Pharmacokinetics of a Novel Orodispersible Tablet of Sildenafil in Healthy Subjects

Clinical Therapeutics/Volume 36, Number 2, 2014 Pharmacokinetics of a Novel Orodispersible Tablet of Sildenafil in Healthy Subjects Bharat Damle, PhD 1 ; Gregory Duczynski, MS 2 ; Barrett W. Jeffers, PhD 1 ; Penelope Crownover, MS 1 ; Alastair Coupe, PhD 3 ; and Robert R. LaBadie, MPh 2 1 Pfizer Inc, New York, New York; 2 Pfizer Inc, Groton, Connecticut; and 3 Pfizer Ltd, Sandwich, Kent, United Kingdom ABSTRACT Background: Sildenafil citrate is indicated for the treatment of erectile dysfunction. An orally disintegrating tablet (ODT) of sildenafil citrate has been developed for the benefit of patients who have difficulty swallowing solid dosage forms. Objective: The main goal of this study was to evaluate the bioequivalence of sildenafil ODT with and without water versus marketed sildenafil oral film-coated tablets. A secondary objective was to evaluate the effects of a high-fat meal on the pharmacokinetics of sildenafil ODT. Methods: The bioequivalence study of sildenafil ODT given with and without water versus marketed sildenafil citrate film-coated oral tablets was conducted in 36 subjects. In a food-effect study, the effect of a standard high-fat meal on the pharmacokinetics of sildenafil ODT was evaluated in 12 subjects. Both studies were randomized, open-label, crossover, single-dose (50 mg) studies in healthy men aged Z45 years. Plasma samples were collected for 14 hours postdose, and pharmacokinetics were determined by using noncompartmental analyses. Results: All subjects in both studies were Asian males between the ages of 45 and 69 years. Sildenafil ODT without water was bioequivalent to the marketed sildenafil film-coated oral tablet as the 90% CI for the ratio of geometric means of C max, AUC 0 1, and AUC 0 last were contained within equivalence limits (80% 125%). When sildenafil ODTs were given with water, the 90% CIs for sildenafil AUC 0 1 and AUC 0 last were contained within the range of 80% to 125%; however, the 90% CI for sildenafil C max was not (79.76 92.78). This difference in C max is unlikely to have any clinically meaningful impact. High-fat meals reduced the rate but not the extent of absorption of sildenafil. Mean C max was reduced by 59%, and median T max was delayed from 0.625 hour (fasting) to 4 hours (high-fat meal). However, AUC values were comparable between fed and fasted treatments. Conclusions: Sildenafil ODT, given with or without water, provides equivalent systemic exposure compared with marketed sildenafil film-coated oral tablets, thus offering a convenient alternative method of administration. Considering the results of the food-effect study, sildenafil ODT should be taken on an empty stomach. ClinicalTrials.gov identifiers: NCT01254383 (bioequivalence) and NCT01254396 (food effect). (Clin Ther. 2014;36:236 244) & 2014 Elsevier HS Journals, Inc. All rights reserved. Key words: orodispersible tablet, pharmacokinetics, sildenafil. INTRODUCTION Sildenafil, a competitive and selective inhibitor of cyclic guanosine monophosphate specific phosphodiesterase type 5, is indicated for the treatment of erectile dysfunction. Sildenafil citrate film-coated oral tablets* are approved for the treatment of erectile dysfunction at the doses of 25, 50, and 100 mg. For most patients, the recommended dose is 50 mg to be taken 1 hour before sexual activity. Based on efficacy and tolerability, the dose may be increased to 100 mg or decreased to 25 mg. 1 After oral administration of the sildenafil 100-mg film-coated oral tablet in the fasted state, sildenafil is rapidly absorbed, reaching peak plasma concentration within * Trademark: Viagra s (Pfizer Inc, New York, New York). Accepted for publication December 10, 2013. http://dx.doi.org/10.1016/j.clinthera.2013.12.010 0149-2918/$ - see front matter & 2014 Elsevier HS Journals, Inc. All rights reserved. 236 Volume 36 Number 2

B. Damle et al. 30 to 120 minutes (median, 60 minutes). Mean terminal t ½ is 4 hours. When sildenafil is taken with a high-fat meal, the rate of absorption is reduced, with a mean delay in T max of 60 minutes and a mean reduction in C max of 29%. 2 Oral administration of medication is reliant on the patient s ability to safely swallow the dosage form and can be problematic for individuals who have difficulty swallowing solid oral formulations. Epidemiologic studies indicate that the prevalence of dysphagia may be as high as 22% in patients aged 450 years. 3 Therefore, there is considerable interest in providing patients a dosage form of sildenafil in addition to the conventional tablets. For example, a chewable tablet of sildenafil has been developed and is approved for use in Mexico, 4 and a sublingual formulation 5 and an orally disintegrating film 6 of sildenafil have also been described in the literature. An orally disintegrating tablet (ODT) formulation of sildenafil citrate for the treatment of erectile dysfunction has been developed. It is desirable for prescribers to have the option of alternative oral dosage forms that are easier for patients to swallow and, in this respect, rapidly disintegrating ODTs offer administration benefit and convenience for patients. This additional dosage form could benefit patients who have difficulty swallowing conventional solid oral dosage forms. Sildenafil ODT would also provide a convenient and discreet method for administration and would benefit patients who have a restriction on daily fluid intake (eg, patients with renal impairment, congestive heart failure, endocrine system, and adrenal gland disorders) because it eliminates the need for administration with fluids. ODTs disperse rapidly when placed in the mouth, allowing the constituents to be easily swallowed. The present article describes the bioequivalence and food-effect studies conducted to support the registration of sildenafil ODT tablets. SUBJECTS AND METHODS Study Design This bioequivalence study was a randomized, openlabel, 3-treatment, 3-period, single-dose crossover study in healthy male subjects. Thirty-six subjects were enrolled in the study and randomly assigned to 1 of 6 treatment sequences to receive each of the following 3 treatments, in random order, with a minimum 1-day washout period between successive doses: sildenafil 50 mg film-coated oral tablet, administered with 240 ml of water under fasted conditions (reference treatment); sildenafil ODT 50 mg without water under fasted conditions (test treatment); or sildenafil ODT 50 mg with water under fasted conditions (test treatment). For all 3 treatments, subjects were asked to fast overnight for at least 10 hours followed by a 4-hour fast after dosing. In the sildenafil ODT 50 mg without water condition, subjects were allowedtowettheirmouthbyswallowing20mlof water directly before placing the ODT on the tongue, and water was allowed beginning 1 hour after dosing. In the sildenafil ODT 50 mg with water condition, subjects were asked to allow the tablet to disintegrate completely in their mouth before drinking 240 ml of water. The food-effect study was a randomized, openlabel, 2-treatment, 2-period, single-dose, crossover study in healthy male subjects. Twelve subjects were enrolled in the study and randomly assigned to 1 of the 2 treatment sequences to receive each of the following treatments, in random order, with a minimum 1-day washout period between successive doses: sildenafil ODT 50 mg without water under fasted conditions (reference treatment) and sildenafil ODT 50 mg without water under fed conditions (test treatment). In the fed condition, dosing was undertaken within 5 minutes after completion of a standard high-fat breakfast consisting of 1000 calories, with 50% of calories from fat, consumed over a 25-minute period. For both treatments in the food-effect study, subjects were allowed to wet the mouth by swallowing 20 ml of water directly before placing the ODT on the tongue, and water was allowed to be consumed without restriction beginning 1 hour after dosing. In both studies, serial blood samples (6 ml each) were collected during each period at the following time points: predose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 14 hours postdose. Plasma samples were analyzed for sildenafil and its active metabolite (UK-103,320). Safety was monitored by assessing adverse events (throughout the study and for 28 days after the final dose), clinical laboratory test results (hematology, blood chemistry, and urinalysis), vital signs (pulse rate and blood pressure; assessed predose and at 0.5, 1, and 14 hours postdose), and ECGs. In addition, inspection of the oral cavity for irritation and other treatment-emergent oral abnormalities was performed predose and at 0.5, 1, 4, and 14 hours postdose. Because this was a single-dose, pharmacokinetic, February 2014 237

Clinical Therapeutics crossover study, no visual function tests were performed, and routine safety evaluation was considered adequate for the study. Study Population Subjects eligible to participate in both studies were healthy men aged Z45 years with or without erectile dysfunction. Because the majority of patients who require sildenafil are older adults, the lower end of the age of subjects enrolled in the study was 45 years. Subjects were required to have a body mass index of 17.5 to 32.5 kg/m 2 and a total weight 450 kg. Healthy subjects were defined as having no clinically relevant abnormalities identified by a detailed medical history, full physical examination, 12-lead ECG, and clinical laboratory tests. Considering the age of the study population, the following conditions that would not alter the absorption or safety profile of sildenafil were allowed at the investigator s discretion: hypercholesterolemia, systolic blood pressure up to 150 mm Hg, and mild diabetes controlled by diet alone. Subjects provided written informed consent before initiation of any study-related procedures. These studies were conducted at the Pfizer Clinical Research Unit in Singapore. The protocols were approved by the Singapore General Hospital ethics committee, and the studies were conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonisation Good Clinical Practice guidelines. In addition, all local regulatory requirements were followed. Pharmacokinetic Analyses Pharmacokinetic blood samples were centrifuged at 1700 g for 10 minutes at 41C. The plasma was stored in appropriately labeled screw-capped polypropylene tubes at 201C within 1 hour of collection. Bioanalytical assays were conducted at Covance Bioanalytical Service (Shanghai, China). Sildenafil and UK-103,320 samples were assayed by using a validated, sensitive, and specific HPLC-MS/MS method. 7 Calibration standard responses were linear over the range of 1.00 to 500 ng/ml. The lower limit of quantitation for sildenafil and UK-103,320 was 1.00 ng/ml. For the sildenafil assay, the accuracy (percent difference from nominal) of the quality control samples used during sample analysis ranged from 0.1% to 3.0% and 2.3% to 8.0% with a precision (as measured by percent relative SD) of r5.1% and r9.8% for the bioequivalence and food-effect studies, respectively. The pharmacokinetics of sildenafil and its metabolite were determined by standard noncompartmental methods using an internal validated software system (enca version 2.2.2; Pfizer Inc, New York, New York). The determination of C max and T max was based on observed data. AUC 0 last was determined by using the linear-log trapezoidal method; k e was estimated by linear regression of the linear portion of the log concentration versus time curve. AUC 0 1 was calculated as the sum of AUC 0 last and last observed concentration/k e. The t ½ was calculated as ln(2)/k e. Statistical Analyses Sample size determinations for both studies were based on the variability observed from 4 previous studies of the pharmacokinetics of the ODT formulation (ClinicalTrials.gov identifiers: NCT00866463, NCT00795938, NCT00950404, and NCT01027117); the mean within-subject SDs obtained from these 4 studies were 0.125 and 0.235 for log e AUC 0 t and log e C max, respectively. For the bioequivalence study, a sample size of 36 subjects was required to provide sufficient power (99% power for AUC 0 last, 91% power for C max ) so that 90% CIs for the ratio of test-toreference treatment would lie between 80% and 125% (acceptance region). Consequently, the study had at least 90% power overall to demonstrate bioequivalence (ie, equivalence in both AUC 0 last and C max )inwhich overall study power was based on the product of the individual powers of each parameter. For the foodeffect study, a sample size of 12 subjects was required to have adequate precision to document the magnitude of the known food effect. This sample size provides 90% probability that the 90% CIs between treatments will be within 0.1169 and 0.2199 (on the natural log scale) for AUC 0 last and C max, respectively. For each study separately, ln-transformed AUC 0 last, AUC 0 1 (if data permitted), and C max of sildenafil were analyzed by using a mixed-effects model with sequence, period, and treatment as fixed effects and subject within sequence as a random effect. Estimates of the mean differences (test treatment reference treatment) and corresponding 90% CIs were obtained from the model. The mean differences and 90% CIs for the differences were exponentiated to provide estimates 238 Volume 36 Number 2

B. Damle et al. of the ratio of geometric means (test treatment/reference treatment) and 90% CIs for the ratios. For the bioequivalence study, bioequivalence of the test treatment (sildenafil ODT without water) relative to the reference treatment (sildenafil film-coated tablet with water) was to be concluded if the 90% CI for the ratio of geometric means for both AUC 0 last, AUC 0 1, and C max fell wholly within the acceptance range (80% 125%). In addition, relative bioavailability was to be estimated as the ratio of geometric means for the test treatment (sildenafil ODT with water) relative to the reference treatment (sildenafil film-coated tablet with water) for AUC 0 last and C max. The pharmacokinetic parameters AUC 0 last, AUC 0 1, C max, T max, and t ½ were summarized descriptively according to treatment and analyte (sildenafil and its metabolite UK-103,320). For the food-effect study, the food effect was to be estimated as the ratio of geometric means for the test treatment (sildenafil ODT with food) relative to the reference treatment (sildenafil ODT under fasted conditions) for AUC 0 last and C max. The pharmacokinetic parameters AUC 0 last, AUC 0 1,C max,t max, and t ½ were summarized descriptively according to treatment and analyte (sildenafil and its metabolite UK- 103,320). RESULTS Study Population In the bioequivalence study, 36 subjects were enrolled and completed the study as planned. All subjects were Asian, male, and between the ages of 45 and 66 years (mean age, 51.3 years). The mean body mass index was 24.7 kg/m 2 (range, 19.2 32.4 kg/m 2 ). In the food-effect study, 12 subjects were enrolled and completed the study as planned. All subjects were Asian, male, and between the ages of 47 and 69 years (mean age, 56.6 years). The mean body mass index was 24.8 kg/m 2 (range, 19.9 32.2 kg/m 2 ). Pharmacokinetics Bioequivalence Study The mean (SD) concentration time profiles for sildenafil are shown in Figure 1. The mean sildenafil plasma concentration time profiles for all 3 treatments were essentially overlapping. The corresponding pharmacokinetic parameters are provided in Table I. Systemic exposure (C max and AUC) of sildenafil and its Mean Plasma Concentration (ng/ml) 300 250 200 150 100 50 0 Sildenafil 0 2 4 6 8 Time Postdose (h) ODT with water 10 12 14 Figure 1. Mean plasma concentration time profile for sildenafil (solid lines) and its metabolite, UK-103,320 (dashed lines), after administration of a 50-mg dose of sildenafil film-coated tablets and sildenafil orally disintegrating tablets (ODTs) given with or without water in the bioequivalence study. metabolite were comparable across the 3 treatments. Median T max values were also comparable across all treatments, with a median T max of 0.75 hour. Mean terminal t ½ was 3 hours for all treatments. The variability for C max and AUC, based on %CV, was generally similar for all treatments (32% 44%). The protocol-specified bioequivalence criteria were met for sildenafil ODT given without water relative to sildenafil film-coated tablets because all the 90% CIs for the ratios of geometric means of sildenafil C max, AUC 0 1, and AUC 0 last were entirely contained within the equivalence interval of 80% to 125% (Table I). When sildenafil ODT was given with water, the 90% CIs for the ratios of geometric means of sildenafil AUC 0 1 and AUC 0 last were both entirely contained within the equivalence interval of 80% to 125%. The 90% CI for the geometric mean ratio for sildenafil C max (79.76 92.78) fell outside the limits for the lower boundary of 80%. The concentration time profiles for the metabolite UK-103,320 were generally similar for all 3 treatments and almost superimposable on each other (Figure 1). Consistent with sildenafil, the systemic exposure (C max and AUC) of UK-103,320 was February 2014 239

Clinical Therapeutics Table I. Summary of pharmacokinetic parameters in the bioequivalence study. Values are given as geometric mean (%CV) for all except median (range) for T max and arithmetic mean (%CV) for t ½. Parameter Sildenafil Film-Coated Tablet (N ¼ 36) * Sildenafil ODT: Without Water (N ¼ 36) Sildenafil ODT: With Water (N ¼ 36) Sildenafil AUC 0 1,ng h/ml 846.3 (37) 890.8 (37) 840.4 (37) Ratio (90% CI) 105.27 (100.98 109.74) 99.31 (95.26 103.52) AUC 0 last,ng h/ml 823.4 (36) 860.9 (36) 813.5 (36) Ratio (90% CI) 104.55 (100.25 109.03) 98.80 (94.74 103.03) C max, ng/ml 296.9 (32) 271.8 (44) 255.4 (33) Ratio (90% CI) 91.54 (84.87 98.72) 86.03 (79.76 92.78) T max, h 0.750 (0.250 2.00) 0.750 (0.250 2.00) 0.750 (0.250 1.50) t ½, h 3.012 (15) 3.104 (14) 2.990 (14) UK-103,320 AUC 0 1,ng h/ml 555.4 (39) 538.2 (38) 534.2 (40) AUC 0 last,ng h/ml 517.2 (37) 502.3 (36) 496.4 (39) C max, ng/ml 158.2 (29) 132.2 (31) 135.2 (30) T max, h 0.750 (0.500 2.00) 1.00 (0.500 3.00) 0.750 (0.500 2.00) t ½, h 4.061 (23) 3.848 (20) 4.078 (20) *n ¼ 35 and n ¼ 34 for AUC 0 1 and t ½ of sildenafil and UK-103,320, respectively. n ¼ 34 for AUC 0 1 and t ½ of UK-103,320. Ratio of geometric mean (90% CI) for test treatment (sildenafil orally disintegrating tablet [ODT] with or without water) versus reference treatment (sildenafil film-coated tablet with water). similar across all 3 treatments (Table I). Median T max values were comparable across treatments, with a range of 0.75 to 1.00 hour. Terminal t ½ was similar across treatments, with a mean value of 4 hours. Food-Effect Study The mean (SD) plasma sildenafil concentration time profiles after administration of sildenafil ODT under fed and fasted conditions are displayed in Figure 2. As evident by the shift in the profile, the rate of sildenafil absorption was slower in the presence of food compared with fasted conditions. Because T max was delayed with food, estimates of t ½ and AUC 0 1 under fed conditions could not be reliably obtained in some subjects due to a lack of data during terminal elimination. After attainment of C max, the median sildenafil plasma concentration time profiles for both regimens (with and without food) seemed to decline in a parallel manner. The AUC values seemed to be similar between treatments; however, sildenafil C max was considerably reduced when ODT was given with a high-fat meal compared with fasted conditions (Table II). Median T max under fasted conditions was 0.625 hour, which was delayed to 4.00 hours when the ODT was given with a high-fat meal. Betweensubject variability estimates for AUC 0 1 (%CV, 23% 34%), AUC 0 last (%CV, 22% 33%), and C max (%CV, 31% 44%) were similar between fed and fasted treatments. For the comparison of sildenafil ODT fed versus fasted treatments, the ratio (90% CI) of the geometric mean for AUC 0 1 and AUC 0 last was 93.42% (80.23 108.78) and 87.66% (77.62 98.99), respectively; for C max, it was 41.35% (32.40 52.76) (Table II). The mean plasma UK-103,320 concentration time profiles after fed and fasted treatments are shown in Figure 2. Consistent with sildenafil, the appearance of UK-103,320 in plasma was slower in the presence of food compared with under fasted conditions. Median T max was delayed from 0.750 hour when fasted to 4.00 hours under fed conditions (Table II). The C max of UK-103,320 was considerably lower with food 240 Volume 36 Number 2

B. Damle et al. Mean Plasma Concentration (ng/ml) 250 200 150 100 50 0 ODT fasted ODT with high-fat meal 0 2 4 6 8 10 12 14 Time Postdose (h) Figure 2. Mean plasma concentration time profile for sildenafil (solid lines) and its metabolite, UK-103,320 (dashed lines), after administration of a 50-mg dose of a sildenafil orally disintegrating tablet (ODT) given under fasting conditions or with a high-fat meal. compared with fasted conditions, but the AUC values were reasonably comparable between treatments. Safety Bioequivalence Study The number of treatment-emergent (defined as occurring during treatment and up to 7 days after the last dose of study medication) adverse events (AEs) reported after administration of sildenafil ODT 50 mg (with water), sildenafil ODT 50 mg (without water), and sildenafil 50-mg film-coated oral tablet was similar (17, 14, and 14 AEs, respectively). All AEs were of mild to moderate intensity, and there were no discontinuations due to AEs. No serious AEs or deaths were reported during the study. The most frequent treatment-emergent AEs reported after administration of sildenafil ODT 50 mg (with water), sildenafil ODT 50 mg (without water), and sildenafil 50-mg filmcoated oral tablet were flushing (3, 4, and 3 subjects, respectively), nasal congestion (3, 3, and 3 subjects), and myalgia (2, 2, and 2 subjects). Food-Effect Study The number of treatment-emergent AEs reported was the same after administration of sildenafil 50 mg ODT under fed and fasted conditions (5 and 5 AEs, respectively). All AEs were of mild intensity, and there were no discontinuations due to AEs. No serious AEs or deaths were reported during the study. The most common treatment-emergent AE reported after fed and fasted administrations of sildenafil ODT 50 mg was nasal congestion (2 subjects and 1 subject, respectively). DISCUSSION The bioequivalence study demonstrated that sildenafil ODT given without water was bioequivalent with respect to both C max and AUC relative to the currently marketed sildenafil film-coated tablet. When the ODT was given with water, the tablet was allowed to disintegrate on the tongue, and subjects were instructed to swallow the dispersed tablet, which was then followed by administration of 240 ml of water. Because water would be expected to aid in drug dissolution in the stomach, it is surprising that the ODT with water did not meet the criteria for bioequivalence for C max (ratio [90% CI], 86.03 [79.76 92.78]), whereas AUC completely satisfied the criteria. It should be noted that the reduction in C max when the ODT is given with water is of much lesser magnitude than has been observed historically for fed/fasted results with the currently marketed sildenafil film-coated tablets. When currently marketed 100-mg sildenafil film-coated tablets were given with a high-fat meal compared with on an empty stomach, the point estimate (90% CI) for the C max ratio was 71% (62 81), whereas the point estimate (90% CI) for AUC was 89% (84 94), and the T max was delayed by 1 hour. 2 However, the currently marketed sildenafil film-coated tablets can be administered without regard to meals with no significant clinical implications other than a potential delay in onset of activity due to delayed T max. 1 Because the reduction in C max when the proposed ODT is given with water is of lesser magnitude than the fed/fasted effect with the currently marketed sildenafil filmcoated tablet, this technical artifact with regard to C max in the study is unlikely to have any clinically meaningful impact. Consequently, the sildenafil 50 mg ODT, given with or without water, can be considered clinically interchangeable with the currently marketed 50-mg sildenafil film-coated tablet. Because the pharmacokinetics of sildenafil are roughly dose related over the therapeutic dose range, 2 patients who would February 2014 241

Clinical Therapeutics Table II. Summary of pharmacokinetic parameters in the food-effect study. Values are given as geometric mean (%CV) for all except median (range) for T max and arithmetic mean (%CV) for t ½. Parameter Sildenafil ODT: Fed (N ¼ 12) * Sildenafil ODT: Fasted (N ¼ 12) Ratio of Geometric Means (90% CI) Sildenafil AUC 0 1,ng h/ml 804.0 (34) 838.6 (23) 93.42 (80.23 108.78) AUC 0 last,ng h/ml 712.8 (33) 813.2 (22) 87.66 (77.62 98.99) C max, ng/ml 121.0 (44) 292.6 (31) 41.35 (32.40 52.76) T max, h 4.00 (0.50 6.00) 0.625 (0.25 1.50) t ½, h 2.503 (14) 3.039 (16) UK-103,320 AUC 0 1,ng h/ml 516.6 (34) 569.6 (37) AUC 0 last,ng h/ml 427.2 (39) 523.1 (34) C max, ng/ml 66.29 (41) 144.9 (37) T max, h 4.00 (0.783 6.02) 0.750 (0.500 1.50) t ½, h 3.158 (14) 4.004 (27) *n ¼ 9 and n ¼ 10 for AUC 0 1 and t ½ of sildenafil and UK-103,320, respectively. need a 100-mg dose can be administered two 50 mg ODTs. For ease of administration, the two 50-mg ODT tablets could be taken sequentially (ie, allow 1 ODT tablet to be dispersed and swallowed before administering the next ODT tablet). In the present study, the high-fat meal affected the rate, but not the extent, of absorption of sildenafil after administration of the ODT. It should be noted that the study enrolled 12 subjects and was not statistically powered for bioequivalence but was rather designed to estimate the magnitude of the effect of a high-fat meal on the pharmacokinetics of sildenafil. Although the 90% CI for the AUC 0 last ratio was not contained within the range of 80% to 125%, the 90% CI for the AUC 0 1 ratio was fully contained in that range and, hence, it appears that a high-fat meal has no appreciable effect on total drug exposure. The change in the rate of absorption of sildenafil after administration of the ODT with food was manifested as a mean reduction in C max of 59% and a delay in median T max from 0.625 hour (fasting) to 4.00 hours (high-fat meal). The food effect with the ODT was greater in magnitude than the food effect seen with the sildenafil film-coated tablets, in which the mean reduction in C max was only 29% and median T max was delayed by 1 hour due to a high-fat meal. 2 Sildenafil film-coated tablets are administered with water and disintegrate much more slowly than the sildenafil ODT, which disintegrates within seconds of being placed on the tongue. Furthermore, in the foodeffect study with the ODT, there was no water allowed after drug administration. Therefore, it is plausible that the rapidly disintegrating ODT causes a stronger physical interaction with food than the conventional tablets, resulting in a higher magnitude of food effect. The primary end point for the bioequivalence study was based on the parent drug, which has a terminal phase t ½ of 4 hours. The 14-hour sampling schedule accounted for 490% of the AUC 0 1. Previous foodeffect data with the commercial film-coated tablet indicated that the T max shifts by 1 hour with food, which was factored into the consideration for a 14- hour sampling period for the food-effect study. However, the T max of sildenafil shifted by 3 hours for the ODT. Consequently, AUC 0 1 could not be reported in some patients because the predicted AUC after the last sampling time was 420%. A longer sampling time in the food-effect study would have avoided this. Nonetheless, the food-effect study designed was able to predict the extent of the food effect with the ODT. For both treatments, the median of T max values was 0.750 hour (range, 0.250 2.00 hours). A review of the 242 Volume 36 Number 2

B. Damle et al. individual subject data indicated that only 1 subject in each treatment (not the same subject) had a T max value of 0.25 hour. Partial AUCs were not determined in the study. However, the T max data suggest that absorption of sildenafil from both formulations was quick and that the early sampling time points in the study were adequate for the purpose of bioequivalence determination. Although the potential for buccal absorption with an ODT formulation exists, it is unlikely to have occurred to any significant extent after administration of sildenafil ODT. This is supported by the following lines of evidence. First, ratios of metabolite to parent drug were virtually identical after receiving the ODT or film-coated formulations, whereas buccal absorption would have been expected to alter first-pass metabolism affecting this ratio. 8 For instance, the mean (SD) metabolite to parent drug ratio for AUC 0 1 after administration of the film-coated tablet was 0.68 (0.22), whereas that of ODT without and with water was 0.68 (0.23) and 0.63 (0.19), respectively. Second, the present study demonstrated bioequivalence, which would have been unlikely with any substantial buccal absorption of sildenafil. Third, the known solubility of sildenafil at ph 6.5 (0.03 mg/ml), typical steady-state volume of the saliva ( 1 ml), and the time duration the drug will be in the buccal cavity (o1 minute) would preclude any significant dissolution and subsequent absorption of the drug after administration of the ODT. There is no pharmacokinetic/pharmacodynamic model developed for assessing the relationship between plasma sildenafil concentrations and measures of efficacy for the treatment of erectile dysfunction. Two randomized, double-blind, placebo-controlled, crossover studies conducted in men with erectile dysfunction indicated that, based on RigiScan monitoring (Timm Medical Technologies, Inc, Lake Forest, Illinois), penetrative erection can occur as early as 12 minutes, and for most patients, within 30 minutes after dosing, with a duration of action lasting at least 4 hours. 9 Patients in these studies were dosed under fasting conditions, in which case the reported mean T max is 1 hour. 1 Bioequivalence of the sildenafil film-coated tablet and proposed ODT under fasting conditions would imply that pharmacodynamic activity would be comparable between the 2 dosage forms administered under a fasting condition. However, the delayed T max when the ODT is administered with a high-fat meal would imply that onset of action could be dramatically delayed if the ODT is taken with a high-fat meal. CONCLUSIONS Sildenafil has been available for many years for the treatment of erectile dysfunction, and its safety and efficacy are well established. In addition to the presently marketed sildenafil film-coated tablets, the novel ODT formulation of sildenafil offers an option for patients who have difficulty swallowing, as well as a convenient and discreet method of administration without the need for water. ACKNOWLEDGEMENTS The authors thank Sung Boon Chew for her contribution to the study. Editorial support in the form of preparing the manuscript for submission was provided by Abegale Templar, PhD, of Engage Scientific and funded by Pfizer Inc. CONFLICTS OF INTEREST Both studies were sponsored by Pfizer Inc. All authors were employees of Pfizer at the time the studies were conducted. The study sponsor (Pfizer) and the manuscript authors were involved in study design; collection, analysis, and interpretation of data; in the writing of the manuscript; and in the decision to submit the manuscript for publication. The authors have indicated that they have no other conflicts of interest regarding the content of this article. REFERENCES 1. Pfizer Inc. VIAGRA (sildenafil citrate) tablets. United States package insert. http://www.pfizer.com/files/products/uspi_ viagra.pdf. Accesses July 25, 2012. 2. Nichols DJ, Muirhead GJ, Harness JA. Pharmacokinetics of sildenafil after single oral doses in healthy male subjects: absolute bioavailability, food effects and dose proportionality. Br J Clin Pharmacol. 2002;53(Suppl 1):5S 12S. 3. Howden CW. Management of acid-related disorders in patients with dysphagia. Am J Med. 2004;117(Suppl 5A):44S 48S. 4. Valenzuela F, Davila G, Ibanez Y, et al. Relative bioavailability of chewable and conventional film-coated tablet formulations of sildenafil 100 mg in healthy volunteers under fasting conditions. J Bioequiv Availab. 2011;3:207 210. 5. Deveci S, Peskircioglu L, Aygun C, et al. Sublingual sildenafil in the treatment of erectile dysfunction: faster onset of action with less dose. Int J Urol. 2004;11:989 992. February 2014 243

Clinical Therapeutics 6. Roh H, Son H, Lee D, et al. Pharmacokinetic comparison of an orally disintegrating film formulation with a film-coated tablet formulation of sildenafil in healthy Korean subjects: a randomized, open-label, singledose, 2-period crossover study. Clin Ther. 2013;35:205 214. 7. Eerkes A, Addison T, Naidong W. Simultaneous assay of sildenafil and desmethylsildenafil in human plasma using liquid chromatography-tandem mass spectrometry on silica column with aqueous-organic mobile phase. J Chromatogr B Analyt Technol Biomed Life Sci. 2002;768:277 284. 8. Pond SM, Tozer TN. First-pass elimination. Basic concepts and clinical consequences. Clin Pharmacokinet. 1984;9:1 25. 9. Eardley I, Ellis P, Boolell M, et al. Onset and duration of action of sildenafil for the treatment of erectile dysfunction. Br J Clin Pharmacol. 2002;53(Suppl 1):61S 65S. Address correspondence to: Bharat Damle, Pfizer Inc, 235 East 42nd Street, New York, NY 10017. E-mail: bharat.damle@pfizer.com 244 Volume 36 Number 2

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