics (PD) data from a large phase III study in adult patients with SLE [BEL112341 (NCT01484496)] [10]. 2 Methods 1 Introduction 2.1 Objectives Systemic lupus erythematosus (SLE) is a chronic multi- The objectives of the popPK analysis were to develop a system autoimmune disease presenting a broad spectrum of model that characterizes the PK disposition of SC clinical manifestations [1]. B-lymphocyte stimulator belimumab following 200-mg weekly (QW) administration (BLyS) is a member of the tumor necrosis factor family, in healthy subjects and patients with SLE, to evaluate the and plays an integral role in the selection and survival of B potential effect of selected covariates on key PK parame- cells [2]. Although the definitive role of BLyS in SLE has ters, and to estimate individual subject PK parameters such not yet been fully elucidated, B cells and BLyS have been as steady-state area under the curve, average steady-state identified as playing critical roles in SLE pathogenesis [2]. concentration (C ), steady-state maximum concentration, avg Belimumab is a recombinant, human, immunoglobulin steady-state minimum concentration (C ), elimination min G1 (IgG1) monoclonal antibody that targets BLyS, half-life for the first phase, elimination half-life for the inhibiting B-cell survival and differentiation without terminal phase, and steady-state volume of distribution. In directly causing B-cell death [2, 3]. Two phase III, ran- addition, an exploratory exposure-response analysis was domized, double-blind, placebo-controlled studies [BLISS- proposed, plotting exposure (C ) vs. the selected avg 52 (NCT00424476) and BLISS-76 (NCT00410384)] have PD/efficacy/safety endpoints at week 52, alongside a demonstrated that intravenous (IV) belimumab plus stan- popPK/PD analysis on a selected PD/efficacy/safety end- dard SLE care is associated with a significant reduction in point(s) of special interest (phase III study only). disease activity in active autoantibody-positive SLE [4, 5]. The IV formulation of belimumab is indicated for the 2.2 Study Design treatment of active autoantibody-positive SLE in patients receiving standard SLE care, at a dose of 10 mg/kg at In this popPK/PD analysis, PK data from 688 individuals 2-week intervals for the first three doses and every 4 weeks from three studies [phase I: BEL116119 and BEL114448 thereafter [6]. A population-pharmacokinetic (popPK) (n = 134); phase III: BEL112341 [10] (NCT01484496; model for IV belimumab was developed [7] using pooled n = 554)] and PD data from BEL112341, for which the data from phase I and II studies [8, 9] and the two pivotal methods and results have been described previously phase III studies, BLISS-52 and BLISS-76 [4, 5]. [10, 12, 14], were analyzed using a popPK/PD approach A subcutaneous (SC) formulation of belimumab is cur- (Table 1). The primary efficacy endpoint for Study rently under investigation, the use of which may improve BEL112341 was the SLE responder index 4 (SRI4), a Population Pharmacokinetics/Pharmacodynamics of Subcutaneous Belimumab 719 Table 1 Studies included in the belimumab population pharmacokinetic/pharmacodynamic (PK/PD) analysis Study Population Dose and administration Planned PK data PD/efficacy/safety endpoints Phase I n = 16 Two single-dose groups Not available (BEL116119 Healthy IV group: 200-mg single- IV group: pre-dose (day 0), 5 min, 1 h, 6 h, days 1, [12]) volunteers dose IV infusion over 1 h 2, 4, 7, 14, 21, 28, 42, 56, and 70 post-dose (Japan) (n = 8) SC group: 200-mg SC SC group: pre-dose (day 0), 6 h, days 1, 2, 3, 4, 5, 6, single dose 7, 10, 14, 21, 28, 42, 56, and 70 post-dose over 10–15 s (n = 8) Phase I n = 118 Four single-dose groups Not available (BEL114448) Healthy Group 1: SC, 2 sequential Groups 1, 2, 3 (SC dosing): pre-dose (day 0), 6 h, volunteers injections (0.6 mL/ days 1, 2, 3, 4, 5, 6, 7, 10, 14, 21, 28, 42, 56, and (USA) injection; 200 mg/mL) 70 post-dose Group 2: SC, 1 injection (1.2 mL/injection; 200 mg/mL) Group 3: SC, 1 injection (1.2 mL/injection; 200 mg/mL) Group 4: IV control Group 4 (IV dosing): pre-dose (day 0), 5 min, 1 h, (240 mg lyophilized 3 h, 6 h, days 1, 2, 4, 7, 14, 21, 28, 42, 56, and 70 formulation) post-dose Two groups with 4-weekly SC doses Group 5: weekly 9 4; SC, Groups 5 and 6: pre-dose (day 0), 6 h, days 1, 2, 3, 2 sequential injections 4, 5, 6, 7 (prior to second dosing), 14 (prior to (0.6 mL/injection; third dosing), 21 (prior to fourth dosing), 6 h post- 200 mg/mL) fourth dose, days 22, 23, 24, 25, 26, 27, 28, 31, 35, 42, 49, 63, 77, 91, and 119 post-dose Group 6: weekly 9 4; SC, 1 injection (1.2 mL/ injection; 200 mg/mL) Phase III n = 833 (554 on SC 200 mg, weekly for Pre-dose (day 0), weeks 4, 8, 16, 24, and 52, SRI response (BEL112341) belimumab; 51 weeks 1–4 weeks after the last dose (for patients exiting Change in SELENA- 279 on before week 52), 8 weeks after the last dose (for SLEDAI score placebo) patients not entering the extension phase or Change in naı¨ve withdrawing from the study at any time) Patients with peripheral B-cell SLE (global) subset (CD20?/ CD27-) Change in complement (C3, C4) level Change in anti- dsDNA antibody level Change in total serum IgG level Frequency of SAEs Frequency of serious/severe infections CD cluster of differentiation, dsDNA double-stranded DNA, IgG immunoglobulin G, IV intravenous, SAEs serious adverse events, SC subcu- taneous, SELENA-SLEDAI Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus, SLE systemic lupus erythematosus, SRI systemic lupus erythematosus responder index 720 H. Struemper et al. composite index that includes a C4-point reduction in parametric bootstrap analysis (500 datasets, random the Safety of Estrogens in Lupus Erythematosus sampling with replacement with subjects as the sampling National Assessment-SLE Disease Activity Index unit). Following popPK model development, PK profiles (SELENA-SLEDAI) [10]. were simulated using population parameters from this All subjects with evaluable dosing, actual sampling analysis for the SC curves (Table 3) and from the IV time, and belimumab concentration data were included in popPK model [7] for the IV curves. Steady-state param- the popPK dataset and analysis. All subjects and placebo eters were derived from profiles following 24 weeks of subjects with evaluable PD efficacy/safety data were dosing. included in the popPK/PD dataset and analysis. 2.3.3 Population Pharmacokinetic/Pharmacodynamic 2.2.1 Assay Methods Model Development Serum concentrations of belimumab were determined by a Following a graphical exposure-response analysis for validated electrochemiluminescence-based immunoassay selected PD/efficacy/safety endpoints, a logistic regression with a lower limit of quantitation of 100 ng/mL of model was developed to characterize SRI4 response in belimumab in human serum. relation to C (generally considered relevant for both avg efficacy and safety dose response) and other subject char- acteristics as potential predictors of efficacy. The proba- 2.3 Modeling bility of being a SRI responder was obtained by the equation: 2.3.1 Software and Estimation Methods P ¼ expðLPÞ=ð1 þ expðLPÞÞ: When the observed response is 0, the variable to be fitted Models were developed with a non-linear mixed-effects is Y = 1 - P and when the observation is 1, Y = P. modeling approach using NONMEM Version VII level The main logistic regression analysis was applied to the 3.0 (ICON Development Solutions, Ellicott City, MD, combined placebo and belimumab-treated SRI data set. USA) and PDx-Pop (Version 5.1). Population pharma- Consistent with covariate model development of the cokinetic parameters were estimated using the first-order popPK model, this model was developed using a hybrid conditional estimation method with interaction; popPK/PD full model/backward elimination approach to identify sig- (logistic regression) parameters were estimated using the nificant predictors (a = 0.05). The full covariate model Laplace estimation method. included the effects of 18 predictors including demo- graphic variables, baseline disease characteristics, presence of co-medications, and belimumab exposure (difference of 2.3.2 Population Pharmacokinetic Model Development C to median C in the belimumab-treated population). avg avg To characterize the SRI response in belimumab-treated A linear two-compartment model (ADVAN3, TRANS4 patients, these covariate effects were only applied to subroutine) was chosen as the structural PK model, based belimumab-treated patients; the response for placebo on the previously characterized IV popPK model [7], and patients being represented by the intercept parameter. The two-compartment behavior was confirmed via exploratory final model was derived by stepwise backwards elimination data analysis of the serially sampled IV/SC PK data. First- of effects not meeting the significance criterion for the log- order absorption into the central compartment with rate likelihood ratio test. constant and a lag time was added to model the SC data. In a sensitivity analysis to explore any impact of Inter-individual variability was tested and included with placebo data on the effects retained in the final model of lognormal random-effect distributions. A hybrid full the main analysis, an alternate analysis was conducted by model/backward elimination approach was used to develop restricting the exposure-response data to belimumab- the covariate model. The full model was determined by a treated patients only, i.e., removing data for placebo selection of 26 covariate effects guided by the covariate patients. The final model of the sensitivity analysis was analysis for the IV popPK analysis. The full model was derived by constructing a full model with the same reduced to the final model by step-wise removal (backward covariate effects (except for the treatment effect) as in elimination) of effects not meeting the statistical signifi- the main analysis and applying the same stepwise cance criterion (a = 0.001, as for IV popPK analysis). backwards elimination procedure to arrive at an alternate The model was qualified with diagnostic plots, visual final model. predictive checks (500 data sets), and with a non- Population Pharmacokinetics/Pharmacodynamics of Subcutaneous Belimumab 721 Table 2 Subject demographics and baseline characteristics (popula- concentrations from six subjects were excluded from the tion-pharmacokinetic analyses: N = 688) analysis. Study-specific median values were imputed for missing continuous covariate values in the dataset. Demographics Sex: female, n (%) 584 (85) 3.1.2 Population Pharmacokinetic Modeling Race, n (%) White 422 (61) The pharmacokinetics of SC belimumab was best descri- Asian 137 (23.5) bed by a linear two-compartment base model with an African American 76 (11) absorption lag time followed by first-order absorption into American Indian or Alaska Native 41 (6) the central compartment and elimination from the central Other 12 (1.7) compartment. No evidence for substantial target-mediated Mean (SD) age, years 37.6 (11.8) disposition of belimumab was found. The random-effects Median (range) 37 (18–77) structure of the model included inter-individual variability Mean (SD) weight, kg 70.0 (17.6) on central clearance (CL), inter-compartmental clearance Median (range) 67.0 (34.1–138) (Q), central (V ) and peripheral (V ) volumes of distribu- c p Mean (SD) BMI, kg/m 26.1 (6.18) tion, as well as a combined proportional and additional Median (range) 24.7 (14.8–72.7) residual error model. Significant covariate effects (a = 0.001) retained in the Characteristics Mean (SD) Median (range) final model after backward elimination included body mass IgG, g/L 14.9 (5.43) 13.7 (4.70–53.5) index (BMI) on V (power coefficient of -0.6110) and Proteinuria, mg/mg 0.340 (0.651) 0.118 (0.0210–6.23) body weight on CL and V (power coefficients of 0.75 and Albumin levels, g/L 40.7 (4.47) 41.0 (18.0–55.0) 1.00, respectively), and albumin (Fig. 1a) and IgG Creatinine clearance, mL/min 115 (38.3) 109 (35.0–353) (Fig. 1b) on CL. In general, belimumab CL increased with Hemoglobin, g/L 126 (15.8) 126 (73.0–173) increasing levels of baseline IgG (power coefficient of WBC count, Gi/L 6.09 (2.41) 5.70 (1.30–13.9) 0.347). An inverse relationship was seen between baseline albumin levels and belimumab CL, whereby CL decreased BMI body mass index, IgG immunoglobulin G, SD standard devia- with albumin (power coefficient of -0.736). The only tion, WBC white blood cell pharmacokinetically relevant covariates (defined as a Study BEL112341 determined proteinuria by measuring the spot urine protein:creatinine ratio (mg/mg). In the BEL112341 clinical change relative to the population median beyond the -20 study report and other submission documents, these values are to ?25% range in CL or V for the 5th to 95th percentile reported as g/24-h equivalent proteinuria values. In Study range of the patient covariate distribution) were BMI and BEL112341, 99 subjects (18% of subjects in Study BEL112341) had body weight. The predicted effects of age, sex, race, dis- proteinuria [0.5 g/24 h and 19 subjects (3% of subjects in Study ease activity, concomitantly administered medications BEL112341) had proteinuria C2 g/24 h (corticosteroids, angiotensin-converting enzyme inhibitors, azathioprine, methotrexate, mycophenolate mofetil, anti- malarial medications, statins, non-steroidal anti-inflamma- 3 Results tory drugs, and aspirin), baseline characteristics, or other tested factors were neither statistically significant nor 3.1 Population-Pharmacokinetic Model pharmacokinetically relevant (the exposure-response anal- ysis demonstrated that the SRI response was at the 200-mg 3.1.1 Subject Disposition QW dose level, which is not significantly correlated with exposure variability). Pharmacokinetic parameters and SC A total of 4958 belimumab concentrations (on average, belimumab exposure were consistent between healthy seven per subject) from 688 healthy volunteers and patients subjects and patients with SLE. with SLE were included in the popPK analysis (Table 2). The parameters of the final SC belimumab popPK model Of these 4958 concentrations, 2298 were contributed by were estimated with good precision (relative standard error 134 subjects who were serially sampled [17 concentrations % 0.3–28%) and agreement between model and bootstrap per subject on average, from healthy volunteers in two parameters (Table 3). Goodness-of-fit plots for the final phase I studies (BEL116119 [12] and BEL114448 [14])] model indicate that the model provided an appropriate and 2660 concentrations were contributed by 554 patients description of the data (Fig. 2). Visual predictive checks who were sparsely sampled [five concentrations per patient indicated that the final model represented both central on average, from patients with SLE in one phase III study tendency and variability of belimumab pharmacokinetics (BLISS SC BEL112341 [10])]. Quantifiable pre-first dose well for both routes of administration (Fig. 3) and for each 722 H. Struemper et al. A B 800 800 600 600 400 400 200 200 20 30 40 50 60 10 20 30 40 50 60 Baseline albumin (g/L) Baseline IgG (g/L) Fig. 1 Covariate effect of baseline albumin (a) and immunoglobulin indicates the predicted relationship; the light gray rectangle indicates G [IgG] (b) on clearance. Margin box plots: black bar median; box the 5th to 95th percentiles; and the dark gray rectangle indicates the interquartile range; circles outliers. The red line indicates the locally interquartile range weighted scatterplot smoothing fit of observed data; the black line of the three studies [Fig. 2 of the Electronic Supplementary and fixed SC dosing, two additional PK profiles for a low- Material (ESM)], the latter indicating that the model weight and heavy subject were simulated by setting both appropriately represents both healthy subjects and patients body weight and BMI to the 5th and 95th percentiles, with SLE. respectively, in Study BEL112341 (Fig. 4, dotted and Based on the popPK parameters, belimumab is absorbed dashed lines, respectively, other covariates were kept at following SC administration with a lag time of 0.18 days, median values). As expected, increased body size resulted absorption half-life of 3 days, and bioavailability of 74%. in a smaller exposure for SC belimumab and a larger Key structural popPK parameters included total systemic exposure for IV belimumab (and vice versa), while the CL of 204 mL/day; V and volume of distribution of the range of deviation from the prototypical popPK profile was peripheral compartment (2300 and 2650 mL, respectively); comparable for both routes of administration. Figure 3 of and inter-compartmental CL of 698 mL/day (Table 3). A the ESM illustrates this relationship by comparing indi- terminal half-life of 18 days, distribution half-life of vidual C estimates for this and the IV popPK analysis avg 1.1 days, and steady-state volume of distribution of [7]: geometric means and ranges of C are well matched avg 4950 mL were derived from the structural parameters. between SC 200-mg QW dosing and IV 10-mg/kg every To compare chronic exposures resulting from the IV 4 weeks dosing with reversed trends in relation to body dosing regimen approved for SLE with the SC phase III weight. dosing regimen, PK profiles based on the popPK parame- ters of the IV [7] and SC models were simulated (Fig. 4, 3.2 Exposure-Response Analysis solid line). First-dose and steady-state time to maximum concentration for SC belimumab were shown to be 5.5 and 3.2.1 Patient Disposition 2.6 days, respectively. Steady-state exposure for SC belimumab was reached after approximately 11 weeks of A total of 833 patients (554 on belimumab and 279 on 200-mg QW dosing (at C11 weeks C exceeds 95% of placebo; all from Study BEL112341) had SRI response min steady state C ). Steady-state area under the curve from values that were included in the popPK/PD analysis. In the min pre-dose to the end of the dosing interval for SC belimumab arm, 340/554 (61%) patients were responders belimumab 200-mg QW dosing was 726 day 9 lg/mL, and 214/554 (39%) were non-responders; in the placebo and steady-state maximum concentration, C , and C arm, 135/279 (48%) patients were responders and 144/279 min avg were 108, 97, and 104 lg/mL, respectively (Fig. 4). Sub- (52%) were non-responders. cutaneous belimumab C exceeded that of IV belimumab min steady-state C after \4 weeks, and C of SC 3.2.2 Graphical Exposure-Response Analysis min avg belimumab was similar to that achieved following IV administration (Fig. 4). Selected efficacy (SRI, change from baseline in SELENA- To illustrate how the impact of body weight and BMI on SLEDAI at week 52), safety (presence of serious adverse chronic exposure differs between weight-proportional IV events, presence of serious infections), and PD data CL (mL/day) Population Pharmacokinetics/Pharmacodynamics of Subcutaneous Belimumab 723 Table 3 Parameter estimates of the final population-pharmacokinetic model Parameter Implementation Point estimate (%RSE , 95% CI) Bootstrap estimates, median (%RSE, 95% CI) Fixed effects F [fraction] THETA (6) 0.742 (6.75, 0.644–0.840) 0.742 (5.1, 0.673–0.824) ALAG [day] THETA (7) 0.179 (1.99, 0.172–0.186) 0.179 (3.2, 0.168–0.189) Kabs [1/day] THETA (5) 0.235 (5.74, 0.209–0.261) 0.232 (9, 0.198–0.282) CL [mL/day] THETA (1) 204 (6.76, 177–231) 204 (5.0, 186–226) 0.75 Effect of BWT [kg] 9 (BWT/67)–– Effect of BALB [g/L] 9 (BALB/41) -0.736 (14.1, -0.940 to -0.532) -0.737 (14.6, -0.953 to -0.533) Effect of BIGG [g/L] 9 (BIGG/13.7) 0.347 (10.4, 0.276–0.418) 0.352 (11.7, 0.272–0.436) V [mL] THETA (2) 2300 (9.83, 1860–2740) 2290 (8.9, 1890–2705) Effect of BWT 9 (BWT/67) – – 2 h Effect of BBMI [kg/m ] 9 (BBMI/24.7) -0.610 (28.2, -0.947 to -0.273) -0.608 (36.7, –0.997 to -0.16) Q [mL/day] THETA (3) 698 (13.3, 517–879) 683 (22.1, 494–1115) 0.75 Effect of BWT 9 (BWT/67)–– V [mL] 0.8 THETA (4) 2650 (7.09, 2280–3020) 2650 (6.8, 2360–3045) Effect of BWT 9 (BWT/67) – – Inter-individual variability x OMEGA (1,1) 0.0910 (6.11, 0.0801–0.102) 0.0901 (8.1, 0.077–0.105) CL x OMEGA (2,2) 0.497 (9.94, 0.400–0.594) 0.488 (16.9, 0.316–0.650) V1 x OMEGA (2,1) 0.0630 (19.7, 0.0387–0.0873) 0.0632 (749.5, 0.013–0.103) CL/V1 x OMEGA (3,3) 1.07 (21.1, 0.627–1.51) 1.03 (46.4, 0.206–1.892) x OMEGA (4,4) 0.110 (16.5, 0.0743–0.146) 0.111 (19.9, 0.076–0.166) V2 Residual variability r SIGMA (1) 0.0327 (2.63, 0.0310–0.0344) 0.0328 (6.6, 0.029–0.0375) proportional r SIGMA (2) 0.134 (23.7, 0.0717–0.196) 0.138 (39.1, 0.056–0.291) additive ALAG absorption lag time, BALB baseline albumin level, BBMI baseline body mass index, BIGG baseline immunoglobulin G level, BWT baseline body weight, CI confidence interval, CL systemic clearance, F bioavailability for SC dosing, Kabs absorption rate constant, Q inter- compartmental clearance, RSE relative standard error, SC subcutaneous, THETA or h corresponding structural model parameter, Vc central volume of distribution, V peripheral volume of distribution Calculated as (standard error/mean) 9 100% (change from baseline of naı¨ve peripheral B cells, com- applied to belimumab-treated patients: sex, age, race cat- plement C3, complement C4, anti-double-stranded DNA egories, body weight quartiles, SELENA-SLEDAI score, antibody level, and IgG at week 52) were graphically anti-double-stranded DNA antibody presence, low com- examined for a relationship with SC belimumab exposure plement, proteinuria, belimumab treatment, difference to (C ). For the safety endpoints, the C interquartile median belimumab steady-state C , corticosteroid treat- avg avg avg ranges of subjects with serious adverse events or infections ment, antimalarial treatment, and immunosuppressant contained the interquartile ranges of subjects without such treatment. events (Fig. 1 of the ESM). Similarly, none of the other After reducing the full model to statistically significant endpoints showed a strong consistent correlation with SC predictors (a = 0.05), only the following effects remained belimumab exposure (data not shown). in the final model (Table 4). A baseline SELENA-SLEDAI score C10 or American Indian/Alaska Native ethnicity was 3.2.3 Systemic Lupus Erythematosus Responder Index found to increase the probability of being an SRI responder Logistic Regression Modeling for patients treated with belimumab; baseline proteinuria [0.5 g/24 h or African American ethnicity decreased the To identify any predictors of efficacy and to further explore probability of being an SRI responder for these patients (the lack of) exposure effects on efficacy, a logistic (Fig. 5). For patients with SLE receiving belimumab regression analysis of the SRI, the primary efficacy end- 200 mg QW, exposure variations were not a significant point, was conducted. The starting point was a logistic predictor of SRI response, whether the exposure effect was regression model with the following candidate predictors implemented linearly (change in objective function 724 H. Struemper et al. Fig. 2 Goodness-of-fit plots for the final population- pharmacokinetic model. Blue 100 100 circles indicate the observed/ predicted belimumab concentrations; black lines 10 10 indicate the identity or zero lines; and red lines indicated the locally weighted scatterplot smoothing line 1 1 0.1 0.1 1 10 100 1 10 100 Population pr edictions (µg/mL) Individual predictions (µg/mL) 4 4 2 2 0 0 -2 -2 -4 -4 1 10 100 0 100 200 300 400 Population pr edictions (µg/mL) Time after first dose (days ) Fig. 3 Visual predictive check for IV SC final population-pharmacokinetic 500.0 model stratified by route of administration. Open circle observed concentrations; solid line 100.0 median of observed concentrations; dashed lines 5th 50.0 and 95th percentile of observed 50.0 concentration. The red shaded region indicates the 95% prediction interval for the median 10.0 10.0 of predicted concentrations and the blue shaded regions indicated the 5.0 5.0 95% prediction interval for the 5th and 95th percentiles of predicted concentrations. IV intravenous, SC subcutaneous 1.0 1.0 0.5 0.5 0 20 40 60 80 100 0 20 40 60 80 100 Time after dose (days) Time after dose (days) Serum belimumab concentration (µg/mL) Observations (µg/mL) Conditional weighted r esiduals Serum belimumab concentration (µg/mL) Observations (µg/mL) Conditional weighted r esiduals Population Pharmacokinetics/Pharmacodynamics of Subcutaneous Belimumab 725 C (µg/mL) C (µg/mL) C (µg/mL) max min avg IV 10 mg/kg 313 56 110 SC 200 mg 108 97 104 0 2 4 6 8 10 12 14 16 Time (weeks) Fig. 4 Comparison of pharmacokinetic (PK) profiles and steady-state represent PK profiles based on identical popPK parameters except for PK parameters for intravenous (IV) belimumab 10 mg/kg 3 9 every setting body weight and body mass index (BMI) parameters to the 5th 2 weeks (Q2W) then every 4 weeks (Q4W) vs. subcutaneous (SC) and 95th percentiles of body weight (46.6 and 105.1 kg) and BMI belimumab 200 mg once weekly (QW) based on simulations with (18.4 and 38.5 kg/m ) in Study BEL112341; and the black dashed population-PK (popPK) parameters. Red or blue solid lines represent line represents steady-state minimum (trough) concentration (C ) min deterministic simulations based on popPK parameters from IV [7] and for chronic IV dosing. C average steady-state concentration, C avg max SC (Table 3) popPK analyses; red or blue dotted/dashed lines maximum concentration Table 4 Parameter estimates of Parameter NONMEM estimates the final logistic regression model Point estimate %RSE 95% CI Intercept -0.0190 494 -0.203 to 0.165 Effect of SS on SRI 0.922 16.8 0.618–1.23 Effect of proteinuria on SRI -0.468 49.1 -0.919 to -0.0172 Effect of RACE3 on SRI -0.840 34.9 -1.41 to -0.266 Effect of RACE4 on SRI 1.10 41.7 0.200–2.00 CI confidence interval, RACE3 African American, RACE4 American Indian or Alaska Native, RSE relative standard error, SRI systemic lupus erythematosus responder index, SS SELENA-SLEDAI All the covariate effects were evaluated on subjects receiving belimumab Calculated as (standard error/parameter estimate) 9 100% value =-1.25) or with a power model (change in objec- response (removal of which resulted in a change in tive function value =-2.10). objective function value =-4.53, i.e., the effect was sig- The effects retained in the final model of the main nificant at the a = 0.05, but not at the a = 0.01 level). analysis were also significant, with qualitatively similar parameter values in the final model of the sensitivity analysis, which was restricted to belimumab-treated 4 Discussion patients. Furthermore, in the sensitivity analysis, the exposure effect was not statistically significant. The sen- Population-pharmacokinetic model parameters for SC sitivity analysis retained one additional predictor, namely belimumab in this analysis were consistent with outcomes baseline corticosteroid use increasing the likelihood of SRI from the IV belimumab popPK analysis [7] and with Serum belimumab concentrations (µg/mL) 726 H. Struemper et al. Fig. 5 Systemic lupus erythematosus responder index odds ratios in the final logistic 2.51 regression model. All covariate SELENA SLEDAI >10 effects were added as a linear function. SELENA-SLEDAI Safety of Estrogens in Lupus Erythematosus National 0.63 Assessment-Systemic Lupus Proteinuria >0.5 g/24h Erythematosus 0.43 African American 3.00 American Indian or Alaska Native 0 2 4 6 results reported for other IgG1 monoclonal antibodies contradictory as albumin and IgG bind to different sites on without substantial target-mediated disposition [16]. The FcRn and do not compete for binding with FcRn [17]. bioavailability of SC belimumab was estimated to be 74%. Therefore, albumin might be an indicator of the total Subcutaneous belimumab 200 mg QW in patients with capacity of FcRn-mediated recycling, while endogenous SLE resulted in steady-state belimumab C ; similar to the IgG levels indicate how much of that capacity can be used avg C seen for IV 10-mg/kg dosing [7]. The efficacy of SC by exogenous IgG, such as belimumab. These effects of avg belimumab [10] is at least equivalent to that observed in albumin and IgG on belimumab CL are consistent with the IV belimumab pivotal trials [4, 5], with a similar safety similar size effects identified in the earlier IV belimumab profile. These results indicate that SC belimumab 200-mg popPK analysis [7], and have also been previously QW dosing is suitable for SC administration in patients observed for other monoclonal antibodies [16]. with SLE. As expected, with BLyS (the target of belimumab) The derivation and analysis of the popPK model largely levels (median 1.31 ng/mL) being several orders of mag- reflect phase III study data, which constitute the majority of nitude lower than steady-state belimumab concentrations, the data analyzed. These data provide the primary evidence no evidence for substantial target-mediated disposition of for the safety and efficacy of belimumab in patients with belimumab was found. The serially sampled PK profiles of SLE, and consequently the model can be considered to the IV and SC phase I studies [7, 12, 14] reflect linear reasonably predict the serum drug concentrations of SC elimination kinetics and no substantial contribution of belimumab expected in clinical practice. target-mediated clearance at the observed exposure con- No effects of patient age, sex, race, disease activity, co- centrations. This was confirmed during the covariate medications, or baseline characteristics were found to alter analysis by the fact that neither BLyS levels nor other SC belimumab exposure in a manner to suggest that dose disease characteristics had a significant impact on adjustments are required for maintenance of efficacy and belimumab clearance. However, target-mediated clearance safety in adults with SLE. Higher levels of baseline albu- at very low belimumab exposures only relevant in the late min were shown to decrease belimumab CL. A high wash-out phase cannot be excluded. albumin level may be an indicator of a high degree of The logistic regression analysis demonstrated that neonatal Fc receptor (FcRn) expression, leading to a high among the candidate effects, only baseline disease char- degree of protection of IgG and albumin from lysosomal acteristics (high SLE disease activity, proteinuria) and two degradation [17] and therefore also to reduced belimumab of the race categories were significant predictors of SRI CL. By comparison, higher baseline IgG levels increased response. These predictors are consistent with the results the CL of belimumab, likely owing to increased competi- the subgroup analysis carried out as part of the statistical tion between endogenous IgG and belimumab for binding analysis for Study BEL112341 [10]; however, their clinical to saturable levels of FcRn. These two effects are not significance is not known. Population Pharmacokinetics/Pharmacodynamics of Subcutaneous Belimumab 727 with the 1964 Helsinki Declaration and its later amendments or The analysis further demonstrated that SC belimumab comparable ethical standards. exposure did not have a statistically significant impact on the SRI response or on the incidence of serious adverse Consent to Participate Informed consent was obtained from all events. This was consistent with a graphical exposure-re- individual participants included in the study. sponse analysis for key biomarkers (naı¨ve B cells, IgG, Open Access This article is distributed under the terms of the anti-double-stranded DNA antibodies, and complement) in Creative Commons Attribution-NonCommercial 4.0 International Study BEL112341, which did not reveal a dependence of License (http://creativecommons.org/licenses/by-nc/4.0/), which per- the biomarkers response at week 52 on C (data not avg mits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) shown). Moreover, these exposure response results for SC and the source, provide a link to the Creative Commons license, and belimumab results are consistent with the dose response indicate if changes were made. seen in the phase III IV belimumab studies [5, 7]. The 10-mg/kg dose groups were consistently superior across multiple efficacy endpoints compared with the 1-mg/kg dosing groups in the IV phase III studies, which led to the References choice of the 200-mg weekly SC belimumab dose as the SC dose approximating the C for IV 10-mg/kg every avg 1. Adinolfi A, Valentini E, Calabresi E, Tesei G, Signorini V, Barsotti S, et al. One year in review 2016: systemic lupus ery- 4 weeks dosing. However, the increase in efficacy for the thematosus. Clin Exp Rheumatol. 2016;34(4):569–74. 10-mg/kg IV dose was relatively moderate given the ten- 2. Cancro MP, D’Cruz DP, Khamashta MA. The role of B lym- fold difference in dose, which is consistent with the phocyte stimulator (BLyS) in systemic lupus erythematosus. interpretation that the 200-mg dose results in a range of J Clin Invest. 2009;119(5):1066–73. 3. Baker KP, Edwards BM, Main SH, Choi GH, Wager RE, Halpern exposures located in the shallow upper domain of a satu- WG, et al. Generation and characterization of LymphoStat-B, a rating exposure-efficacy response curve. Surprisingly, in human monoclonal antibody that antagonizes the bioactivities of the combined belimumab/placebo population of the B lymphocyte stimulator. Arthritis Rheumatol. BLISS-SC study, the odds ratio of SRI response was 2003;48(11):3253–65. 4. Furie R, Petri M, Zamani O, Cervera R, Wallace DJ, Tegzova D, numerically improved for patients with SLE in the heavier et al. A phase III, randomized, placebo-controlled study of beli- body weight quartiles [10]. The SC belimumab popPK/PD mumab, a monoclonal antibody that inhibits B lymphocyte analysis demonstrated that no dose adjustment is required stimulator, in patients with systemic lupus erythematosus. based on body weight or other analyzed patient Arthritis Rheum. 2011;63(12):3918–30. 5. Navarra SV, Guzman RM, Gallacher AE, Hall S, Levy RA, characteristics. Jimenez RE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, pla- cebo-controlled, phase 3 trial. Lancet. 2011;377(9767):721–31. 6. GlaxoSmithKline. Benlysta prescribing information. http://www. 5 Conclusion gsksource.com/gskprm/htdocs/documents/BENLYSTA-PI-MG. PDF. Accessed 3 Aug 2017. 7. Struemper H, Chen C, Cai W. Population pharmacokinetics of This analysis indicates that belimumab 200 mg QW is belimumab following intravenous administration in patients with appropriate for SC administration in patients with SLE and systemic lupus erythematosus. J Clin Pharmacol. 2013;53(7):711–20. that no dose adjustments are required for adult patients to 8. Furie R, Stohl W, Ginzler EM, Becker M, Mishra N, Chatham W, maintain efficacy and safety. et al. Biologic activity and safety of belimumab, a neutralizing anti-B-lymphocyte stimulator (BLyS) monoclonal antibody: a Acknowledgements Medical writing assistance was provided by phase I trial in patients with systemic lupus erythematosus. Louisa Pettinger, PhD, and Jennie McLean, PhD, of Fishawack Arthritis Res Ther. 2008;10(5):R109. Indicia Ltd, and was funded by GlaxoSmithKline. The authors wish to 9. Wallace DJ, Stohl W, Furie RA, Lisse JR, McKay JD, Merrill JT, thank the patients and trial investigators involved in this study. et al. A phase II, randomized, double-blind, placebo-controlled, dose-ranging study of belimumab in patients with active systemic Compliance with Ethical Standards lupus erythematosus. Arthritis Rheumatol. 2009;61(9):1168–78. 10. Stohl W, Schwarting A, Okada M, Scheinberg M, Doria A, Funding This study was funded by GlaxoSmithKline. Hammer AE, et al. Efficacy and safety of subcutaneous beli- mumab in systemic lupus erythematosus: a fifty-two-week ran- Conflict of Interest Herbert Struemper is a former employee of and domized, double-blind, placebo-controlled study. Arthritis owns stock in GlaxoSmithKline. David Roth is an employee of and Rheumatol. 2017;69(5):1016–27. owns stock in GlaxoSmithKline. Mita Thapar has no conflicts of 11. Sheikh SZ, Hammer AE, Fox NL, Groark J, Struemper H, Roth interest directly relevant to the contents of this study. D, et al. Evaluation of a novel autoinjector for subcutaneous self- administration of belimumab in systemic lupus erythematosus. Ethics Approval All procedures performed in studies involving Int J Clin Pharmacol Ther. 2016;54(11):914. human participants were in accordance with the ethical standards of 12. Shida Y, Takahashi N, Sakamoto T, Ino H, Endo A, Hirama T. the investigational review board or human subjects committee and The pharmacokinetics and safety profiles of belimumab after 728 H. Struemper et al. single subcutaneous and intravenous doses in healthy Japanese 15. Chilton F, Collett RA. Treatment choices, preferences and deci- volunteers. J Clin Pharm Ther. 2014;39(1):97–101. sion-making by patients with rheumatoid arthritis. Musculoskelet 13. Yapa SW, Roth D, Gordon D, Struemper H. Comparison of Care. 2008;6(1):1–14. intravenous and subcutaneous exposure supporting dose selection 16. Dirks NL, Meibohm B. Population pharmacokinetics of thera- of subcutaneous belimumab systemic lupus erythematosus phase peutic monoclonal antibodies. Clin Pharmacokinet. 3 program. Lupus. 2016;25(13):1448–55. 2010;49(10):633–59. 14. Cai WW, Fiscella M, Chen C, Zhong ZJ, Freimuth WW, Subich 17. Chaudhury C, Mehnaz S, Robinson JM, Hayton WL, Pearl DK, DC. Bioavailability, pharmacokinetics, and safety of belimumab Roopenian DC, et al. The major histocompatibility complex-re- administered subcutaneously in healthy subjects. Clin Pharmacol lated Fc receptor for IgG (FcRn) binds albumin and prolongs its Drug Dev. 2013;2(4):349–57. lifespan. J Exp Med. 2003;197(3):315–22.

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Clinical PharmacokineticsSpringer Journals

Published: Sep 8, 2017

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