Pharmacokinetics of posaconazole coadministered with antacid in fasting or nonfasting healthy men.

Posaconazole is a potent broad-spectrum azole antifungal agent in clinical development for the treatment of invasive fungal infections. This study evaluated the potential for a pH-dependent pharmacokinetic interaction between posaconazole and an antacid (Mylanta), under fasting and nonfasting conditions. Twelve men completed this randomized, four-period crossover, single-dose study. Subjects received 200 mg of posaconazole following a 10-h fast, with 20 ml of Mylanta and a 10-h fast, with 20 ml of Mylanta and a high-fat breakfast, and with a high-fat breakfast alone. Antacid coadministration had no statistically significant effects on posaconazole bioavailability under fasting or nonfasting conditions. In the fasting state, antacid slightly increased the relative oral bioavailability of posaconazole by 15% (P = 0.296); in the nonfasting state, antacid decreased the relative bioavailability of posaconazole by 12% (P = 0.352). Food increased the relative oral bioavailability of posaconazole by 400% (P = 0.001). In conclusion, the effect of antacid on posaconazole exposure in the fasting or nonfasting state was small and is not considered clinically significant.

Effect of food on the relative bioavailability of two oral formulations of posaconazole in healthy adults.

AIMS: This randomized, crossover, single-dose study evaluated the relative oral bioavailability of posaconazole suspension and coprecipitate tablet formulations. Additionally, the study determined whether systemic exposure to posaconazole was affected by prandial status or by the fat content of a meal. METHODS: This was a randomized, open-label, four-way crossover, single-dose study in 20 healthy men. Posaconazole pharmacokinetics were evaluated over 72 h following a single oral dose of posaconazole suspension (200 mg/5 ml) administered with a high-fat meal, a nonfat breakfast, or after a 10 h fast, or posaconazole tablets (2 x 100 mg) administered with a high-fat meal. RESULTS: The posaconazole suspension showed a significant increase in bioavailability compared with the tablet (increase in AUC(0,72 h) = 137% (90% confidence interval (CI) 119%, 156% and Cmax = 123% (90% CI 104%, 146%). The mean increases in AUC(0,72 h) and Cmax values were about 400% when administered with a high-fat meal compared with administration of the suspension in the fasting state (AUC(0,72 h) 90% CI 343%, 448%; Cmax 90% CI 352%, 493%). Administration of the suspension with a nonfat meal enhanced exposure, resulting in an increase in AUC(0,72 h) of 264% (90% CI 231%, 302%) and in Cmax of 296% (90% CI 250%, 350%) relative to the fasted state. CONCLUSIONS: The suspension formulation of posaconazole was associated with enhanced systemic exposure and increased relative bioavailability compared with the tablet. Food substantially enhanced the rate and extent of posaconazole absorption in healthy subjects.

Pharmacokinetics of the active antifungal enantiomer, SCH 42427 (RR), and evaluation of its chiral inversion in animals following its oral administration and the oral administration of its racemate genaconazole (RR/SS).

Genaconazole (SCH 39304) is a potent triazole antifungal agent that is active both orally and topically. Genaconazole is a racemic mixture which contains 50% of the RR (SCH 42427) and 50% of the SS (SCH 42426) enantiomers. The RR isomer accounts for most of the antifungal activity of genaconazole. Serum concentrations of the RR and SS enantiomers were analyzed by a chiral HPLC method which involved extraction of serum with organic solvent followed by separation on a Cyclobond I column and quantification by UV absorbance at 205 nm. The bioavailability and pharmacokinetic profiles of the two enantiomers after oral administration of the racemate (genaconazole) were very similar in cynomolgus monkeys. In rats following dosing with genaconazole, the RR enantiomer had a lower C(max) and a longer t(1/2) than the SS enantiomer, while the AUC(I) values of the two enantiomers were similar. Based on chiral HPLC analysis, there was no evidence for the inversion of the RR to the SR isomer, or of the SS to the SR isomer, indicating that there was no chiral inversion of the RR or SS enantiomers in either species. Genaconazole at 20 mg/kg and the RR (SCH 42427) enantiomer at 10 mg/kg had very similar serum concentration-time profiles and C(max), AUC(I), and t(1/2) values for the RR enantiomer in both rats and monkeys, indicating that the two treatments were equivalent with respect to the bioavailability of the RR enantiomer.

Pharmacokinetics of Loratadine in Pediatric Subjects.

The pharmacokinetics of loratadine, a new nonsedating antihistamine, was studied in 14 pediatric volunteers between the ages of 8 to 12 years. In an open-label design, one volunteer (with body weight less than 30 kg) received 5 mg of loratadine syrup and 13 volunteers (with body weights greater than 30 kg) received 10 mg of loratadine syrup. Blood samples were collected up to 72 h after dosing. Plasma concentrations of loratadine and its metabolite, descarboethoxyloratadine, were determined by a specific and sensitive gas-liquid chromatographic method. Following a 10-mg dose as a syrup, plasma concentrations of loratadine and descarboethoxyloratadine could be determined up to 8 and 48 h, respectively. The maximum concentration (C(max)) of loratadine and descarboethoxyloratadine were approximately 4 ng ml(minus sign1) each. However, the AUC of the metabolite was about six times that of loratadine. The elimination phase half-life of descarboethoxyloratadine averaged about 13.8 hr. The pharmacokinetics of loratadine in pediatric subjects was similar to that in healthy adult volunteers.

Multiple-Dose Pharmacokinetics of Ceftibuten in Healthy Adults and Geriatric Volunteers.

The steady-state pharmacokinetics of ceftibuten, an orally active cephalosporin were investigated in 12 healthy male volunteers (19--38 years) and in 12 geriatric volunteers (65--76 years). Each received one 200-mg ceftibuten capsule every 12 h on days 1--3 and one capsule in the morning on day 4. Plasma and urine samples were collected at various times on days 1--4 and assayed by high-pressure liquid chromatographic method for ceftibuten and ceftibuten-trans, a conversion product. The T(max) for ceftibuten and ceftibuten-trans occurred at about 2 and 3 h, respectively, in both populations. The C(max) and AUC((0--12 h)) ranged from 10.8 to 12.4 &mgr;g ml(minus sign1) and from 47.5 to 55.1 &mgr;g h ml(minus sign1), respectively, for normal volunteers compared to 12.9--17.5 &mgr;g ml(minus sign1) and 62.3--87.1 &mgr;g h ml(minus sign1), respectively, for geriatric volunteers. The respective values for ceftibuten-trans in normal and geriatric volunteers were 1.3 and 1.3 &mgr;g ml(minus sign1), respectively, and 6.9--8.2 and 5.9--9.8 &mgr;g h ml(minus sign1). At steady state, the C(max) and AUC((0--12 h)) of ceftibuten-trans were about 10--11% and 13--16% those of ceftibuten in normal volunteers and about 8--9% and 9--11% those of ceftibuten, respectively, in geriatric volunteers. The accumulation factor of ceftibuten in normal volunteers was 1.1 as compared to 1.3 in geriatric volunteers. The terminal phase half-life was 2.5 h in healthy volunteers and 3.2 h in geriatric volunteers. Urinary excretion appeared to be the major route of elimination in both populations accounting for more than 90% of the dose recovered in the urine during the dosing interval. The results of this study demonstrate that ceftibuten, 200 mg given twice a day, is safe and well tolerated, is well absorbed, and that steady-state is achieved on days 3 and 4. There is some accumulation in the elderly, but dosage regimen based on age is not warranted.