Abstract Objectives To determine the effect of etravirine on the pharmacokinetics of darunavir/cobicistat and vice versa. Safety and tolerability of this combination were also evaluated. Methods Open-label, fixed-sequence trial in two cohorts of HIV-infected patients on therapy with darunavir/cobicistat 800/150 mg once daily (DRV cohort; n = 15) or etravirine 400 mg once daily (ETR cohort; n = 15). Etravirine or darunavir/cobicistat were added on days 1–14 and 1–7 in participants in the DRV or ETR cohort, respectively. Full pharmacokinetic profiles were obtained on days 0 and 14 in the DRV cohort, and on days 0 and 7 in the ETR cohort. Darunavir, cobicistat and etravirine pharmacokinetic parameters [AUC0–24, Cmax and trough concentrations in plasma (C24)] were calculated for each individual by non-compartmental analysis and were compared using linear mixed-effects models. Adverse events and HIV-1 RNA in plasma were monitored. Results Etravirine co-administration decreased cobicistat AUC0–24, Cmax and C24 by 30%, 14% and 66%, respectively. Although darunavir AUC0–24 and Cmax were unchanged by etravirine, darunavir C24 was 56% lower for darunavir/cobicistat co-administered with etravirine relative to darunavir/cobicistat alone. Etravirine pharmacokinetics were unchanged by darunavir/cobicistat. Treatments were well tolerated, and HIV-1 RNA remained undetectable in all participants. Conclusions Although etravirine pharmacokinetics was unchanged by darunavir/cobicistat, there was a significant decrease in cobicistat exposure and in darunavir C24 when darunavir/cobicistat was co-administered with etravirine. Boosting darunavir with ritonavir instead of with cobicistat may be preferred if darunavir is to be combined with etravirine in clinical practice. Introduction Despite the high efficacy of combined ART (cART) to suppress viral replication in HIV-infected patients, current cART is not able to eradicate HIV from the body. HIV persists within long-lived latently infected CD4+ T cells of infected individuals, and cessation of suppressive cART leads to a viral rebound within a few weeks.1,2 Consequently, HIV-infected patients need lifelong cART. This limitation highlights the imperative for cART regimens to maximize simplicity, safety and tolerability, while maintaining antiviral efficacy. Interest in evaluating fewer-drug NRTI-sparing antiretroviral regimens has grown in recent years.3 This is driven by the long-term toxicity of NRTIs, even with the newer and relatively safer NRTIs in current use.4 Dual therapy with etravirine + darunavir may be an attractive NRTI-sparing antiretroviral regimen. Both etravirine and darunavir have been shown to be safe and effective as part of triple cART.5–8 Additionally, this regimen would allow once-daily administration, and would provide a moderate to high genetic barrier against the development of viral resistance. However, combining darunavir with etravirine might result in potential drug–drug interactions. Darunavir is extensively metabolized by the CYP3A4 isoform of the cytochrome P450. Therefore, to attain therapeutic concentrations of darunavir throughout the dosing interval, darunavir needs to be combined with a CYP3A4 inhibitor (i.e. ritonavir or cobicistat).9 On the other hand, etravirine is a CYP3A4 inducer.10 Consequently, the combination of etravirine with darunavir may decrease darunavir exposure, which might ultimately put the patient at risk of treatment failure, even in the presence of a pharmacoenhancer. Previous studies specifically aimed at assessing drug–drug interactions between ritonavir-boosted darunavir and etravirine showed no clinically relevant changes in the pharmacokinetic parameters of darunavir, ritonavir or etravirine.11–13 However, a fixed-dose combination (FDC) of darunavir with the new pharmacoenhancer cobicistat has been recently developed (darunavir/cobicistat 800/150 mg, Rezolsta®),14 and interest in its combination with etravirine has emerged. Results from studies with darunavir/ritonavir might not necessarily be applicable to darunavir/cobicistat, and the possible presence of drug interactions between etravirine and darunavir/cobicistat needs to be assessed before recommending this combination in clinical practice. The aim of this pharmacokinetic interaction study was, therefore, to determine the effect of etravirine 400 mg once daily on the pharmacokinetics of darunavir/cobicistat 800/150 mg once daily and vice versa. Methods Study design This was an open-label, fixed-sequence, Phase I clinical trial including two separate cohorts of 15 HIV-infected patients each (DRV cohort and ETR cohort). The primary endpoint of the study was to determine the effect of etravirine on the pharmacokinetics of darunavir/cobicistat and vice versa. The short-term safety and tolerability of this drug combination were also evaluated. Ethics Each participant gave written informed consent before screening for eligibility criteria, the protocol was approved by an independent ethics committee and by Spanish national regulatory authorities, and the study was performed according to the stipulations of the Declaration of Helsinki. The study was registered at https://www.clinicaltrialsregister.eu (trial number NCT02818348). Study population HIV-infected patients receiving stable ART during at least 4 weeks including either darunavir/cobicistat (800/150 mg once daily; DRV cohort) or etravirine (400 mg once daily; ETR cohort) were eligible for the study. Patients were required to have an HIV-1 RNA load in plasma <50 copies/mL for at least 12 weeks. Key exclusion criteria included a prior history of intolerance to darunavir/cobicistat or etravirine; ART adherence <90% during the previous week; use of concomitant medications that might interact with darunavir, cobicistat or etravirine within 2 weeks before inclusion; and any condition that, in the opinion of the investigator, could compromise the patient’s safety, protocol adherence or the outcome of the study. Females could be included if they were of non-childbearing potential or had a negative serum pregnancy test and committed themselves to using effective non-hormonal birth control methods during the study. Procedures Etravirine (400 mg once daily) or darunavir/cobicistat (800/150 mg once daily) was added to the antiretroviral regimen of participants included in the DRV or ETR cohort, respectively. Patients in the DRV cohort received etravirine from day 1 to 14, to reach maximal induction of CYP3A4 by etravirine; while patients in the ETR cohort received darunavir/cobicistat from day 1 to 7, to reach maximal inhibition of CYP3A4 by cobicistat (Figure 1). Patients were told to take medications in the morning, with food. Treatment adherence was assessed by pill count during the study appointments. Figure 1. View largeDownload slide Schematic representation of the study design. DRV/c, darunavir/cobicistat; ETR, etravirine; q24h, once daily; SCR, screening; FU, follow-up. Figure 1. View largeDownload slide Schematic representation of the study design. DRV/c, darunavir/cobicistat; ETR, etravirine; q24h, once daily; SCR, screening; FU, follow-up. Full pharmacokinetic profiles were obtained from each participant on days 0 and 14 in the DRV cohort, and on days 0 and 7 in the ETR cohort. Finally, each participant underwent a follow-up visit 2 weeks after the second pharmacokinetic session. Assessments Demographic and clinical variables including age, body weight and height, and use of concomitant drugs, including over-the-counter medications, were recorded for each participant at enrolment. Safety was evaluated during the trial by clinical interview, physical examination and laboratory assessment (blood counts, chemistry, CD4+ T cell count and HIV-1 RNA load). Serial blood sampling for pharmacokinetics was performed over 24 h on days 0 (darunavir/cobicistat) and 14 (darunavir/cobicistat + etravirine) in the DRV cohort, and on days 0 (etravirine) and 7 (etravirine + darunavir/cobicistat) in the ETR cohort. Blood samples were taken immediately before and 1, 2, 4, 6, 8, 10, 12 and 24 h after a witnessed morning dose. Samples were collected into potassium- and EDTA-containing 10 mL tubes. Plasma was isolated by centrifugation (3200 g for 15 min) and stored at –20 °C until analysis. Darunavir, cobicistat and etravirine concentrations in plasma were determined using LC-MS/MS at the Department of Molecular and Clinical Pharmacology, University of Liverpool, according to a validated method; the lower limits of quantification for darunavir, cobicistat and etravirine were 15, 5 and 5 ng/mL, respectively. The laboratory participates in the external quality assurance programme organized by the Association for Quality Assessment in Therapeutic Drug Monitoring and Clinical Toxicology of Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.15 Statistical analysis Descriptive statistics were used to characterize baseline demographics, safety assessments and pharmacokinetic parameters for etravirine, cobicistat and darunavir. Darunavir, cobicistat and etravirine pharmacokinetic parameters were calculated for each individual using a non-compartmental approach by means of Winnonlin software (Phoenix, version 7.0). The primary pharmacokinetic parameters used in the statistical analysis were the AUC during the dose interval (AUC0–24), maximum concentrations (Cmax), the concentrations at the end of the dosing interval (C24) and the elimination half-life (t1/2). The AUC0–24 was calculated by means of the linear trapezoidal rule, t1/2 was obtained by linear regression analysis of the terminal log-linear portion of the plasma concentration curve, and Cmax and C24 were obtained by inspection of the concentration data. Darunavir and cobicistat pharmacokinetic parameters were compared between day 0 and 14 in the DRV cohort. Similarly, etravirine pharmacokinetic parameters were compared between day 0 and 7 in the ETR cohort. For these comparisons, co-administration of darunavir/cobicistat and etravirine was regarded as the test, and treatment with either darunavir/cobicistat or etravirine alone as the reference. The least-squares mean (LSM) of the primary parameters were estimated with a linear mixed-effects model with treatment as a fixed effect and subject as a random effect. Pharmacokinetic parameters were natural log-transformed before analysis. A 90% CI was constructed around the difference between the LSMs of test and reference, and both the difference between the LSMs and the 90% CI were exponentiated and retransformed to the original scale. Results Fifteen Caucasian patients were included in each study cohort. Baseline demographics and clinical characteristics are summarized in Table 1. At baseline, ART consisted of darunavir/cobicistat monotherapy in all patients included in the DRV cohort, while most patients in the ETR cohort were receiving etravirine plus two NRTI. Table 1. Baseline demographics DRV cohort (n = 15) ETR cohort (n = 15) Age (years), median (range) 45.1 (21.6–62.2) 50.0 (25.2–67.9) Males, n (%) 14 (93.3) 12 (80.0) BMI (kg/m2), median (range) 23.9 (20.2–35.8) 24.2 (18.6–34.4) NRTIs in the background regimen, n (%) ABC/3TC – 8 (53.3) TDF/FTC – 5 (33.3) other – 2 (14.4) No. of prior ARV regimens, median (range) 2 (2–7) 5 (1–18) CD4+ T cell count (cells/mm3), median (range) 746 (474–1584) 638 (283–1331) Nadir CD4+ T cell count, median (range) 291 (3–489) 238 (36–439) Time (years) with undetectable HIV-1 RNA, median (range) 5.0 (3.4–9.5) 4.7 (0.8–12.4) HCV coinfection, n (%) 1 (6.7) 4 (26.7) DRV cohort (n = 15) ETR cohort (n = 15) Age (years), median (range) 45.1 (21.6–62.2) 50.0 (25.2–67.9) Males, n (%) 14 (93.3) 12 (80.0) BMI (kg/m2), median (range) 23.9 (20.2–35.8) 24.2 (18.6–34.4) NRTIs in the background regimen, n (%) ABC/3TC – 8 (53.3) TDF/FTC – 5 (33.3) other – 2 (14.4) No. of prior ARV regimens, median (range) 2 (2–7) 5 (1–18) CD4+ T cell count (cells/mm3), median (range) 746 (474–1584) 638 (283–1331) Nadir CD4+ T cell count, median (range) 291 (3–489) 238 (36–439) Time (years) with undetectable HIV-1 RNA, median (range) 5.0 (3.4–9.5) 4.7 (0.8–12.4) HCV coinfection, n (%) 1 (6.7) 4 (26.7) DRV/c, darunavir/cobicistat; ETR, etravirine; TDF, tenofovir disoproxil fumarate; FTC, emtricitabine; ABC, abacavir; 3TC, lamivudine; ARV, antiretroviral. Darunavir/cobicistat pharmacokinetics Darunavir and cobicistat plasma concentration–time profiles following administration of darunavir/cobicistat alone or in combination with multiple doses of etravirine are shown in Figure 2. Table 2 summarizes darunavir and cobicistat pharmacokinetic parameters with and without co-administration of etravirine. Table 2. Pharmacokinetics of darunavir and cobicistat in the DRV cohort Darunavir Cobicistat day 0 (reference) day 14 (test) LSM ratio (90% CI) day 0 (reference) day 14 (test) LSM ratio (90% CI) Cmax (ng/mL) 4885.3 ± 1420.2 5329.3 ± 1158.2 1.11 (0.99–1.24) 822.7 ± 269.0 689.7 ± 170.2 0.86 (0.75–0.98) AUC0–24 (ng·h/mL) 57 173.6 ± 8925.6 54 848.0 ± 9953.7 0.99 (0.86–1.13) 7736.4 ± 2951.7 5490.0 ± 1900.4 0.70 (0.56–0.87) C24 (ng/mL) 1145.9 ± 567.7 539.3 ± 380.0 0.44 (0.33–0.58) 63.1 ± 83.1 17.3 ± 10.6 0.34 (0.23–0.50) t1/2 (h) 16.8 ± 12.0 7.6 ± 7.3 – 5.3 ± 3.2 3.6 ± 0.6 – Darunavir Cobicistat day 0 (reference) day 14 (test) LSM ratio (90% CI) day 0 (reference) day 14 (test) LSM ratio (90% CI) Cmax (ng/mL) 4885.3 ± 1420.2 5329.3 ± 1158.2 1.11 (0.99–1.24) 822.7 ± 269.0 689.7 ± 170.2 0.86 (0.75–0.98) AUC0–24 (ng·h/mL) 57 173.6 ± 8925.6 54 848.0 ± 9953.7 0.99 (0.86–1.13) 7736.4 ± 2951.7 5490.0 ± 1900.4 0.70 (0.56–0.87) C24 (ng/mL) 1145.9 ± 567.7 539.3 ± 380.0 0.44 (0.33–0.58) 63.1 ± 83.1 17.3 ± 10.6 0.34 (0.23–0.50) t1/2 (h) 16.8 ± 12.0 7.6 ± 7.3 – 5.3 ± 3.2 3.6 ± 0.6 – Values shown are means ± SD unless specified otherwise. Figure 2. View largeDownload slide Mean (SD) plasma concentration–time curves for cobicistat (A) and darunavir (B) following administration of darunavir/cobicistat (DRV/c) alone or with etravirine (ETR). Figure 2. View largeDownload slide Mean (SD) plasma concentration–time curves for cobicistat (A) and darunavir (B) following administration of darunavir/cobicistat (DRV/c) alone or with etravirine (ETR). Darunavir Cmax and AUC0–24 were comparable after administration of darunavir/cobicistat alone or with etravirine. Conversely, co-administration of darunavir/cobicistat with etravirine decreased cobicistat Cmax and AUC0–24 by 14% and 30%, respectively. Moreover, compared with darunavir/cobicistat administered alone, there was a shortening in the terminal half-life of both cobicistat and darunavir in the presence of etravirine. The magnitude of the effect of etravirine on cobicistat and darunavir concentrations was particularly marked at the end of the dosing interval, with a 65% decrease in cobicistat C24 and a 56% decrease in darunavir C24 compared with darunavir/cobicistat administered alone. Even so, mean darunavir C24 remained ∼10 times higher than the protein binding-adjusted EC50 for WT HIV (55 ng/mL), and no patient had darunavir C24 below this threshold.16 Etravirine pharmacokinetics The mean plasma concentration–time curves for etravirine in the presence and absence of darunavir/cobicistat are displayed in Figure 3. Summarized results for etravirine pharmacokinetic parameters are shown in Table 3. No significant effects were observed in any of the primary pharmacokinetic parameters of etravirine when comparing the administration of etravirine alone with the combination of etravirine and darunavir/cobicistat. Etravirine exposure was well above the average protein binding-adjusted EC50 for WT strains of HIV-1 (4 ng/mL) in all participants.17 Table 3. Pharmacokinetics of etravirine in the ETR cohort Day 0 (reference) Day 7 (test) LSM ratio (90% CI) Cmax (ng/mL) 783.0 ± 277.6 909.8 ± 459.6 1.06 (0.91–1.23) AUC0–24 (ng·h/mL) 10 481.5 ± 4163.5 12747.6 ± 6603.2 1.11 (0.96–1.28) C24 (ng/mL) 280.5 ± 116.8 348.7 ± 180.0 1.11 (0.95–1.29) t1/2 (h) 24.1 ± 13.4 30.2 ± 19.1 – Day 0 (reference) Day 7 (test) LSM ratio (90% CI) Cmax (ng/mL) 783.0 ± 277.6 909.8 ± 459.6 1.06 (0.91–1.23) AUC0–24 (ng·h/mL) 10 481.5 ± 4163.5 12747.6 ± 6603.2 1.11 (0.96–1.28) C24 (ng/mL) 280.5 ± 116.8 348.7 ± 180.0 1.11 (0.95–1.29) t1/2 (h) 24.1 ± 13.4 30.2 ± 19.1 – Values shown are means ± SD unless specified otherwise. Figure 3. View largeDownload slide Mean (SD) plasma concentration–time curves for etravirine (ETR) following administration of etravirine alone or with darunavir/cobicistat (DRV/c). Figure 3. View largeDownload slide Mean (SD) plasma concentration–time curves for etravirine (ETR) following administration of etravirine alone or with darunavir/cobicistat (DRV/c). Safety No serious adverse events were reported during the trial, and all patients completed the study. The most frequently reported adverse events were diarrhoea (13%) and nausea (10%). All adverse events were mild or moderate in severity, and resolved within 2 weeks. There were no consistent or clinically relevant changes in vital signs or laboratory abnormalities. HIV-1 RNA in plasma remained undetectable in all participants throughout the study. Discussion In this study with HIV-infected patients, co-administration of darunavir/cobicistat with etravirine, all dosed once daily, resulted in a significant decrease in drug concentrations of both cobicistat and darunavir compared with the administration of darunavir/cobicistat alone. The magnitude of this drug–drug interaction was particularly marked at the end of the dosing interval, which might place patients at risk of subtherapeutic drug concentrations. Cobicistat is a new pharmacoenhancer that has been recently developed to boost other antiretroviral drugs.18–20 Cobicistat is a substrate and a potent CYP3A4 inhibitor but, compared with ritonavir, it has no intrinsic antiretroviral activity, is more selective than ritonavir in terms of inhibition of different isoenzymes of the cytochrome P450 system and does not induce CYP isoenzymes or glucuronidation.19 In addition, given its chemical stability, cobicistat can be co-formulated in an FDC, thereby reducing pill burden and medication errors. There is clinical interest in combining the new FDC containing darunavir and cobicistat (Rezolsta®) and etravirine. Combination of darunavir with etravirine may be attractive in clinical practice as a fewer-drug NRTI-sparing antiretroviral regimen. However, co-administration of darunavir with etravirine may result in complex drug–drug interactions. In this regard, clinical trials to evaluate the presence of drug–drug interactions between darunavir/ritonavir and etravirine have shown the absence of clinically relevant changes in pharmacokinetic parameters.11–13 Moreover, although data from randomized clinical trials are lacking, the safety and efficacy of dual ART with darunavir/ritonavir + etravirine has been demonstrated in several cohort studies.21–23 None the less, as was shown in the present clinical trial, results from studies with darunavir/ritonavir might not be applicable to darunavir/cobicistat. In this study, we observed a significantly shorter half-life and lower cobicistat and darunavir concentrations in plasma when darunavir/cobicistat was given with etravirine. These effects were particularly evident at the end of the dosing interval, when darunavir and cobicistat concentrations were nearly halved. Contrary to our results, however, previous studies with darunavir/ritonavir showed no significant effect of etravirine on darunavir or ritonavir pharmacokinetics, despite potential CYP3A4 induction by etravirine.11–13 One possible explanation for this discrepancy may be that, although both ritonavir and cobicistat are potent inhibitors of CYP3A4 in vitro,19 at the licensed boosting doses CYP3A4 inhibition might be less complete over the duration of the dosing interval with cobicistat than with ritonavir. In this regard, Mathias et al.20 reported changes in midazolam clearance in a dose-escalation study comparing cobicistat (from 50 to 300 mg once daily) and ritonavir (100 mg once daily). Similar concentration–time profiles of the ratio of the metabolite 1′-hydroxymidazolam to parent drug (midazolam) were obtained for cobicistat administered at a dose of 200 mg and for ritonavir, with nearly complete CYP3A4 inhibition throughout the dosing interval. However, at lower cobicistat doses (100 mg or lower) this inhibitory effect seemed to wane at the end of the dosing interval.20 Our results are in agreement with this observation. During the first part of the concentration–time curve darunavir concentrations were similar when darunavir/cobicistat was given either alone or with etravirine. However, CYP3A4 induction by etravirine led to lower cobicistat concentrations, which could be insufficient to effectively boost darunavir (and cobicistat itself) at some point 12 h after dosing. Based on this rationale, one possible option to overcome this drug interaction could consist of increasing the dose of cobicistat. Although this alternative can be particularly attractive for those patients who are intolerant to ritonavir, the lack of specific data on this approach does not allow us to recommend this strategy in routine clinical practice. Of note, etravirine and darunavir concentrations in plasma were above the protein binding-adjusted EC50 in all participants, and the viral load remained undetectable in all participants during the study. However, the 56% reduction in darunavir trough concentration observed in this study may be clinically relevant. At the end of the dosing interval, the darunavir inhibitory quotient with respect to WT strains of HIV-1 decreased from nearly 20 for darunavir/cobicistat given alone to ∼10 when it was co-administered with etravirine. This decrease in drug exposure may have an impact in the pharmacological robustness of this dual therapy, particularly in patients with prior mutations, or who miss or delay darunavir/cobicistat doses, or who take other co-medications that may further decrease darunavir or cobicistat concentrations. Etravirine concentrations in plasma in our study were comparable when etravirine (400 mg once daily) was given alone or in combination with darunavir/cobicistat (800/150 mg once daily). However, Schöller-Gyüre et al.13 described a 37% decrease in etravirine exposure when etravirine (200 mg twice daily) was combined with darunavir/ritonavir (600/100 mg twice daily) in a clinical trial with healthy volunteers. This discrepancy between studies may be explained by combined induction of CYP2C19 and glucuronosyl transferase by ritonavir in the study by Schöller-Gyüre et al.13 but not by cobicistat in the present trial. Of note, although the dose of etravirine currently approved by regulatory agencies is 200 mg twice daily, we decided to use the 400 mg once-daily dose of etravirine in the present study because it might reflect better the use of etravirine in this clinical scenario. In conclusion, although etravirine pharmacokinetics were unchanged by darunavir/cobicistat, there was a significant decrease in cobicistat exposure and darunavir trough concentrations in plasma when darunavir/cobicistat was co-administered with etravirine. Based on this drug interaction, boosting darunavir with ritonavir instead of with cobicistat should be preferred if darunavir is to be combined with etravirine in clinical practice. Acknowledgements We thank the patients and their care givers for their participation in this study. We also wish to acknowledge the assistance of Michael Kennedy-Scanlon in proofreading the English in the final version of the manuscript. Funding This work was supported by Janssen Cilag and by the ‘Lluita contra la SIDA’ Foundation. M. V. was supported by Fondo de Investigaciones Sanitarias grant CP04/00121 from the Spanish Health Department in collaboration with the Institut de Recerca de l’Hospital de la Santa Creu i Sant Pau, Barcelona, and she is a member of CIBERSAM, a research network funded by the Spanish Health Ministry through the Instituto de Salud Carlos III. We acknowledge infrastructural support from the Liverpool Biomedical Research Centre funded by Liverpool Health Partners. The funders had no role in the study design, data collection and interpretation, or the decision to submit this work for publication. Transparency declarations J. M., A. C., E. R., J. R. S., S. K. and B. C. have received research funding, consultancy fees, and lecture sponsorships from and have served on advisory boards for various laboratories (MSD, Abbvie, Boehringer Ingelheim, Gilead Sciences, Viiv Healthcare, Janssen-Cilag and Bristol-Myers-Squibb). The remaining authors have none to declare. 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Journal of Antimicrobial Chemotherapy – Oxford University Press
Published: Mar 1, 2018
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