Effects of desvenlafaxine on the pharmacokinetics of desipramine in healthy adults.

The results of two single-center, two-period, open-label trials that evaluated the effects of multiple doses of desvenlafaxine on the pharmacokinetics of desipramine, a cytochrome P450 (CYP) 2D6 enzyme substrate, are presented. Healthy individuals aged 18-45 years were administered a single oral dose of 50 mg desipramine with and without 100 mg daily (n=34) or 400 mg daily (n=23) desvenlafaxine for 5 days. After coadministration of 100 mg desvenlafaxine, desipramine exposure, measured by peak plasma concentration (C(max)) and total area under the plasma concentration-versus-time curve (AUC), showed minimal increases of 25 and 17%, respectively; coadministration of 400 mg desvenlafaxine resulted in a 52% increase in desipramine C(max) and a 90% increase in AUC. For the 100 mg dose, the geometric least squares mean ratios and 90% confidence intervals (CIs) for desipramine AUC (117%; 90% CI 110-125%), 2-hydroxydesipramine AUC (114%; 90% CI 110-119%), and C(max) (110%; 90% CI 104-116%) were all within the 80-125% interval, showing the bioequivalence for AUC between desipramine administered alone and in combination with 100 mg desvenlafaxine. These results indicate that desvenlafaxine is a relatively weak inhibitor of CYP2D6 and that desvenlafaxine 100 mg, twice the recommended therapeutic dose of 50 mg, is unlikely to cause drug-drug interactions with CYP2D6 substrates.

Pharmacokinetics and metabolic disposition of sirolimus in healthy male volunteers after a single oral dose.

The pharmacokinetics and metabolic disposition of sirolimus (rapamycin, Rapamune), a macrocyclic immunosuppressive agent for the prevention of allograft rejection in organ transplantation, were investigated in 6 healthy male volunteers after a single nominal 40-mg oral dose of the C-radiolabeled drug, with the added aim of assessing the potential role of sirolimus metabolites in the clinical pharmacology of the parent drug. The absorption of parent drug and derived materials was rapid (tmax 1.3 +/- 0.5 hours, mean +/- SD), and the elimination of sirolimus was slow (t(1/2) 60 +/- 10 hours, mean +/- SD) in whole blood. The high whole blood to plasma (B/P) concentration ratio of sirolimus (142 +/- 39) was consistent with its extensive partitioning into formed blood elements. The markedly lower B/P value based on radioactivity (2.7 +/- 0.4) suggested that drug-derived products partitioned into formed blood elements to a much lesser extent. Based on AUC0-144h values, unchanged sirolimus represented an average 35% of total radioactivity in whole blood. Drug-derived products in whole blood were characterized by HPLC, LC/MS, and LC/MS/MS as 41-O-demethyl, 7-O-demethyl, and several hydroxy, dihydroxy, hydroxy-demethyl and didemethyl sirolimus metabolites. The percentage distribution of sirolimus metabolites in whole blood ranged from 3%-10% at 1 hour to 6%-17% at 24 hours after drug administration. Based on their low immunosuppressive activities and relative abundance in whole blood of humans after sirolimus administration, metabolites of sirolimus do not appear to play a major role in the clinical pharmacology of the parent drug. A majority of the administered radioactivity (91.0 +/- 8.0%) was recovered from feces, and only 2.2% +/- 0.9% was renally excreted.

Oral bioavailability of pantoprazole suspended in sodium bicarbonate solution.

The bioavailability of pantoprazole when administered as a suspension in sodium bicarbonate solution and as the oral tablet was studied. In an open-label, randomized, two-period crossover study, healthy fasting subjects received either one enteric-coated 40-mg pantoprazole tablet by mouth with 240 mL of water or 20 mL of a suspension prepared from one crushed pantoprazole tablet and 840 mg of sodium bicarbonate solution and administered via a nasogastric tube. Treatments were separated by a 48-hour washout period. Blood samples were collected at intervals up to 24 hours after drug administration for measurement of pantoprazole concentration by high-performance liquid chromatography (HPLC) and estimation of pharmacokinetic values. A separate study was conducted to determine pantoprazole's stability in the suspension for up to three months at 25, 5, and -20 degrees C; concentrations were measured by HPLC. Twelve subjects completed the study. The suspension yielded pantoprazole Cmax values similar to those of the tablet formulation, but the drug was 25% less bioavailable. There was no lag time for the suspension. The suspension was stable for up to two weeks at 5 degrees C and up to three months at -20 degrees C. A suspension of pantoprazole in sodium bicarbonate solution yielded a Cmax similar to that of the tablet formulation, and the drug was quickly absorbed. However, bio-availability was slightly lower with the suspension than with the tablet.