Evaluation of the pharmacokinetics of posaconazole and rifabutin following co-administration to healthy men.

OBJECTIVE: Posaconazole is a triazole antifungal agent for the treatment and prophylaxis of invasive fungal infections. This non-randomized, open-label, parallel-group, multiple-dose, drug-interaction study was conducted to evaluate the pharmacokinetics of posaconazole and rifabutin following co-administration to healthy subjects. METHODS: Subjects were assigned to treatment groups: Group 1 (posaconazole, 200-mg tablet once daily for 10 days) or Group 2 (rifabutin, 300-mg capsule once daily for 17 days [Days -7 to 10] co-administered with posaconazole, 200 mg tablet once daily for 10 days [Days 1-10]). Posaconazole was administered after rifabutin steady-state was reached. Individual plasma concentration-time data for posaconazole (Day 10, Groups 1 and 2) and rifabutin (Days -1 and 10, Group 2) were analyzed using model-independent methods. RESULTS: Twenty-four men were enrolled in the study. All subjects in Group 1 completed the study; however, four subjects in Group 2 discontinued because of adverse events. When co-administered with rifabutin, posaconazole maximum plasma concentration (C(max)) and area under the plasma concentration-time curve over the dosing interval (AUC([tau])) were reduced 43% (p = 0.005) and 49% (p = 0.008), respectively. Conversely, rifabutin C(max) and AUC([tau]) increased 31% (p = 0.016) and 72% (p < 0.001), respectively, when co-administered with posaconazole. CONCLUSION: Based on the reduced exposure to posaconazole observed in the limited number of subjects in this study and the increased risk for adverse events associated with elevated rifabutin concentrations, concomitant use of rifabutin and posaconazole should be avoided unless the benefit outweighs the risk.

Effects of age, gender, and race/ethnicity on the pharmacokinetics of posaconazole in healthy volunteers.

Posaconazole is a triazole antifungal for prophylaxis of invasive fungal infection and treatment of oropharyngeal candidiasis. We evaluated the effects of gender, age, and race/ethnicity (black or white) on the steady-state pharmacokinetics of posaconazole in two studies on healthy adult subjects (>or=18 years of age). Additionally, we explored the effect of P-glycoprotein expression and MDR1 genotype on posaconazole pharmacokinetics in black and white subjects. Age, gender, and race/ethnicity had no clinically relevant effects on posaconazole pharmacokinetics. No association was observed between any MDR1 single-nucleotide polymorphism and the area under the concentration-time curve for posaconazole. Posaconazole was safe and well tolerated regardless of age, gender, or race/ethnicity. In conclusion, age, gender, and race/ethnicity have no clinically relevant effects on the steady-state pharmacokinetics of posaconazole in healthy adults; therefore, dosage adjustments based on these covariates are unnecessary.

Pharmacokinetic and safety profile of desloratadine and fexofenadine when coadministered with azithromycin: a randomized, placebo-controlled, parallel-group study.

BACKGROUND: Significant cardiac toxicity has been associated with some older antihistamines (eg, terfenadine and astemizole) when their plasma concentrations are increased. There is thus a need for a thorough assessment of the cardiac safety of newer antihistamine compounds. OBJECTIVE: This study was undertaken to assess the effects of coadministration of desloratadine or fexofenadine with azithromycin on pharmacokinetic parameters, tolerability, and electrocardiographic (ECG) findings. METHODS: Healthy volunteers aged 19 to 46 years participated in this randomized, placebo-controlled, parallel-group, third-party-blind, multiple-dose study. Subjects received desloratadine 5 mg once daily, fexofenadine 60 mg twice daily, or placebo for 7 days. An azithromycin loading dose (500 mg) followed by azithromycin 250 mg once daily for 4 days was administered concomitantly starting on day 3. Group 1 received desloratadine and azithromycin, group 2 received desloratadine and placebo, group 3 received placebo and azithromycin, group 4 received fexofenadine and azithromycin, and group 5 received fexofenadine and placebo. RESULTS: The results of the pharmacokinetic analysis revealed little change in mean maximum concentration (Cmax) and area under the concentration-time curve (AUC) values for desloratadine with concomitant administration of azithromycin: Cmax ratio, 115% (90% CI, 92-144); AUC, ratio 105% (90% CI, 82-134). The corresponding ratios for 3-hydroxydesloratadine were 115% (90% CI, 98-136) and 104% (90% CI, 88-122), respectively. A substantial increase was observed in mean Cmax and AUC values for fexofenadine when administered with azithromycin: Cmax, ratio, 169% (90% CI, 120-237); AUC ratio, 167% (90% CI, 122-229). Compared with the group receiving desloratadine and azithromycin, subjects receiving fexofenadine and azithromycin also displayed greater variability in pharmacokinetic parameters for the antihistamine. Mean Cmax and AUC values of azithromycin were slightly higher when administered with desloratadine (Cmax ratio, 131% [90% CI, 92-187]; AUC ratio, 112% [90% CI, 83-153]) but were lower when given in combination with fexofenadine (Cmax ratio, 87% [90% CI, 61-124]; AUC ratio, 88% [90% CI, 65-1201). The most common adverse event for all regimens was headache, reported in 20 (22%) subjects. All combinations of desloratadine or fexofenadine with and without azithromycin were well tolerated, and no statistically significant changes in PR, QT, or QT, interval, QRS complex, or ventricular rate were observed. CONCLUSIONS: Small increases (<15%) in mean pharmacokinetics of desloratadine were observed with coadministration of azithromycin. By contrast, peak fexofenadine concentrations were increased by 69% and the AUC was increased by 67% in the presence of the azalide antibiotic. Based on the reported adverse-events profile and the absence of changes in ECG parameters, the combination of desloratadine and azithromycin was well tolerated. This study suggests that desloratadine has a more favorable drug-interaction potential than does fexofenadine.

Bioavailability and metabolism of mometasone furoate following administration by metered-dose and dry-powder inhalers in healthy human volunteers.

These studies were conducted to assess the systemic bioavailability of mometasone furoate (MF) administered by both the dry-powder inhaler (DPI) and the metered-dose inhaler with an alternate propellant (MDI-AP). The pharmacokinetics of single doses (400 micrograms) of MF administered by intravenous (i.v.) and inhalation routes was assessed in a randomized, three-way crossover study involving 24 healthy volunteers. In a separate study, 6 healthy subjects were administered a single dose of tritiated (3H-) MF by DPI, and the radioactivity in blood, urine, feces, and expired air was determined. Following i.v. administration, MF was detected in all subjects for at least 8 hours postdose. The half-life (t1/2) following i.v. administration was 4.5 hours. In contrast, following DPI administration, plasma MF concentrations were below the limit of quantification (LOQ, 50 pg/mL) for many subjects (10 of 24), and the systemic bioavailability by this route was estimated to be less than 1%. Only two plasma samples following MDI-AP administration had plasma concentrations of MF above the LOQ indicating no detectable systemic bioavailability in 92% of the subjects. A separate study with 6 healthy male subjects administered a single dose of 3H-MF (200 microCi) by DPI revealed that much of the dose (approximately 41%) was excreted unchanged in the feces (0-72 hours), while that which was absorbed was extensively metabolized. These results indicate that inhaled MF has negligible systemic bioavailability and is extensively metabolized and should therefore be well tolerated in the chronic treatment of asthma.