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.

Pharmacokinetics of a novel orodispersible tablet of sildenafil in healthy subjects.

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 ≥45 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 Cmax, AUC0-∞, and AUC0-last were contained within equivalence limits (80%-125%). When sildenafil ODTs were given with water, the 90% CIs for sildenafil AUC0-∞ and AUC0-last were contained within the range of 80% to 125%; however, the 90% CI for sildenafil Cmax was not (79.76-92.78). This difference in Cmax is unlikely to have any clinically meaningful impact. High-fat meals reduced the rate but not the extent of absorption of sildenafil. Mean Cmax was reduced by 59%, and median Tmax 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).

Steady-state pharmacokinetics of sirolimus in stable adult Chinese renal transplant patients.

This open-label, nonrandomized study was conducted to evaluate the steady-state pharmacokinetics of sirolimus in 24 stable Chinese renal transplant patients receiving daily oral maintenance doses of sirolimus (1-4 mg). Repeated trough and serial whole blood sirolimus concentrations over a 24-hour dosing interval were collected and assayed using high-performance liquid chromatography with tandem mass spectrometry (HPLC/MS/MS). Non-compartmental analysis (NCA) was employed to calculate sirolimus pharmacokinetic parameters. Cytochrome P450 (CYP) 3A5 genotyping was performed. Cyclosporine (CsA) levels were determined for patients who took concomitant CsA. Mean (±SD) sirolimus maximum concentration (Cmax ), area under the concentration-time curve within a dosing interval of τ (AUCτ ), oral clearance (CL/F), and trough concentration (Ctrough ) at steady state were: 14.1 ± 13.4 ng/mL, 199 ± 210 ng · h/mL, 10.1 ± 4.4 L/h, and 5.9 ± 6.3 ng/mL, respectively. Median tmax (range) was 2.49 hours (1-12 hours). A strong correlation was observed between Ctrough and AUCτ . Pharmacokinetics of sirolimus in patients with and without concomitant CsA were comparable. Allele frequency of CYP3A5*3 was 70.9% and a trend of higher oral clearance was observed in CYP3A5 expressers compared with non-expressers although the number of subjects in each genotype was small.

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.

Comparison of pharmacokinetic variability of fesoterodine vs. tolterodine extended release in cytochrome P450 2D6 extensive and poor metabolizers.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Tolterodine and 5-hydroxymethyl tolterodine (5-HMT) are equipotent active moieties of tolterodine; 5-HMT is the singular active moiety of fesoterodine. The formation of 5-HMT from tolterodine occurs via CYP2D6, and some subjects are poor metabolizers CYP2D6. On the other hand, the formation of 5-HMT from fesoterodine occurs via ubiquitous esterases. Cross-study comparisons of data from phase 1 studies suggest that active moiety exposures are considerably more variable following tolterodine extended release vs. fesoterodine. WHAT THIS STUDY ADDS: This head-to-head study confirmed the findings of reduced pharmacokinetic variability of fesoterodine and further delineates that tolterodine, and not 5-HMT, was the principal source of variability after administration of tolterodine extended release. The data suggest that fesoterodine delivers 5-HMT consistently, regardless of CYP2D6 status, with up to 40% higher bioavailability compared with tolterodine. AIMS: Tolterodine and 5-hydroxymethyl tolterodine (5-HMT) are equipotent active moieties of tolterodine; 5-HMT is the singular active moiety of fesoterodine. Formation of 5-HMT from fesoterodine and tolterodine occurs via esterases and CYP2D6 respectively. This randomized, crossover, open-label, multiple-dose study in CYP2D6 extensive metabolizers (EMs) and poor metabolizers (PMs) compared the pharmacokinetics of fesoterodine vs. tolterodine extended release (ER). METHODS: Subjects received fesoterodine and tolterodine ER with a ≥3-day washout period. Treatment comprised 4-mg once daily doses for 5 days escalated to 8-mg once daily for 5 days. Pharmacokinetics of active moieties were compared by drug, dose and genotype. RESULTS: Active moiety exposures following fesoterodine and tolterodine ER increased proportional to dose in EMs and PMs. In EMs only, coefficients of variation for AUC and C(max) following fesoterodine (up to 46% and 48% respectively) were lower than those following tolterodine ER (up to 87% and 87% respectively). Following fesoterodine and tolterodine ER administration, active moiety exposures ranged up to sevenfold and 40-fold respectively. Mean urinary excretion of 5-HMT following fesoterodine 4 and 8 mg, respectively, was 0.44 and 0.89 mg in EMs and 0.60 and 1.32 mg in PMs. Following tolterodine ER 4 and 8 mg, it was 0.38 and 0.71 mg respectively (EMs only). Renal clearance was similar regardless of administered drug, dose or genotype. CONCLUSIONS: Tolterodine, not 5-HMT, was the principal source of variability after tolterodine ER administration. Fesoterodine delivers 5-HMT with less variability than tolterodine, regardless of CYP2D6 status, with up to 40% higher bioavailability. The pharmacokinetics of fesoterodine were considerably less variable than TER.

Assessment of the pharmacokinetics of co-administered maraviroc and raltegravir.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Maraviroc is a CCR5 receptor antagonist, while raltegravir is a HIV-1 integrase inhibitor. * Based on the known metabolic pathways (CYP3A4 for maraviroc and UGT1A1 for raltegravir), interaction between the two drugs is unlikely. However, unexpected interactions have been reported for other antiretroviral drugs. * As both these drugs are likely to be used in combination, this study evaluated the pharmacokinetic interaction between them. WHAT THIS STUDY ADDS: * Relative to individual monotherapy, co-administration resulted in a 20% and 33% decrease in mean C(max), and 14% and 37% decrease in mean AUC of maraviroc and raltegravir, respectively. * Co-administration was generally safe and well tolerated in healthy subjects. * These changes are not likely to be clinically relevant, thus no dose adjustment is necessary. AIMS: To assess the two-way pharmacokinetic interaction between maraviroc and raltegravir. METHODS: In this open-label, multiple-dose, fixed-sequence study, 18 healthy, human immunodeficiency virus (HIV)-seronegative subjects received the following: days 1-3 raltegravir 400 mg q12h, days 4-5 washout, days 6-11 maraviroc 300 mg q12h, and days 12-14 raltegravir 400 mg q12h + maraviroc 300 mg q12h. Serial 12-h blood samples were collected on days 3 (raltegravir), 11 (maraviroc) and 14 (raltegravir + maraviroc). Plasma samples were assayed by validated liquid chromatography tandem mass spectrometry assays. Test/reference ratios and 95% confidence intervals (CIs) were determined for pharmacokinetic parameters. RESULTS: For maraviroc, the test/reference % ratio (95% CI) for AUC(tau) was 85.8 (78.7, 93.5), for C(max) was 79.5 (64.8, 97.5) and for C(min) was 90.3 (84.2, 96.9). For raltegravir, the test/reference % ratio (95% CI) for AUC(tau) was 63.3 (41.0, 97.6), for C(max) was 66.8 (37.1, 120.0) and for C(min) was 72.4 (55.1, 95.2). In all subjects, maraviroc average concentrations (AUC(tau) divided by 12) were >100 ng ml(-1), the threshold value below which there is an increased risk of virological failure. Based on clinical experience for raltegravir, mean C(min) decreases >60% are considered to be clinically relevant for short-term activity; however, in the present study mean changes were only 28% and thus not considered to be of clinical relevance. CONCLUSIONS: Co-administration of maraviroc and raltegravir decreased systemic exposure of both drugs; however, these are not likely to be clinically relevant. Safety and efficacy studies may help in understanding the role of this combination in the treatment of HIV infection.

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.

Influence of CYP2C19 polymorphism on the pharmacokinetics of nelfinavir and its active metabolite.

AIMS: This study reports the pharmacokinetics of nelfinavir, its active metabolite, M8, and active moiety (nelfinavir + M8) in volunteers genotyped for CYP2C19 as extensive metabolizer (*1*1; n = 38), heterozygous poor metabolizer (PM) (*1*2; n = 22) and homozygous PM (*2*2; n = 6). METHODS: Subjects received nelfinavir at normal dose (3.5 days of 1250 mg q12h) or high dose (1250 mg q12h for 3 days and single dose of 3125 mg on day 4). Steady-state plasma samples were analysed by high-performance liquid chromatography/ultraviolet assay to determine pharmacokinetics. RESULTS: At steady state, the mean C(max) was 42% [95% confidence interval (CI) 19, 69] and 63% (95% CI 20, 122) higher, and mean AUC was 51% (95% CI 24, 83) and 85% (95% CI 32, 159) higher for *1*2 and *2*2 compared with *1*1 subjects, respectively. For M8, the mean C(max) and AUC were 35% (95% CI 6, 55) and 33% (95% CI -3, 56), respectively, lower for *1*2 compared with *1*1 subjects. M8 was not detectable in *2*2 subjects. The mean C(max) and AUC values for the active moiety were higher by 30-35% for the *1*2 and *2*2 compared with *1*1 subjects. CONCLUSIONS: Mutation in CYP2C19 increased the systemic exposure of nelfinavir and reduced the exposure of M8. No significant differences were noted among the heterozygous (*1*2) and homozygous (*2*2) PMs. These changes are not considered to be clinically relevant and hence the use of nelfinavir does not require prior assessment of CYP2C19 genotype.

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.

Pharmacokinetics and tolerability of voriconazole and a combination oral contraceptive co-administered in healthy female subjects.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Voriconazole, a broad-spectrum antifungal drug, is a substrate and inhibitor of CYP2C19 and CYP3A4 isozymes. * Ethinyl oestradiol and norethindrone, components of the combination oral contraceptive drug Ortho-Novum 1/35, also are substrates of cytochrome P450 CYP2C19 and CYP3A4 isozymes. * Because co-administration of voriconazole and Ortho-Novum 1/35 could potentially result in pharmacokinetic interactions that increase systemic exposure of one or both drugs to unsafe levels, clinical studies are needed to define better the two-way pharmacokinetic interaction between these drugs. WHAT THIS STUDY ADDS: * Although co-administered voriconazole and oral contraceptive did result in increased systemic exposures of all three drugs relative to respective monotherapy, co-administered treatment was generally safe and well tolerated. * It is recommended, however, that patients receiving co-administered voriconazole and oral contraceptives be monitored for the development of adverse events commonly associated with these medications. AIM: To assess the two-way pharmacokinetic interaction between voriconazole and Ortho-Novum 1/35, an oral contraceptive containing norethindrone 1 mg and ethinyl oestradiol 35 microg. METHODS: In this open-label, three-period, fixed-sequence study, 16 healthy females received voriconazole (400 mg q12 h, day 1; 200 mg q12 h, days 2-4) (period 1), oral contraceptive (q24 h, days 12-32) (period 2), and combination voriconazole (400 mg q12 h, day 57; 200 mg q12 h, days 58-60) and oral contraceptive (q24 h, days 40-60) (period 3). RESULTS: Voriconazole geometric mean AUC(tau) and C(max) increased 46% (12 682-18 495 ng h ml(-1); 90% confidence interval [CI] 32, 61) and 14% (2485-2840 ng ml(-1); 90% CI 3, 27), respectively, when co-administered with oral contraceptive vs. voriconazole alone. Ethinyl oestradiol geometric mean AUC(tau) and C(max) increased 61% (1031-1657 ng h ml(-1); 90% CI 50, 72) and 36% (119-161 ng ml(-1); 90% CI 28, 45), respectively, and norethindrone geometric mean AUC(tau) and C(max) increased 53% (116-177 ng h ml(-1); 90% CI 44, 64) and 15% (18-20 ng ml(-1); 90% CI 3, 28), respectively, during voriconazole co-administration vs. oral contraceptive alone. Neither ethinyl oestradiol nor norethindrone levels were reduced in subjects following voriconazole co-administration. Adverse events (AEs) were generally mild, occurring less in subjects receiving voriconazole alone (36 events) vs. oral contraceptive alone (88 events) or combination treatment (68 events); four subjects experienced a severe AE. CONCLUSIONS: Co-administration of voriconazole and oral contraceptive increased systemic exposures of all analytes relative to respective monotherapy. Although generally safe and well tolerated, it is recommended that patients receiving co-administered voriconazole and oral contraceptive be monitored for development of AEs commonly associated with these medications.

Pharmacokinetic interactions of efavirenz and voriconazole in healthy volunteers.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Efavirenz 400 mg q24 h reduces exposure to voriconazole 200 mg q12 h when the two drugs are co-administered. * Furthermore, voriconazole increases the systemic exposure of efavirenz. * Co-administration was therefore initially contraindicated. WHAT THIS STUDY ADDS: * The doses of efavirenz and voriconazole can be adjusted to provide adequate exposure to both drugs when the two are co-administered, without compromising safety. * Appropriate adjustment of doses for both drugs may thus represent an alternative to a mere contraindication. AIMS: Co-administration of standard-dose voriconazole and efavirenz results in a substantial decrease in voriconazole levels, while concurrently increasing efavirenz levels. Hence, concomitant use of standard doses of these drugs was initially contraindicated. This study assessed different dose combinations of efavirenz and voriconazole, with the goal of attaining a dose combination that provides systemic exposures similar to standard-dose monotherapy with each drug. METHODS: This was an open-label, four-treatment, multiple-dose, fixed-sequence study in 16 healthy males. Steady-state pharmacokinetics were assessed following two test treatments (voriconazole 300 mg q12 h + efavirenz 300 mg q24 h and voriconazole 400 mg q12 h + efavirenz 300 mg q24 h) and compared with standard-dose monotherapy (voriconazole 200 mg q12 h or efavirenz 600 mg q24 h). RESULTS: Dose adjustment to voriconazole 300 mg q12 h with efavirenz 300 mg q24 h decreased voriconazole area under the concentration-time curve (AUC(tau)) and maximum concentration (C(max)), with changes of -55% [90% confidence interval (CI) -62, -45] and -36% (90% CI -49, -21), respectively, when compared with monotherapy. Voriconazole 400 mg q12 h plus efavirenz 300 mg q24 h decreased voriconazole AUC(tau) (-7%; 90% CI -23, 13) and increased C(max) (23%; 90% CI -1, 53), while increasing efavirenz AUC(tau) (17%; 90% CI 6, 29) and not changing C(max) when compared with the respective monotherapy regimens. No serious adverse events were observed with voriconazole plus efavirenz. CONCLUSIONS: When co-administered, voriconazole dose should be increased to 400 mg q12 h and efavirenz dose decreased to 300 mg q24 h in order to provide systemic exposures similar to standard-dose monotherapy.

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.