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Pharmacokinetics of a Novel Sildenafil Orodispersible Film Administered by the Supralingual and the Sublingual Route to Healthy Men

Pharmacokinetics of a Novel Sildenafil Orodispersible Film Administered by the Supralingual and... Background Sildenafil was the first selective drug available on the market as oral therapy for erectile dysfunction (ED). A novel sildenafil orodispersible film (ODF) for ED treatment, containing sildenafil citrate, has recently been marketed. Objectives Study objective was to investigate sildenafil bioavailability of the novel ODF formulation after sublingual and supralingual administration. Methods In this randomised, two-way cross-over study, 12 healthy male volunteers received a single 50 mg sildenafil dose by the sublingual and supralingual administration routes. Plasma sildenafil was determined up to 12 h post-dose. Peak concentration (C ) and area under concentration-time curve (AUC ) were calculated and compared between the two max 0–t administration routes by analysis of variance (ANOVA). Results Sublingual and supralingual administration can be claimed equivalent regarding the extent of sildenafil exposure since AUC 90 % CIs corresponded to 94.90–110.58% and were within the pre-specified acceptance range. C 90% CIs 0–t max (79.92–125.57%) were only slightly outside the 80.00–125.00% limits, due to the small sample size, while the time to achieve C did not differ between treatments ( p = 0.9277). Rate of exposure of the two administration routes was therefore similar. max Reported treatment-related adverse events were mild to moderate headache (33.3% of subjects) and vomiting (8.3%). Conclusions In healthy men, sublingual and supralingual administration of sildenafil ODF resulted in a remarkably similar pharmacokinetic profile and confirmed the safety of both study treatments. The recently marketed sildenafil ODF, adminis - tered by both investigated routes, can provide a valuable alternative to the marketed solid oral forms (tablets) in ED treatment. 1 Introduction Key Points Penile erection is the result of smooth muscle relaxation in In healthy men, sublingual and supralingual admin- the penis. It includes arterial dilatation, trabecular smooth istrations of sildenafil orodispersible film resulted muscle relaxation, and activation of the corporeal veno- in a remarkably similar pharmacokinetic profile and occlusive mechanism [1–3]. Erectile dysfunction (ED) is confirmed the safety of both study treatments. defined as the persistent inability to attain and maintain a penile erection sufficient to permit satisfactory sexual perfor - The recently marketed orodispersible film, admin- mance [1–3]. Phosphodiesterase type 5 (PDE5) is a regulator istered by both investigated routes, can provide a of vascular smooth muscle contraction in all smooth muscle valuable alternative to the marketed solid oral forms districts and especially in penis, and PDE5 inhibitors are (tablets) in erectile dysfunction treatment. currently the first-line therapy for ED. Sildenafil was the first selective inhibitor of cGMP-spe - cific PDE5 available on the market as oral therapy for ED * Luca Loprete [2–6]. luca.loprete@croalliance.com Sildenafil is rapidly absorbed, with maximum observed CROSS Research S.A., Via F.A. Giorgioli 14, 6864 Arzo, plasma concentrations (C ) reached within 30–120 min max Switzerland (median time 60 min) after oral administration under fasting IBSA Institut Biochimque S.A., Via del Piano, conditions. The mean absolute oral bioavailability is 41% 6915 Pambio-Noranco, Lugano, Switzerland Vol.:(0123456789) 766 L. Loprete et al. (range 25–63%). The area under the concentration–time administration. However, due to its higher vascularisation curve (AUC) and C increase proportionally with the with respect to the rest of oral cavity, the sublingual mucosa max dose over the recommended oral dose range (25–100 mg) represents a specific route of absorption, that can possibly indicating a dose-proportional rate and extent of absorp- lead to modifications in the rate, extent or subject variability tion. When sildenafil is taken after a heavy and fatty meal, of drug absorption [15]. For this reason, in the present pilot the rate of absorption is reduced with a delay in t and a study, the possibility of significant differences in sildenafil max mean reduction in C by 29% [7, 8]. The mean steady-state bioavailability after sublingual and supralingual adminis- max sildenafil volume of distribution is 105 L, indicating distri- tration of sildenafil ODF formulation was investigated. bution into the tissues. The total sildenafil body clearance The pharmacokinetics of sildenafil N -desmethyl metabo- is 41 L/h with a resultant terminal half-life (t ) of 3–5 h. lite and the safety profile of the study treatments were also 1/2 Sildenafil is cleared predominantly by the CYP3A4 (major investigated. route) and CYP2C9 (minor route) hepatic microsomal iso- enzymes. The major circulating metabolite, resulting from N-demethylation of sildenafil, has a PDE selectivity pro -2 Methods file similar to sildenafil and an in vitro potency for PDE5 approximately 50% of the parent drug. Plasma concentra- 2.1 Study Design and Procedures tions of this metabolite are approximately 40% of those found for sildenafil. The N -desmethyl metabolite is further The study protocol (code 17CH-SDF06) was approved by metabolised, with a t of approximately 4 h [9, 10]. The the Ethics Committee of Canton Ticino, Switzerland, and 1/2 drug and its major circulating N-desmethyl metabolite are the Swiss Federal Health Authorities. All subjects were bound to plasma proteins in the amount of 96% and binding given a detailed description of the study and all gave writ- is independent of total drug concentrations [7, 11]. ten informed consent before enrolment. The study was per- The good tolerability and safety profile of sildenafil for formed in accordance with the Declaration of Helsinki and treating ED was established in approximately 74 double- harmonised European standards for Good Clinical Practice blind placebo-controlled trials performed in more than 9000 (ICH E6 1.24), from November to December 2017. patients, confirming that sildenafil is well tolerated at the The study was single-centre, single-dose, open, ran- recommended dose regimen. The most commonly reported domised, two-way cross-over and was designed according adverse reactions in clinical studies among sildenafil-treated to the EMA guideline for bioequivalence studies [14]. patients were headache, flushing, dyspepsia, nasal conges - The investigational product was sildenafil ODF, a thin, tion, dizziness, nausea, hot flush, visual disturbance, cyano- flexible, opaque, light blue, orodispersible film (IBSA psia and blurred vision. Adverse reactions from post-market- Institut Biochimique S.A., Switzerland) containing 70.2 ing surveillance have been gathered covering an estimated mg of sildenafil citrate, equivalent to 50 mg of sildenafil. period > 10 years [12]. It was orally administered in two study periods, below the A novel sildenafil orodispersible film (ODF) contain- tongue (tested alternative method of administration) and ing sildenafil citrate has recently been marketed. The ODF above the tongue (the approved method of administration formulation disintegrates rapidly in the oral cavity, usually of the product), with a wash-out interval of 6 days between within few minutes, without drinking or chewing, thus pro- administrations. viding a valuable alternative to the marketed solid oral forms The study randomisation list was computer-generated by (tablets) in ED treatment. The ODF, available in 4 different the Biometry Unit of CROSS Research S.A., Switzerland, dosage forms (i.e. 25, 50, 75 and 100 mg), obtained mar- using the PLAN procedure of the SAS/STAT software ver- keting authorisation in Switzerland and several European sion 9.3. Countries in 2016 and has been very recently made available Subjects were confined at the clinical centre from the on the market. evening before administration up to 12 h post-dose and were In a previous single-dose, randomised, two-way cross- in fasting conditions for 10 h before administration and up to over Phase I study [13], the bioequivalence between the new 4 h post-dose. Water was allowed as desired, except for 1 h Sildenafil IBSA 100 mg ODF, administered supralingually, before and 1 h after dosing. In both study periods, the inves- and the marketed V iagra 100-mg film-coated tablet, Pfizer tigational product was administered on day 1 at 08:00 ± 1 h Limited UK, was proven in terms of rate and extent of silde- and under fasting conditions. The subjects took a standard- nafil absorption after single-dose administration [14]. In ised, small amount of still mineral water (20 mL) to moisten addition, no significant differences in sildenafil and N-des- the oral cavity just before the ODF intake. methyl-sildenafil t values between the two products were Thereafter, the investigator placed the investigational max observed, confirming that no significant sildenafil absorp- product either beneath the volunteer’s tongue after fold- tion differences occurred in the oral cavity after supralingual ing the ODF once (sublingual route) or directly on the PK of Supra- and Sublingual Sildenafil ODF 767 volunteer’s tongue, taking care not to fold the ODF (supra- FDA guidelines on bioanalytical method validation [16, lingual route). Once administered, after the film had dis- 17]. The method had a lower quantification limit (LQL) solved completely (without chewing), the subjects could of 0.5 ng/mL and an upper quantification limit (UQL) of swallow saliva. 2000 ng/mL for both analytes and adhered to the regu- latory requirements for selectivity, sensitivity, precision, 2.2 Subjects accuracy, recovery, carry-over, matrix effect, and stability. Internal standards for the analysis were deuterated Healthy male volunteers aged 18–45 years, with a body mass forms of the analytes (sildenafil-D and N-desmethyl index of 18.5–30.0 kg/m , were enrolled in the study. All sildenafil-D ). volunteers were in good physical health, as assessed through Calibration standards for sildenafil and for N-desmethyl full physical examination, electrocardiogram (ECG) record- sildenafil in the range from 0.500 to 2000 ng/mL were pre- ing, vital signs measurement and clinical laboratory assays, pared freshly in human Li-heparin plasma on the day of according to the study inclusion criteria. No subjects were analysis. on abnormal diets or had a history of drug, alcohol, caf- Sildenafil and N-desmethyl sildenafil QC samples at feine or tobacco abuse. Exclusion criteria included history or the levels low (1.50 ng/mL), medium 1 (75.0 ng/mL), QC presence of significant diseases, history of vision or hearing medium 2 (1000 ng/mL) and high (1600 ng/mL) were pre- problems related to drugs of the PDE5 inhibitor pharmaco- pared in a batch and stored at ≤ − 18 °C prior to the start of logical class, history of priapism; anatomical deformation the bioanalytical study. of the penis, history of ophthalmologic diseases and hyper- Isolation of sildenafil, N-desmethyl sildenafil, sildenafil- sensitivity or allergic reactions to sildenafil. Medications, D and N-desmethyl sildenafil-D from human Li-heparin 8 8 including organic nitrates, were not allowed for 4 weeks plasma was performed by liquid/liquid extraction (LLE) before the study, while over-the-counter drugs and herbal with methyl tert-butyl ether. After extraction, the organic remedies were not allowed for 2 weeks before screening. layer was evaporated to dryness under a gentle stream of Subjects were not enrolled if they had participated in other nitrogen. The residue was reconstituted in injection solvent. clinical trials or donated blood in the past 3 months. Chromatographic separation was performed on a Waters XTerra MS C18 column using gradient elution. An API 2.3 Blood Sampling 4000 tandem mass spectrometry equipped with a turbo spray ionization source operating in the positive multiple reaction Blood samples for sildenafil and N -desmethyl-sildenafil monitoring mode was used for quantification. measurements were collected at pre-dose (0) and 6, 15, 30, Data acquisition was performed using Analyst software 45 min and 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 8, 12 h post-dose. (version 1.6.2) from AB Sciex. Following peak area integra- Sampling time points were selected based on previously tion, regression was also performed using Analyst. Concen- reported data [13]. trations were calculated using 13-point curves with weighted Blood samples were collected using an indwelling cath- linear regression. eter with switch valve. The cannula was rinsed, after each sampling, with about 1 mL of sterile saline solution con- taining 20 IU/mL Na-heparin. The first 2 mL of blood were 2.5 Pharmacokinetic Parameters discarded at each collection time to avoid contamination of the sample with heparin. The remaining 8 mL were col- Pharmacokinetic parameters were determined or calculated lected from the catheter and transferred with a syringe into using the validated software Phoenix W inNonLin 6.3 heparinised tubes (Li-heparin). The samples were stored on (Certara, Inc). The primary study outcome measures were ice for a maximum of 20 min and then centrifuged at 4 °C plasma sildenafil peak concentration (C ), time to C max max for 10 min at 2500g to obtain plasma. Each plasma sample (t ) and area under the concentration–time curve up to max was immediately transferred into pre-labelled polypropylene the last sampling point (AUC ) and extrapolated to infinity 0–t tubes, and stored frozen at ≤ − 20 °C. (AUC ), calculated using the linear trapezoidal rule. The 0–∞ primary end-point of the study was the evaluation of the 2.4 Bioanalytical Assay similarity of the two administration routes in terms of rate (C and t ) and extent (AUC ) of plasma sildenafil con- max max 0–t Concentrations of sildenafil and N -desmethyl sildena- centration. The following sildenafil pharmacokinetic param- fil in plasma were determined by a blinded analyst at eters were also calculated: terminal volume of distribution Analytisch Biochemisch Laboratorium BV (ABL), the (V /F), total clearance (Cl/F) and half-life (t ). The same z ½ Netherlands, using a LC–MS/MS method developed and pharmacokinetic parameters were also calculated for the validated according to the requirements of the EMA and metabolite N-desmethyl-sildenafil, except for V /F and Cl/F. z 768 L. Loprete et al. 2.6 Safety Table 1 Demographic data of study subjects (N = 12) Parameter Value The safety profile of the investigational product was assessed by evaluating treatment-emergent adverse events (AEs), Sex, [n (%)]  Male 12 (100.0%) physical examination, ECG, routine laboratory tests and vital signs checks. Vital signs (blood pressure and heart Race, [n (%)]  Black 1 (8.3%) rate) were measured at screening, final visit, and on day 1  White 11 (91.7%) of each study period at pre-dose, 1.75, and 5 h post-dose. Age (years) A 12-lead resting ECG was recorded at screening and final  Mean ± SD 36.2 ± 5.2 visit. Blood and urine samples were collected for routine  Range 23–45 haematology, blood chemistry, virology and urinalysis at Height (cm) screening and final visit. AEs were assessed throughout the  Mean ± SD 176.9 ± 5.7 study and were coded using MedDRA version 20.1. A full  Range 167–187 physical examination was performed by the investigator at Body weight (kg) screening and at the final visit.  Mean ± SD 79.5 ± 7.1  Range 68.5–88.4 2.7 Sample Size and Statistical Analyses Body mass index (kg/m )  Mean ± SD 25.5 ± 2.9  Range 19.6–29.3 Twelve healthy men were included in the study. The sample size was not based on any statistical evaluation, considering SD standard deviation the exploratory purpose of the study. The statistical analyses were performed using S AS software version 9.3 (TS1M1) for Windows and Phoenix WinNonLin 6.3, Certara Inc. Fig.  1 for sildenafil and in Fig.  2 for the N-desmethyl- A classical bioequivalence test was used for the compari- sildenafil metabolite. son of sildenafil and N -desmethyl-sildenafil pharmacokinetic The main plasma pharmacokinetic parameters data parameters [14]. Log-transformed C , AUC and AUC max 0–t 0–∞ (mean ± SD) and the results of their statistical compari- were analysed by ANOVA, with treatment, period, sequence sons are presented in Table 2 for sildenafil and in Table  3 and subject-within-sequence as x fi ed ee ff cts. Similarity crite - for N-desmethyl-sildenafil. rion was a geometric means ratio (PE) around 100 % and its 90 Maximum plasma concentration (C ) of sildenafil was max % confidence interval (CI) within the range 80.00–125.00%. 296.50 ± 142.69 ng/mL for the sublingual route (test) and Wilcoxon signed-rank test was used to analyse t . max 288.92 ± 118.78 ng/mL for the supralingual route (refer- ence). The peak concentration was rapidly reached, at a similar median time for the two study treatments (i.e. 0.63 3 Results and 0.75 h for the test and reference treatments, respec- tively). Both the terminal volume of distribution and the 3.1 Subjects total clearance (see Table 2) were almost the same for the two administration routes. Plasma concentrations declined Nineteen subjects were screened and twelve were ran- rapidly after C with nearly identical half-lives, i.e. 2.55 max domised in the study. They received the treatment by the ± 0.26 h and 2.69 ± 0.32 h for the sublingual and supralin- allocated route of administration, completed the study per gual administration routes, respectively. AUC values were 0–t protocol and were included in the pharmacokinetic and 761.72 ± 217.71 h∙ng/mL for the test treatment and 750.76 safety analyses. Demographic characteristics of the analysed ± 246.10 h∙ng/mL for the reference. AUC too was very 0–∞ subjects are presented in Table 1. similar for the two treatments, corresponding to 798.78 ± All subjects were in good physical and mental health, 227.68 and 793.44 ± 269.63 h∙ng/mL for the sublingual based on physical examination, medical and surgical history. and supralingual administration routes, respectively. The ratios of test/reference geometric means (point estimate, PE 3.2 Pharmacokinetics %) were 100.18, 102.44 and 102.13% for sildenafil C , max AUC and AUC respectively, with their correspond- 0–t 0–∞, The mean ± standard deviation (SD) plasma concentra- ing 90% CIs within the pre-specified acceptance limits for tion-time profiles obtained after sildenafil administration AUC (94.90–110.58%) and AUC (94.58–110.29%) 0–t 0–∞ by the sublingual and supralingual routes are shown in PK of Supra- and Sublingual Sildenafil ODF 769 Fig. 1 Mean (+ SD) plasma sildenafil concentration (ng/mL) versus time profiles after single administration of sildenafil 50 mg orodispersible film by sub- lingual and supralingual route. Linear scale N = 12 Fig. 2 Mean (+ SD) plasma N-desmethyl-sildenafil con- centration (ng/mL) versus time profiles after single administra- tion of sildenafil 50 mg orodis- persible film by sublingual and supralingual route. Linear scale N = 12 and only just slightly outside the 80–125% range for C 3.3 Safety max (79.92–125.57%). N-desmethyl-sildenafil metabolite AUC and AUC Both tested treatments showed a good safety profile and no 0–t 0–∞ values were, on average, similar following administration of serious AEs were reported. Four subjects (33.3%) reported the two treatments (see Table 3) and their 90% CI fell within mild-to-moderate headache and one subject (8.3%) experi- the limits of 80.00–125.00%. Extent of N-desmethyl-sildena- enced vomiting during the study. These AEs were deemed fil exposure was therefore equivalent when the investigational by the Investigator as possibly related to study treatments. product was administered sublingually and supralingually. No clinically relevant effects on vital signs, ECGs or labo- After sublingual administration, N-desmethyl-sildenafil ratory parameters were observed. metabolite C was approximately 10% higher compared to max the supralingual route (PE %: 109.75%). On the other hand, the metabolite t and t were nearly identical for the two max ½ administration routes. 770 L. Loprete et al. Table 2 Sildenafil pharmacokinetic parameters and statistical analysis results after single administration of sildenafil 50 mg orodispersible film by sublingual and supralingual route N = 12 Sildenafil Pharmacokinetic parameter Sublingual route (test) Supralingual route (refer- PE % 90% CI (%) ence) C (ng/mL), mean ± SD 296.50 ± 14 2.69 288.92 ± 118.78 100.18 79.92–125.57 max t (h) , median (range) 0.63 (0.50–2.00) 0.75 (0.25–1.50) max AUC (h∙ng/mL), mean ± SD 761.72 ± 217.71 750.76 ± 246.10 102.44 94.90–110.58 0–t AUC (h∙ng/mL), mean ± SD 798.78 ± 227.68 793.44 ± 269.63 102.13 94.58–110.29 0–∞ V /F (L), mean ± SD 255.35 ± 107.88 266.46 ± 75.55 Cl/F (L/h), mean ± SD 68.50 ± 23.90 70.87 ± 27.00 t (h), mean ± SD 2.55 ± 0.26 2.69 ± 0.32 AUC area under the concentration–time curve from time 0 to the last observed concentration time t, CI confidence interval, Cl/F total clear - 0–t ance after oral administration, C maximum plasma concentration, PE ratio test/reference of geometric means, SD standard deviation, t termi- max ½ nal half-life, t time to achieve maximum plasma concentration, V /F terminal volume of distribution after oral administration max z Comparison between sublingual and supralingual route by Wilcoxon signed-rank test: p = 0.9277 Table 3 N-desmethyl-sildenafil pharmacokinetic parameters and statistical analysis results after single administration of sildenafil 50 mg orodis- persible film by sublingual and supralingual route N = 12 N-desmethyl-sildenafil Pharmacokinetic parameter Sublingual route (test) Supralingual route (refer- PE % 90% CI (%) ence) C (ng/mL), mean ± SD 42.58 ± 17.20 37.38 ± 11.15 109.75 92.73–129.90 max t (h) , median (range) 1.13 (0.50–2.00) 1.00 (0.50–2.50) max AUC (h∙ng/mL), mean ± SD 121.58 ± 33.17 117.69 ± 25.68 102.09 91.21–114.28 0–t AUC (h∙ng/mL), mean ± SD 138.51 ± 38.22 133.73 ± 35.94 103.43 93.35–114.59 0–∞ t (h), mean ± SD 4.10 ± 1.37 4.07 ± 1.28 AUC area under the concentration–time curve from time 0 to the last observed concentration time t, CI confidence interval, C maximum 0–t max plasma concentration, PE ratio test/reference of geometric means, SD standard deviation, t terminal half-life, t time to achieve maximum ½ max plasma concentration Comparison between sublingual and supralingual route Wilcoxon signed-rank test: p = 1.0000 outside the pre-specified limits for the peak concentra- 4 Discussion tion, due to a high within-subject variability and the lim- ited number of subjects in the study. The nearly identical A sildenafil ODF containing sildenafil citrate has recently t , volume of distribution, total clearance and t values been marketed to meet the rising interest for sildenafil for - max ½ obtained with the two administration routes confirmed mulations able to dissolve very rapidly in the oral cavity that sildenafil presented the same absorption, distribution without drinking or chewing, and to provide a more practi- and elimination kinetics after sublingual and supralingual cal and user-friendly alternative to the marketed products dosing. for the treatment of ED. A comparison of the present results with the literature Mean sildenafil plasma concentration-time profiles data [13], obtained after supralingual administration of the up to 12 h after single-dose sublingual and supralingual sildenafil 100 mg ODF during a bioequivalence study versus administration were nearly superimposable. The ratio of Viagra 100 mg, showed similar rate and extent of exposure. test/reference geometric means was very close to 100% for The data obtained in the present study and previously in sildenafil C , AUC and AUC , indicating a compa- max 0–t 0–∞ the bioequivalence study between the ODF formulation and rable rate and extent of sildenafil exposure with the two Viagra film-coated tablets [13] indicated that the absorp- treatments. The 90% CIs were within the equivalence lim- tion of sildenafil in the mucosa of the oral cavity was neg- its of 80.00–125.00% for the two AUCs and just slightly ligible and had no significant impact on the drug kinetics. PK of Supra- and Sublingual Sildenafil ODF 771 which was contracted by IBSA Institut Biochimique SA as CRO for the After the complete dissolution of the ODF in the mouth, conduction of this study and received financial support for its services. sildenafil was likely swallowed and absorbed further down The authors declare that they have no other relationships or activities in the gastro-intestinal tract, regardless of the place of disag- that could appear to have influenced the submitted work. gregation (sublingual or supralingual) of the film. Ethical approval The study protocol (code 17CH-SDF06) was The 90% CIs for N-desmethyl sildenafil AUCs fell within approved by the Ethics Committee of Canton Ticino, Switzerland, and the limits of 80.00–125.00%, and therefore the two admin- the Swiss Federal Health Authorities. istration routes were also equivalent with respect to the extent of metabolite exposure. The peak metabolite plasma Informed consent All subjects provided written informed consent before enrolment. concentration was slightly different between the two treat- ments, likely due to the small sample size considered. The sublingual route of administration showed a 10% higher C Open Access This article is distributed under the terms of the Crea- max tive Commons Attribution-NonCommercial 4.0 International License and, consequently, the 90% CI did not fall within the accept- (http://creativecommons.org/licenses/by-nc/4.0/), which permits any ance limits of 80.00–125.00%. However, the metabolite t max noncommercial use, distribution, and reproduction in any medium, and t values were nearly identical (p = 1.0000) for the two provided you give appropriate credit to the original author(s) and the administration methods, confirming that both the forma- source, provide a link to the Creative Commons license, and indicate if changes were made. tion rate and the elimination rate of the metabolite were not significantly different. Considering that N -desmethyl silde- nafil had a peak concentration less than 15% of its parent References compound and 40% of its biological activity, the difference between the two administration routes in the metabolite C max 1. Yafi FA, Jenkins L, Albersen M, Corona G, Isidori AM, Goldfarb value can be considered clinically not significant. S, et al. Erectile dysfunction. Nat Rev Dis Primers. 2016;2:16003. Safety data confirmed a favourable safety profile of the 2. Andersson KE. Mechanisms of penile erection and basis for phar- investigational product, administered as single oral dose of macological treatment of erectile dysfunction. Pharmacol Rev. 2011;63(4):811–59. 50 mg sildenafil by both the sublingual and supralingual 3. Gratzke C, Angulo J, Chitaley K, Dai YT, Kim NN, Paick JS, et al. routes. Anatomy, physiology, and pathophysiology of erectile dysfunc- The limited sample size (due to the exploratory nature tion. J Sex Med. 2010;7(1 Pt 2):445–75. of the study) did not permit to establish a formal bioequiva- 4. Bender AT, Beavo JA. Cyclic nucleotide phosphodiester- ases: molecular regulation to clinical use. Pharmacol Rev. lence between the two routes of administration, but the 2006;58(3):488–520. design and number of subject enrolled is deemed adequate 5. Puzzo D, Sapienza S, Arancio O, Palmeri A. Role of phosphodi- by international guidelines [14] to obtain a reliable phar- esterase 5 in synaptic plasticity and memory. Neuropsychiatr Dis macokinetic and statistical comparison between treatments. Treat. 2008;4(2):371–87. 6. Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA. Oral sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group. N Engl J Med. 1998;338(20):1397–404. 5 Conclusion 7. Nichols DJ, Muirhead GJ, Harness JA. Pharmacokinetics of silde- nafil after single oral doses in healthy male subjects: absolute bioavailability, food effects and dose proportionality. Br J Clin In conclusion, in healthy men the sublingual administration Pharmacol. 2002;53(Suppl 1):5S–12S. of sildenafil 50 mg ODF produced the same pharmacokinetic 8. Moncada I, Jara J, Subira D, Castano I, Hernandez C. Efficacy of profile as the supralingual administration. Study data con- sildenafil citrate at 12 hours after dosing: re-exploring the thera- firm the similarity between the two routes of administration, peutic window. Eur Urol. 2004;46(3):357–60 (discussion 360–1). 9. Hyland R, Roe EG, Jones BC, Smith DA. Identification of the thus suggesting that sildenafil ODF formulation, adminis- cytochrome P450 enzymes involved in the N-demethylation of tered both sublingually and supralingually, can be an effec- sildenafil. Br J Clin Pharmacol. 2001;51(3):239–48. tive and safe treatment for ED. 10. Muirhead GJ, Rance DJ, Walker DK, Wastall P. Comparative human pharmacokinetics and metabolism of single-dose oral Acknowledgements We would like to gratefully acknowledge CROSS and intravenous sildenafil. Br J Clin Pharmacol. 2002;53(Suppl Research S.A. for study coordination, Analytisch Biochemisch Labora- 1):13S–20S. torium BV (The Netherlands) for sildenafil and N -desmethyl-sildenafil 11. Walker DK, Ackland MJ, James GC, Muirhead GJ, Rance bio-analyses. DJ, Wastall P, et  al. Pharmacokinetics and metabolism of sildenafil in mouse, rat, rabbit, dog and man. Xenobiotica. Complaince with Ethical Standards 1999;29(3):297–310. 12. Viagra  (sildenafil citrate) tablets, for oral use, full prescribing Funding This study was funded by IBSA Institut Biochimique SA., information. LAB-0220-11.0, Pfizer Labs, Revised: 08/2017. Switzerland. 13. Radicioni M, Castiglioni C, Giori A, Cupone I, Frangione V, Rovati S. Bioequivalence study of a new sildenafil 100 mg oro- dispersible film compared to the conventional film-coated 100 Conflict of interest V.F. is an employee of IBSA Institut Biochimique SA, L.L., C.L. and M.R. are employees of CROSS Research S.A., 772 L. Loprete et al. mg tablet administered to healthy male volunteers. Drug Des Dev 16. Guideline on bioanalytical method validation. EMEA/CHMP/ Ther. 2017;11:1183–92. EWP/192217/2009 Rev. 1 Corr.*, 21 Jul 2011. European Medi- 14. Guidance on the investigation of bioequivalence. CPMP/EWP/ cines Agency, Committee for Medicinal Products for Human Use. QWP/1401/98 Rev. 1/Corr **, London, 20 Jan 2010. European 17. Guidance for Industry. Bioanalytical method validation. New Medicines Agency, Committee for Medicinal Products for Human York: U.S. Department of Health and Human Services Food and Use. Drug Administration; 2001. 15. Gerrits M, de Greef R, Peeters P. Effect of absorption site on the pharmacokinetics of sublingual asenapine in healthy male sub- jects. Biopharm Drug Dispos. 2010;31(5–6):351–7. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Drug Investigation Springer Journals

Pharmacokinetics of a Novel Sildenafil Orodispersible Film Administered by the Supralingual and the Sublingual Route to Healthy Men

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References (18)

Publisher
Springer Journals
Copyright
Copyright © 2018 by The Author(s)
Subject
Medicine & Public Health; Pharmacotherapy; Pharmacology/Toxicology; Internal Medicine
ISSN
1173-2563
eISSN
1179-1918
DOI
10.1007/s40261-018-0665-x
pmid
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Abstract

Background Sildenafil was the first selective drug available on the market as oral therapy for erectile dysfunction (ED). A novel sildenafil orodispersible film (ODF) for ED treatment, containing sildenafil citrate, has recently been marketed. Objectives Study objective was to investigate sildenafil bioavailability of the novel ODF formulation after sublingual and supralingual administration. Methods In this randomised, two-way cross-over study, 12 healthy male volunteers received a single 50 mg sildenafil dose by the sublingual and supralingual administration routes. Plasma sildenafil was determined up to 12 h post-dose. Peak concentration (C ) and area under concentration-time curve (AUC ) were calculated and compared between the two max 0–t administration routes by analysis of variance (ANOVA). Results Sublingual and supralingual administration can be claimed equivalent regarding the extent of sildenafil exposure since AUC 90 % CIs corresponded to 94.90–110.58% and were within the pre-specified acceptance range. C 90% CIs 0–t max (79.92–125.57%) were only slightly outside the 80.00–125.00% limits, due to the small sample size, while the time to achieve C did not differ between treatments ( p = 0.9277). Rate of exposure of the two administration routes was therefore similar. max Reported treatment-related adverse events were mild to moderate headache (33.3% of subjects) and vomiting (8.3%). Conclusions In healthy men, sublingual and supralingual administration of sildenafil ODF resulted in a remarkably similar pharmacokinetic profile and confirmed the safety of both study treatments. The recently marketed sildenafil ODF, adminis - tered by both investigated routes, can provide a valuable alternative to the marketed solid oral forms (tablets) in ED treatment. 1 Introduction Key Points Penile erection is the result of smooth muscle relaxation in In healthy men, sublingual and supralingual admin- the penis. It includes arterial dilatation, trabecular smooth istrations of sildenafil orodispersible film resulted muscle relaxation, and activation of the corporeal veno- in a remarkably similar pharmacokinetic profile and occlusive mechanism [1–3]. Erectile dysfunction (ED) is confirmed the safety of both study treatments. defined as the persistent inability to attain and maintain a penile erection sufficient to permit satisfactory sexual perfor - The recently marketed orodispersible film, admin- mance [1–3]. Phosphodiesterase type 5 (PDE5) is a regulator istered by both investigated routes, can provide a of vascular smooth muscle contraction in all smooth muscle valuable alternative to the marketed solid oral forms districts and especially in penis, and PDE5 inhibitors are (tablets) in erectile dysfunction treatment. currently the first-line therapy for ED. Sildenafil was the first selective inhibitor of cGMP-spe - cific PDE5 available on the market as oral therapy for ED * Luca Loprete [2–6]. luca.loprete@croalliance.com Sildenafil is rapidly absorbed, with maximum observed CROSS Research S.A., Via F.A. Giorgioli 14, 6864 Arzo, plasma concentrations (C ) reached within 30–120 min max Switzerland (median time 60 min) after oral administration under fasting IBSA Institut Biochimque S.A., Via del Piano, conditions. The mean absolute oral bioavailability is 41% 6915 Pambio-Noranco, Lugano, Switzerland Vol.:(0123456789) 766 L. Loprete et al. (range 25–63%). The area under the concentration–time administration. However, due to its higher vascularisation curve (AUC) and C increase proportionally with the with respect to the rest of oral cavity, the sublingual mucosa max dose over the recommended oral dose range (25–100 mg) represents a specific route of absorption, that can possibly indicating a dose-proportional rate and extent of absorp- lead to modifications in the rate, extent or subject variability tion. When sildenafil is taken after a heavy and fatty meal, of drug absorption [15]. For this reason, in the present pilot the rate of absorption is reduced with a delay in t and a study, the possibility of significant differences in sildenafil max mean reduction in C by 29% [7, 8]. The mean steady-state bioavailability after sublingual and supralingual adminis- max sildenafil volume of distribution is 105 L, indicating distri- tration of sildenafil ODF formulation was investigated. bution into the tissues. The total sildenafil body clearance The pharmacokinetics of sildenafil N -desmethyl metabo- is 41 L/h with a resultant terminal half-life (t ) of 3–5 h. lite and the safety profile of the study treatments were also 1/2 Sildenafil is cleared predominantly by the CYP3A4 (major investigated. route) and CYP2C9 (minor route) hepatic microsomal iso- enzymes. The major circulating metabolite, resulting from N-demethylation of sildenafil, has a PDE selectivity pro -2 Methods file similar to sildenafil and an in vitro potency for PDE5 approximately 50% of the parent drug. Plasma concentra- 2.1 Study Design and Procedures tions of this metabolite are approximately 40% of those found for sildenafil. The N -desmethyl metabolite is further The study protocol (code 17CH-SDF06) was approved by metabolised, with a t of approximately 4 h [9, 10]. The the Ethics Committee of Canton Ticino, Switzerland, and 1/2 drug and its major circulating N-desmethyl metabolite are the Swiss Federal Health Authorities. All subjects were bound to plasma proteins in the amount of 96% and binding given a detailed description of the study and all gave writ- is independent of total drug concentrations [7, 11]. ten informed consent before enrolment. The study was per- The good tolerability and safety profile of sildenafil for formed in accordance with the Declaration of Helsinki and treating ED was established in approximately 74 double- harmonised European standards for Good Clinical Practice blind placebo-controlled trials performed in more than 9000 (ICH E6 1.24), from November to December 2017. patients, confirming that sildenafil is well tolerated at the The study was single-centre, single-dose, open, ran- recommended dose regimen. The most commonly reported domised, two-way cross-over and was designed according adverse reactions in clinical studies among sildenafil-treated to the EMA guideline for bioequivalence studies [14]. patients were headache, flushing, dyspepsia, nasal conges - The investigational product was sildenafil ODF, a thin, tion, dizziness, nausea, hot flush, visual disturbance, cyano- flexible, opaque, light blue, orodispersible film (IBSA psia and blurred vision. Adverse reactions from post-market- Institut Biochimique S.A., Switzerland) containing 70.2 ing surveillance have been gathered covering an estimated mg of sildenafil citrate, equivalent to 50 mg of sildenafil. period > 10 years [12]. It was orally administered in two study periods, below the A novel sildenafil orodispersible film (ODF) contain- tongue (tested alternative method of administration) and ing sildenafil citrate has recently been marketed. The ODF above the tongue (the approved method of administration formulation disintegrates rapidly in the oral cavity, usually of the product), with a wash-out interval of 6 days between within few minutes, without drinking or chewing, thus pro- administrations. viding a valuable alternative to the marketed solid oral forms The study randomisation list was computer-generated by (tablets) in ED treatment. The ODF, available in 4 different the Biometry Unit of CROSS Research S.A., Switzerland, dosage forms (i.e. 25, 50, 75 and 100 mg), obtained mar- using the PLAN procedure of the SAS/STAT software ver- keting authorisation in Switzerland and several European sion 9.3. Countries in 2016 and has been very recently made available Subjects were confined at the clinical centre from the on the market. evening before administration up to 12 h post-dose and were In a previous single-dose, randomised, two-way cross- in fasting conditions for 10 h before administration and up to over Phase I study [13], the bioequivalence between the new 4 h post-dose. Water was allowed as desired, except for 1 h Sildenafil IBSA 100 mg ODF, administered supralingually, before and 1 h after dosing. In both study periods, the inves- and the marketed V iagra 100-mg film-coated tablet, Pfizer tigational product was administered on day 1 at 08:00 ± 1 h Limited UK, was proven in terms of rate and extent of silde- and under fasting conditions. The subjects took a standard- nafil absorption after single-dose administration [14]. In ised, small amount of still mineral water (20 mL) to moisten addition, no significant differences in sildenafil and N-des- the oral cavity just before the ODF intake. methyl-sildenafil t values between the two products were Thereafter, the investigator placed the investigational max observed, confirming that no significant sildenafil absorp- product either beneath the volunteer’s tongue after fold- tion differences occurred in the oral cavity after supralingual ing the ODF once (sublingual route) or directly on the PK of Supra- and Sublingual Sildenafil ODF 767 volunteer’s tongue, taking care not to fold the ODF (supra- FDA guidelines on bioanalytical method validation [16, lingual route). Once administered, after the film had dis- 17]. The method had a lower quantification limit (LQL) solved completely (without chewing), the subjects could of 0.5 ng/mL and an upper quantification limit (UQL) of swallow saliva. 2000 ng/mL for both analytes and adhered to the regu- latory requirements for selectivity, sensitivity, precision, 2.2 Subjects accuracy, recovery, carry-over, matrix effect, and stability. Internal standards for the analysis were deuterated Healthy male volunteers aged 18–45 years, with a body mass forms of the analytes (sildenafil-D and N-desmethyl index of 18.5–30.0 kg/m , were enrolled in the study. All sildenafil-D ). volunteers were in good physical health, as assessed through Calibration standards for sildenafil and for N-desmethyl full physical examination, electrocardiogram (ECG) record- sildenafil in the range from 0.500 to 2000 ng/mL were pre- ing, vital signs measurement and clinical laboratory assays, pared freshly in human Li-heparin plasma on the day of according to the study inclusion criteria. No subjects were analysis. on abnormal diets or had a history of drug, alcohol, caf- Sildenafil and N-desmethyl sildenafil QC samples at feine or tobacco abuse. Exclusion criteria included history or the levels low (1.50 ng/mL), medium 1 (75.0 ng/mL), QC presence of significant diseases, history of vision or hearing medium 2 (1000 ng/mL) and high (1600 ng/mL) were pre- problems related to drugs of the PDE5 inhibitor pharmaco- pared in a batch and stored at ≤ − 18 °C prior to the start of logical class, history of priapism; anatomical deformation the bioanalytical study. of the penis, history of ophthalmologic diseases and hyper- Isolation of sildenafil, N-desmethyl sildenafil, sildenafil- sensitivity or allergic reactions to sildenafil. Medications, D and N-desmethyl sildenafil-D from human Li-heparin 8 8 including organic nitrates, were not allowed for 4 weeks plasma was performed by liquid/liquid extraction (LLE) before the study, while over-the-counter drugs and herbal with methyl tert-butyl ether. After extraction, the organic remedies were not allowed for 2 weeks before screening. layer was evaporated to dryness under a gentle stream of Subjects were not enrolled if they had participated in other nitrogen. The residue was reconstituted in injection solvent. clinical trials or donated blood in the past 3 months. Chromatographic separation was performed on a Waters XTerra MS C18 column using gradient elution. An API 2.3 Blood Sampling 4000 tandem mass spectrometry equipped with a turbo spray ionization source operating in the positive multiple reaction Blood samples for sildenafil and N -desmethyl-sildenafil monitoring mode was used for quantification. measurements were collected at pre-dose (0) and 6, 15, 30, Data acquisition was performed using Analyst software 45 min and 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 8, 12 h post-dose. (version 1.6.2) from AB Sciex. Following peak area integra- Sampling time points were selected based on previously tion, regression was also performed using Analyst. Concen- reported data [13]. trations were calculated using 13-point curves with weighted Blood samples were collected using an indwelling cath- linear regression. eter with switch valve. The cannula was rinsed, after each sampling, with about 1 mL of sterile saline solution con- taining 20 IU/mL Na-heparin. The first 2 mL of blood were 2.5 Pharmacokinetic Parameters discarded at each collection time to avoid contamination of the sample with heparin. The remaining 8 mL were col- Pharmacokinetic parameters were determined or calculated lected from the catheter and transferred with a syringe into using the validated software Phoenix W inNonLin 6.3 heparinised tubes (Li-heparin). The samples were stored on (Certara, Inc). The primary study outcome measures were ice for a maximum of 20 min and then centrifuged at 4 °C plasma sildenafil peak concentration (C ), time to C max max for 10 min at 2500g to obtain plasma. Each plasma sample (t ) and area under the concentration–time curve up to max was immediately transferred into pre-labelled polypropylene the last sampling point (AUC ) and extrapolated to infinity 0–t tubes, and stored frozen at ≤ − 20 °C. (AUC ), calculated using the linear trapezoidal rule. The 0–∞ primary end-point of the study was the evaluation of the 2.4 Bioanalytical Assay similarity of the two administration routes in terms of rate (C and t ) and extent (AUC ) of plasma sildenafil con- max max 0–t Concentrations of sildenafil and N -desmethyl sildena- centration. The following sildenafil pharmacokinetic param- fil in plasma were determined by a blinded analyst at eters were also calculated: terminal volume of distribution Analytisch Biochemisch Laboratorium BV (ABL), the (V /F), total clearance (Cl/F) and half-life (t ). The same z ½ Netherlands, using a LC–MS/MS method developed and pharmacokinetic parameters were also calculated for the validated according to the requirements of the EMA and metabolite N-desmethyl-sildenafil, except for V /F and Cl/F. z 768 L. Loprete et al. 2.6 Safety Table 1 Demographic data of study subjects (N = 12) Parameter Value The safety profile of the investigational product was assessed by evaluating treatment-emergent adverse events (AEs), Sex, [n (%)]  Male 12 (100.0%) physical examination, ECG, routine laboratory tests and vital signs checks. Vital signs (blood pressure and heart Race, [n (%)]  Black 1 (8.3%) rate) were measured at screening, final visit, and on day 1  White 11 (91.7%) of each study period at pre-dose, 1.75, and 5 h post-dose. Age (years) A 12-lead resting ECG was recorded at screening and final  Mean ± SD 36.2 ± 5.2 visit. Blood and urine samples were collected for routine  Range 23–45 haematology, blood chemistry, virology and urinalysis at Height (cm) screening and final visit. AEs were assessed throughout the  Mean ± SD 176.9 ± 5.7 study and were coded using MedDRA version 20.1. A full  Range 167–187 physical examination was performed by the investigator at Body weight (kg) screening and at the final visit.  Mean ± SD 79.5 ± 7.1  Range 68.5–88.4 2.7 Sample Size and Statistical Analyses Body mass index (kg/m )  Mean ± SD 25.5 ± 2.9  Range 19.6–29.3 Twelve healthy men were included in the study. The sample size was not based on any statistical evaluation, considering SD standard deviation the exploratory purpose of the study. The statistical analyses were performed using S AS software version 9.3 (TS1M1) for Windows and Phoenix WinNonLin 6.3, Certara Inc. Fig.  1 for sildenafil and in Fig.  2 for the N-desmethyl- A classical bioequivalence test was used for the compari- sildenafil metabolite. son of sildenafil and N -desmethyl-sildenafil pharmacokinetic The main plasma pharmacokinetic parameters data parameters [14]. Log-transformed C , AUC and AUC max 0–t 0–∞ (mean ± SD) and the results of their statistical compari- were analysed by ANOVA, with treatment, period, sequence sons are presented in Table 2 for sildenafil and in Table  3 and subject-within-sequence as x fi ed ee ff cts. Similarity crite - for N-desmethyl-sildenafil. rion was a geometric means ratio (PE) around 100 % and its 90 Maximum plasma concentration (C ) of sildenafil was max % confidence interval (CI) within the range 80.00–125.00%. 296.50 ± 142.69 ng/mL for the sublingual route (test) and Wilcoxon signed-rank test was used to analyse t . max 288.92 ± 118.78 ng/mL for the supralingual route (refer- ence). The peak concentration was rapidly reached, at a similar median time for the two study treatments (i.e. 0.63 3 Results and 0.75 h for the test and reference treatments, respec- tively). Both the terminal volume of distribution and the 3.1 Subjects total clearance (see Table 2) were almost the same for the two administration routes. Plasma concentrations declined Nineteen subjects were screened and twelve were ran- rapidly after C with nearly identical half-lives, i.e. 2.55 max domised in the study. They received the treatment by the ± 0.26 h and 2.69 ± 0.32 h for the sublingual and supralin- allocated route of administration, completed the study per gual administration routes, respectively. AUC values were 0–t protocol and were included in the pharmacokinetic and 761.72 ± 217.71 h∙ng/mL for the test treatment and 750.76 safety analyses. Demographic characteristics of the analysed ± 246.10 h∙ng/mL for the reference. AUC too was very 0–∞ subjects are presented in Table 1. similar for the two treatments, corresponding to 798.78 ± All subjects were in good physical and mental health, 227.68 and 793.44 ± 269.63 h∙ng/mL for the sublingual based on physical examination, medical and surgical history. and supralingual administration routes, respectively. The ratios of test/reference geometric means (point estimate, PE 3.2 Pharmacokinetics %) were 100.18, 102.44 and 102.13% for sildenafil C , max AUC and AUC respectively, with their correspond- 0–t 0–∞, The mean ± standard deviation (SD) plasma concentra- ing 90% CIs within the pre-specified acceptance limits for tion-time profiles obtained after sildenafil administration AUC (94.90–110.58%) and AUC (94.58–110.29%) 0–t 0–∞ by the sublingual and supralingual routes are shown in PK of Supra- and Sublingual Sildenafil ODF 769 Fig. 1 Mean (+ SD) plasma sildenafil concentration (ng/mL) versus time profiles after single administration of sildenafil 50 mg orodispersible film by sub- lingual and supralingual route. Linear scale N = 12 Fig. 2 Mean (+ SD) plasma N-desmethyl-sildenafil con- centration (ng/mL) versus time profiles after single administra- tion of sildenafil 50 mg orodis- persible film by sublingual and supralingual route. Linear scale N = 12 and only just slightly outside the 80–125% range for C 3.3 Safety max (79.92–125.57%). N-desmethyl-sildenafil metabolite AUC and AUC Both tested treatments showed a good safety profile and no 0–t 0–∞ values were, on average, similar following administration of serious AEs were reported. Four subjects (33.3%) reported the two treatments (see Table 3) and their 90% CI fell within mild-to-moderate headache and one subject (8.3%) experi- the limits of 80.00–125.00%. Extent of N-desmethyl-sildena- enced vomiting during the study. These AEs were deemed fil exposure was therefore equivalent when the investigational by the Investigator as possibly related to study treatments. product was administered sublingually and supralingually. No clinically relevant effects on vital signs, ECGs or labo- After sublingual administration, N-desmethyl-sildenafil ratory parameters were observed. metabolite C was approximately 10% higher compared to max the supralingual route (PE %: 109.75%). On the other hand, the metabolite t and t were nearly identical for the two max ½ administration routes. 770 L. Loprete et al. Table 2 Sildenafil pharmacokinetic parameters and statistical analysis results after single administration of sildenafil 50 mg orodispersible film by sublingual and supralingual route N = 12 Sildenafil Pharmacokinetic parameter Sublingual route (test) Supralingual route (refer- PE % 90% CI (%) ence) C (ng/mL), mean ± SD 296.50 ± 14 2.69 288.92 ± 118.78 100.18 79.92–125.57 max t (h) , median (range) 0.63 (0.50–2.00) 0.75 (0.25–1.50) max AUC (h∙ng/mL), mean ± SD 761.72 ± 217.71 750.76 ± 246.10 102.44 94.90–110.58 0–t AUC (h∙ng/mL), mean ± SD 798.78 ± 227.68 793.44 ± 269.63 102.13 94.58–110.29 0–∞ V /F (L), mean ± SD 255.35 ± 107.88 266.46 ± 75.55 Cl/F (L/h), mean ± SD 68.50 ± 23.90 70.87 ± 27.00 t (h), mean ± SD 2.55 ± 0.26 2.69 ± 0.32 AUC area under the concentration–time curve from time 0 to the last observed concentration time t, CI confidence interval, Cl/F total clear - 0–t ance after oral administration, C maximum plasma concentration, PE ratio test/reference of geometric means, SD standard deviation, t termi- max ½ nal half-life, t time to achieve maximum plasma concentration, V /F terminal volume of distribution after oral administration max z Comparison between sublingual and supralingual route by Wilcoxon signed-rank test: p = 0.9277 Table 3 N-desmethyl-sildenafil pharmacokinetic parameters and statistical analysis results after single administration of sildenafil 50 mg orodis- persible film by sublingual and supralingual route N = 12 N-desmethyl-sildenafil Pharmacokinetic parameter Sublingual route (test) Supralingual route (refer- PE % 90% CI (%) ence) C (ng/mL), mean ± SD 42.58 ± 17.20 37.38 ± 11.15 109.75 92.73–129.90 max t (h) , median (range) 1.13 (0.50–2.00) 1.00 (0.50–2.50) max AUC (h∙ng/mL), mean ± SD 121.58 ± 33.17 117.69 ± 25.68 102.09 91.21–114.28 0–t AUC (h∙ng/mL), mean ± SD 138.51 ± 38.22 133.73 ± 35.94 103.43 93.35–114.59 0–∞ t (h), mean ± SD 4.10 ± 1.37 4.07 ± 1.28 AUC area under the concentration–time curve from time 0 to the last observed concentration time t, CI confidence interval, C maximum 0–t max plasma concentration, PE ratio test/reference of geometric means, SD standard deviation, t terminal half-life, t time to achieve maximum ½ max plasma concentration Comparison between sublingual and supralingual route Wilcoxon signed-rank test: p = 1.0000 outside the pre-specified limits for the peak concentra- 4 Discussion tion, due to a high within-subject variability and the lim- ited number of subjects in the study. The nearly identical A sildenafil ODF containing sildenafil citrate has recently t , volume of distribution, total clearance and t values been marketed to meet the rising interest for sildenafil for - max ½ obtained with the two administration routes confirmed mulations able to dissolve very rapidly in the oral cavity that sildenafil presented the same absorption, distribution without drinking or chewing, and to provide a more practi- and elimination kinetics after sublingual and supralingual cal and user-friendly alternative to the marketed products dosing. for the treatment of ED. A comparison of the present results with the literature Mean sildenafil plasma concentration-time profiles data [13], obtained after supralingual administration of the up to 12 h after single-dose sublingual and supralingual sildenafil 100 mg ODF during a bioequivalence study versus administration were nearly superimposable. The ratio of Viagra 100 mg, showed similar rate and extent of exposure. test/reference geometric means was very close to 100% for The data obtained in the present study and previously in sildenafil C , AUC and AUC , indicating a compa- max 0–t 0–∞ the bioequivalence study between the ODF formulation and rable rate and extent of sildenafil exposure with the two Viagra film-coated tablets [13] indicated that the absorp- treatments. The 90% CIs were within the equivalence lim- tion of sildenafil in the mucosa of the oral cavity was neg- its of 80.00–125.00% for the two AUCs and just slightly ligible and had no significant impact on the drug kinetics. PK of Supra- and Sublingual Sildenafil ODF 771 which was contracted by IBSA Institut Biochimique SA as CRO for the After the complete dissolution of the ODF in the mouth, conduction of this study and received financial support for its services. sildenafil was likely swallowed and absorbed further down The authors declare that they have no other relationships or activities in the gastro-intestinal tract, regardless of the place of disag- that could appear to have influenced the submitted work. gregation (sublingual or supralingual) of the film. Ethical approval The study protocol (code 17CH-SDF06) was The 90% CIs for N-desmethyl sildenafil AUCs fell within approved by the Ethics Committee of Canton Ticino, Switzerland, and the limits of 80.00–125.00%, and therefore the two admin- the Swiss Federal Health Authorities. istration routes were also equivalent with respect to the extent of metabolite exposure. The peak metabolite plasma Informed consent All subjects provided written informed consent before enrolment. concentration was slightly different between the two treat- ments, likely due to the small sample size considered. The sublingual route of administration showed a 10% higher C Open Access This article is distributed under the terms of the Crea- max tive Commons Attribution-NonCommercial 4.0 International License and, consequently, the 90% CI did not fall within the accept- (http://creativecommons.org/licenses/by-nc/4.0/), which permits any ance limits of 80.00–125.00%. However, the metabolite t max noncommercial use, distribution, and reproduction in any medium, and t values were nearly identical (p = 1.0000) for the two provided you give appropriate credit to the original author(s) and the administration methods, confirming that both the forma- source, provide a link to the Creative Commons license, and indicate if changes were made. tion rate and the elimination rate of the metabolite were not significantly different. Considering that N -desmethyl silde- nafil had a peak concentration less than 15% of its parent References compound and 40% of its biological activity, the difference between the two administration routes in the metabolite C max 1. Yafi FA, Jenkins L, Albersen M, Corona G, Isidori AM, Goldfarb value can be considered clinically not significant. S, et al. Erectile dysfunction. Nat Rev Dis Primers. 2016;2:16003. Safety data confirmed a favourable safety profile of the 2. Andersson KE. Mechanisms of penile erection and basis for phar- investigational product, administered as single oral dose of macological treatment of erectile dysfunction. Pharmacol Rev. 2011;63(4):811–59. 50 mg sildenafil by both the sublingual and supralingual 3. Gratzke C, Angulo J, Chitaley K, Dai YT, Kim NN, Paick JS, et al. routes. Anatomy, physiology, and pathophysiology of erectile dysfunc- The limited sample size (due to the exploratory nature tion. J Sex Med. 2010;7(1 Pt 2):445–75. of the study) did not permit to establish a formal bioequiva- 4. Bender AT, Beavo JA. Cyclic nucleotide phosphodiester- ases: molecular regulation to clinical use. Pharmacol Rev. lence between the two routes of administration, but the 2006;58(3):488–520. design and number of subject enrolled is deemed adequate 5. Puzzo D, Sapienza S, Arancio O, Palmeri A. Role of phosphodi- by international guidelines [14] to obtain a reliable phar- esterase 5 in synaptic plasticity and memory. Neuropsychiatr Dis macokinetic and statistical comparison between treatments. Treat. 2008;4(2):371–87. 6. Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA. Oral sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group. N Engl J Med. 1998;338(20):1397–404. 5 Conclusion 7. Nichols DJ, Muirhead GJ, Harness JA. Pharmacokinetics of silde- nafil after single oral doses in healthy male subjects: absolute bioavailability, food effects and dose proportionality. Br J Clin In conclusion, in healthy men the sublingual administration Pharmacol. 2002;53(Suppl 1):5S–12S. of sildenafil 50 mg ODF produced the same pharmacokinetic 8. Moncada I, Jara J, Subira D, Castano I, Hernandez C. Efficacy of profile as the supralingual administration. Study data con- sildenafil citrate at 12 hours after dosing: re-exploring the thera- firm the similarity between the two routes of administration, peutic window. Eur Urol. 2004;46(3):357–60 (discussion 360–1). 9. Hyland R, Roe EG, Jones BC, Smith DA. Identification of the thus suggesting that sildenafil ODF formulation, adminis- cytochrome P450 enzymes involved in the N-demethylation of tered both sublingually and supralingually, can be an effec- sildenafil. Br J Clin Pharmacol. 2001;51(3):239–48. tive and safe treatment for ED. 10. Muirhead GJ, Rance DJ, Walker DK, Wastall P. Comparative human pharmacokinetics and metabolism of single-dose oral Acknowledgements We would like to gratefully acknowledge CROSS and intravenous sildenafil. Br J Clin Pharmacol. 2002;53(Suppl Research S.A. for study coordination, Analytisch Biochemisch Labora- 1):13S–20S. torium BV (The Netherlands) for sildenafil and N -desmethyl-sildenafil 11. Walker DK, Ackland MJ, James GC, Muirhead GJ, Rance bio-analyses. DJ, Wastall P, et  al. Pharmacokinetics and metabolism of sildenafil in mouse, rat, rabbit, dog and man. Xenobiotica. Complaince with Ethical Standards 1999;29(3):297–310. 12. Viagra  (sildenafil citrate) tablets, for oral use, full prescribing Funding This study was funded by IBSA Institut Biochimique SA., information. LAB-0220-11.0, Pfizer Labs, Revised: 08/2017. Switzerland. 13. Radicioni M, Castiglioni C, Giori A, Cupone I, Frangione V, Rovati S. Bioequivalence study of a new sildenafil 100 mg oro- dispersible film compared to the conventional film-coated 100 Conflict of interest V.F. is an employee of IBSA Institut Biochimique SA, L.L., C.L. and M.R. are employees of CROSS Research S.A., 772 L. Loprete et al. mg tablet administered to healthy male volunteers. Drug Des Dev 16. Guideline on bioanalytical method validation. EMEA/CHMP/ Ther. 2017;11:1183–92. EWP/192217/2009 Rev. 1 Corr.*, 21 Jul 2011. European Medi- 14. Guidance on the investigation of bioequivalence. CPMP/EWP/ cines Agency, Committee for Medicinal Products for Human Use. QWP/1401/98 Rev. 1/Corr **, London, 20 Jan 2010. European 17. Guidance for Industry. Bioanalytical method validation. New Medicines Agency, Committee for Medicinal Products for Human York: U.S. Department of Health and Human Services Food and Use. Drug Administration; 2001. 15. Gerrits M, de Greef R, Peeters P. Effect of absorption site on the pharmacokinetics of sublingual asenapine in healthy male sub- jects. Biopharm Drug Dispos. 2010;31(5–6):351–7.

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Clinical Drug InvestigationSpringer Journals

Published: Jun 16, 2018

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