Bioequivalence and Bioavailability of an Orodispersible Tablet of Sildenafil Citrate in Healthy Chinese Male Subjects.

Sildenafil citrate is approved to treat erectile dysfunction. An orally disintegrating tablet (ODT) of sildenafil citrate that does not require swallowing or administration with fluids has been developed. The bioequivalence and bioavailability of sildenafil citrate ODT (50 mg) without and with water were compared with conventional sildenafil citrate tablets (50 mg) in an open-label, randomized crossover study. Healthy Chinese male subjects (n = 36) were allocated to 1 of 6 sildenafil citrate treatment sequences under fasted conditions, and plasma samples for determination of sildenafil concentrations were collected predose through 14 hours postdose. Bioequivalence was demonstrated for sildenafil citrate ODT administered without water relative to the sildenafil citrate tablet administered with water; 90%CIs for the ratios of adjusted geometric means for sildenafil AUClast , Cmax , and AUCinf (ratio, 101.41%; 90%CI, 95.49%-107.70%; ratio, 93.55%; 90%CI, 84.15%-104.00%; and ratio, 101.03%; 90%CI, 94.80%-107.66%; respectively) were wholly contained within the bioequivalence acceptance range of 80% to 125%, indicating bioequivalence criteria were met. Relative bioavailability of sildenafil citrate ODT administered with water to the sildenafil citrate tablet (50 mg) administered with water was 97.10%, 91.43%, and 97.09% with respect to sildenafil AUClast , Cmax , and AUCinf , respectively (90%CI, 91.43%-03.12%, 82.25%-101.65%, and 90.90%-103.71%, respectively). Both sildenafil citrate formulations were generally well tolerated in healthy Chinese men. Sildenafil citrate ODT administered without or with water was bioequivalent to or met bioequivalence criteria compared with conventional sildenafil citrate tablets administered with water under fasted conditions in healthy Chinese men, thus offering a convenient alternative method of oral administration.

A Thorough QT Study to Evaluate the Effects of a Supratherapeutic Dose of Sertraline on Cardiac Repolarization in Healthy Subjects.

The effect of steady-state supratherapeutic sertraline (Zoloft) on QT interval was assessed in a single-center, randomized, 3-way crossover, double-blind, placebo- and moxifloxacin-controlled thorough QT study. Healthy adults received sertraline 400 mg/day, moxifloxacin 400 mg, and placebo, with a washout period (≥14 days) between treatments. A 12-lead electrocardiogram was recorded in triplicate before dosing and at selected time points up to 72 hours after dosing. Analysis of covariance using a mixed-effect model with sequence, period, treatment, time, and treatment-by-time interaction as fixed effects; subject within sequence as a random effect; and baseline QT corrected for heart rate using Fridericia formula (QTcF) as a covariate was conducted. A 90% confidence interval for the least squares (LS) mean difference in QTcF between active treatment and placebo was computed for each postdose time point. Exposure-response was assessed using linear mixed-effect modeling. Fifty-four subjects were enrolled. Over 24 hours after dosing, the LS mean difference in QTcF for sertraline versus placebo ranged from 5.597 milliseconds to 9.651 milliseconds. The upper bound of the 90% confidence interval for the LS mean difference exceeded a predefined 10-millisecond significance threshold at the 4-hour postdose time point only (LS mean, 9.651 milliseconds [90% confidence interval, 7.635-11.666]). In the exposure-response analysis, QTcF values increased significantly with increasing sertraline concentration (slope = 0.036 milliseconds/ng/mL; P < .0001). Predicted change from baseline in QTcF at therapeutic maximum plasma sertraline concentration was 3.57 milliseconds. This thorough QTc study demonstrated a positive signal for QTc prolongation for sertraline at the steady-state 400-mg/day dose.

Pegvisomant bioavailability of single 30 mg/mL subcutaneous injection compared to two 15 mg/mL subcutaneous injections: a pharmacokinetic, safety and tolerability study.

OBJECTIVE: The study was conducted to evaluate the pharmacokinetics (PK), relative bioavailability (relBA), safety and tolerability of two single-dose pegvisomant subcutaneous (SC) administrations: one injection of 30 mg/mL (1 × 30 mg/mL) versus two injections of two 15 mg/mL (2 × 15 mg/mL). DESIGN: This was a 2-period, single-dose, crossover study in 14 healthy male and female subjects. All subjects received both administrations during the two treatment periods separated by a two-week washout. Serum samples were collected intensively up to 360 h post injection and were assayed by a validated enzyme linked immunosorbent assay (ELISA) for pegvisomant. PK parameters including AUC and Cmax were derived by noncompartmental analyses. Mixed effects model was used to obtain bioavailability estimates. Safety and tolerability were assessed by clinical monitoring, including adverse events, laboratory assessments and injection site reactions. RESULTS: All subjects completed the study. The relBA of 1 × 30 mg/mL relative to 2 × 15 mg/mL was 123.89% with a 90% CI (112.91-135.93%). Adjusted for the difference in actual pegvisomant amounts in both formulations the dose-adjusted relBA reduced to 112.97% with a 90% CI (103.09-123.80%). Single injection with a higher drug concentration in injection solution might have a role in this 13% higher bioavailability for 1 × 30 mg/mL administration. Other PK parameters for the two administrations were comparable. No laboratory abnormalities, vital signs, ECG, or injection site reactions of clinical concern were observed in either treatment. CONCLUSIONS: Comparable BA, safety and tolerability of the new 30 mg/mL strength to the currently marketed 15 mg/mL strength were established in this study.

Comparison of azithromycin pharmacokinetics following single oral doses of extended-release and immediate-release formulations in children with acute otitis media.

An azithromycin extended-release (ER) oral suspension was developed to improve the gastrointestinal tolerability profile without substantially compromising systemic exposure. A single dose of 30 mg/kg azithromycin immediate-release (IR) oral suspension has been used in children to treat acute otitis media (AOM). This study was conducted to compare the pharmacokinetics of a 60-mg/kg azithromycin ER single dose with a 30-mg/kg azithromycin IR single dose in children with AOM aged 6 months to 6 years (n = 19 per treatment). Serum samples were collected at 1, 2, 3, 4, 8, 24, 48, and 72 h after dosing. The area under the curve from time zero to 72 h postdosing (AUC(0-72)) was calculated based on a noncompartmental method. One-way analysis of variance (ANOVA) was used to compare exposure parameters (e.g., AUC(0-72) and peak concentration) as well as concentrations at each time point. The adjusted geometric mean ratio of the ER/IR AUC(0-72) was 157.98% (90% confidence interval [CI], 98.87%, 252.44%), which met the predefined criterion of the lower boundary of the 90% CI of ≥ 80%. As expected, due to the slower-release profile of the ER formulation, the concentrations of the ER formulation during the first 3 h were lower than those of the IR formulation. After 3 h postdosing, the lower boundaries of the 90% CI for the ER/IR concentration ratios were greater than 100%. These results indicated that a 60-mg/kg single dose of ER azithromycin provides similar or greater systemic exposure in children than the 30-mg/kg single dose of IR azithromycin.

The pharmacokinetic profile of fesoterodine 8 mg with daytime or nighttime dosing.

PURPOSE: Diurnal variation can affect drug pharmacokinetics. Fesoterodine is a new antimuscarinic drug for the treatment of overactive bladder (OAB). We estimated the relative bioavailability of 5-hydroxymethyl tolterodine (5-HMT), the active metabolite of fesoterodine, following nighttime and daytime administration. METHODS: In this randomized, open-label, two-period, two-treatment crossover, single-dose study, healthy subjects received daytime and nighttime oral dosing of fesoterodine 8-mg sustained-release tablets, separated by a minimum 60-h washout period. Blood samples for 5-HMT PK determination were collected before dosing and at specified intervals up to 48 h postdose. Safety was assessed by adverse event (AE) reports. RESULTS: Fourteen subjects completed the study. Plasma concentration versus time profiles (AUC) of 5-HMT were similar for daytime and nighttime dosing. Mean AUC(infinity) 5-HMT values were 47.9 and 51.4 ng h/mL for nighttime and daytime dosing, respectively; the mean time to reach maximum concentration (C(max)) values were 3.9 and 5.0 ng/mL, respectively. Nighttime versus daytime AUC(infinity) and C(max) ratios of 5-HMT were 93 and 79%, respectively; 90% confidence intervals (CIs) indicated equivalence for AUC(infinity) but not for C(max). The median time to reach maximum concentration (T(max)) was 5.0 h for both dosing regimens, and the mean terminal elimination half-life (T((1/2))) was 5.9 and 5.7 h for nighttime and daytime dosing, respectively. Seven treatment-related AEs, most commonly headache, occurred in five subjects. CONCLUSIONS: The AUC values for daytime and nighttime administration of fesoterodine were equivalent. The 21% reduction in the C(max) for nighttime dosing is unlikely to be clinically relevant. No safety issues were apparent. These results support both daytime and nighttime administration of fesoterodine for OAB treatment.

Bronchopulmonary disposition of intravenous voriconazole and anidulafungin given in combination to healthy adults.

Voriconazole and anidulafungin in combination are being investigated for use for the treatment of pulmonary aspergillosis. We determined the pulmonary disposition of these agents. Twenty healthy participants received intravenous voriconazole (at 6 mg/kg of body weight every 12 h [q12h] on day 1 and then at 4 mg/kg q12h) and anidulafungin (200 mg on day 1 and then 100 mg every 24 h) for 3 days. Five participants each were randomized for collection of bronchoalveolar lavage samples at times of 4, 8, 12, and 24 h. Drug penetration was determined by the ratio of the total drug area under the concentration-time curve during the dosing interval (AUC(0-tau)) for epithelial lining fluid (ELF) and alveolar macrophages (AM) to the total drug AUC(0-tau) in plasma. The mean (standard deviation) half-life and AUC(0-tau) were 6.9 (2.1) h and 39.5 (19.8) microg h/ml, respectively, for voriconazole and 20.8 (3.1) h and 101 (21.8) microg h/ml, respectively, for anidulafungin. The AUC(0-tau) values for ELF and AM were 282 and 178 microg h/ml, respectively, for voriconazole, and 21.9 and 1,430 microg h/ml, respectively, for anidulafungin. This resulted in penetration ratios into ELF and AM of 7.1 and 4.5, respectively, for voriconazole and 0.22 and 14.2, respectively, for anidulafungin. The mean total concentrations of both drugs in ELF and AM at 4, 8, 12, and 24 h remained above the MIC(90)/90% minimum effective concentration for most Aspergillus species. In healthy adult volunteers, voriconazole achieved high levels of exposure in both ELF and AM, while anidulafungin predominantly concentrated in AM.

Pharmacokinetics of azithromycin in plasma and sinus mucosal tissue following administration of extended-release or immediate-release formulations in adult patients with chronic rhinosinusitis.

This study compared the pharmacokinetics of azithromycin (AZI) following administration of extended-release (ER) and immediate-release (IR) formulations in plasma and sinus mucosa in patients with chronic rhinosinusitis. Patients (n=71) were randomised 1:1 to receive a single dose of AZI-ER 2g or up to three doses of AZI-IR 500 mg daily. Paired plasma and sinus tissue samples were taken during endoscopic sinus surgery at 2-168 h (four patients per time point) after the first dose. Samples were measured by a validated liquid chromatography/mass spectrometry assay. Pharmacokinetics were determined using composite concentration-time profiles. Comparison between formulations showed that within the first 24 h, the AZI area under the plasma concentration-time curve (AUC(24)) for ER was 5.2- and 7.0-fold higher than IR in plasma and sinus tissue, respectively. Comparison between matrices showed that the AUC(24) and AUC(168) in sinus tissue were 28.2- and 62.2-fold higher than in plasma for the ER formulation, whilst the AUC(24) in sinus tissue was 21.1-fold higher than in plasma for IR formulation. These results indicated that AZI has good penetration into sinus tissue regardless of formulation; however, dosing of AZI-ER (2 g) increased AZI exposure within the first 24 h compared with the Day 1 dose of 500 mg IR regimen.

Significant decrease in nelfinavir systemic exposure after omeprazole coadministration in healthy subjects.

STUDY OBJECTIVES: To assess the effect of omeprazole on the multiple-dose (steady-state) pharmacokinetics and safety of nelfinavir, and to evaluate the safety and tolerability of nelfinavir when administered alone and with omeprazole. DESIGN: Open-label, two-period, single-fixed-sequence study. SETTING: Clinical research unit of a large, teaching hospital. PARTICIPANTS: Twenty healthy volunteers (mean age 26 +/- 9 yrs, range 18-48 yrs). Intervention. Subjects received nelfinavir 1250 mg every 12 hours for 4 days (period 1). After a 7-day washout period, subjects were coadministered nelfinavir 1250 mg every 12 hours and omeprazole 40 mg every 24 hours for 4 days (period 2). MEASUREMENTS AND MAIN RESULTS: The pharmacokinetics of nelfinavir and its active metabolite M8 were determined on day 4 of both periods. Plasma samples were assayed by a high-performance liquid chromatography-ultraviolet method for nelfinavir and M8 concentrations, and noncompartmental pharmacokinetic analysis was performed by using analytical software. In the presence of omeprazole, nelfinavir area under the concentration-time curve over the dosing interval (AUC(tau)), maximum observed plasma concentration (C(max)), and minimum observed plasma concentration (C(min)) were reduced by an average of 36%, 37%, and 39%, respectively, relative to administration of nelfinavir alone. The AUC(tau), C(max), and C(min) of M8 were reduced by an average of 92%, 89%, and 75%, respectively. The slopes of the terminal elimination phase of nelfinavir and M8 plasma concentration-time curves were similar between treatments. Nelfinavir was well tolerated when administered alone and when coadministered with omeprazole. CONCLUSION: The observed reduction in the systemic exposure to both nelfinavir and its active metabolite M8 after coadministration with omeprazole could result in loss of virologic control and potential emergence of drug resistance. Hence, omeprazole should not be coadministered to patients taking nelfinavir.

Absolute oral bioavailability of traxoprodil in cytochrome P450 2D6 extensive and poor metabolisers.

BACKGROUND: Traxoprodil, a substituted 4-phenylpiperidine, is an N-methyl-D-aspartate (NMDA) receptor antagonist that is selective for receptors containing the NR2B subunit. In vivo and in vitro studies examining the disposition of traxoprodil have demonstrated that it is mainly metabolised by cytochrome P450 (CYP) 2D6, a major drug-metabolising enzyme that exhibits a genetic polymorphism. OBJECTIVE: To assess the single-dose absolute oral bioavailability of traxoprodil in healthy male volunteers phenotyped as either CYP2D6 extensive or poor metabolisers. METHODS: This was an open-label, three-way crossover study. Traxoprodil was administered as a single dose orally in solution of 50, 100 and 300mg and intravenously as a constant rate 2-hour infusion of 50 and 100mg. CYP2D6 phenotype was assigned following single-dose dextromethorphan administration. RESULTS: In poor metabolisers (n = 6), oral bioavailability was approximately 80% and was consistent with a liver extraction ratio of approximately 20% (plasma clearance of approximately 4 mL/min/kg) indicating near complete absorption. Following intravenous administration, the mean volume of distribution at steady state (V(ss)) was moderate (approximately 6.5 L/kg) and the mean elimination half-life (t((1/2))) was approximately 20 hours. Following oral administration the mean maximum plasma concentration (C(max)) and area under the plasma concentration-time curve from time zero to infinity (AUC(infinity)) increased approximately proportionally with dose. In extensive metabolisers (n = 11), oral bioavailability was dose-dependent and nonlinear. At the 100mg dose, the absolute oral bioavailability was approximately 39.5%. Overall, the oral bioavailability ranged from 22.8% to 62.1% and its estimation was confounded by large differences in plasma concentrations at oral doses without equivalent intravenous doses. Following intravenous administration, plasma clearance was high (approximately 27 mL/min/kg), the V(ss) was moderate (approximately 4 L/Kg) and the t((1/2)) was approximately 2-4 hours. Following oral administration the C(max) and AUC(infinity) increased more than proportionally with dose. Apparent oral clearance decreased with increasing oral dose. However, t((1/2)) was approximately the same at all doses (approximately 4 hours). CONCLUSION: The pharmacokinetics of traxoprodil were quite different in the two phenotypes. In extensive metabolisers, the oral bioavailability was nonlinear and dose-dependent, while in poor metabolisers, oral bioavailability appeared to be linear and dose-independent. Based on the pharmacokinetics in extensive and poor metabolisers, the nonlinear oral bioavailability in extensive metabolisers may be attributed to saturation of hepatic first-pass CYP2D6 metabolism. Thus, at a high oral dose, the impact of CYP2D6 metabolism on traxoprodil pharmacokinetics is minimal.