Bioequivalence of oral and injectable levoleucovorin and leucovorin.

The bioequivalence and bioavailability of oral and intravenous formulations of levoleucovorin and leucovorin were studied, and the absolute bioavailabilities of levoleucovorin and leucovorin tablet formulations were determined. Healthy male volunteers participated in two randomized, single-dose, four-way crossover studies. The treatment groups were as follows: A = five 2.5-mg levoleucovorin tablets, B = five 5-mg leucovorin tablets, C = one 12.5-mg levoleucovorin tablet, D = one 25-mg leucovorin tablet, in study 1; A = 15-mg levoleucovorin injection, B = two 7.5-mg levoleucovorin tablets, C = 30-mg leucovorin injection, D = two 15-mg leucovorin tablets, in study 2. Serum concentrations of N-5-methyltetrahydrofolate (the primary metabolite and circulating form of reduced folate after leucovorin administration) and total tetrahydrofolate were measured over 24 hours after dose administration. Pharmacokinetic values were calculated for N-5-methyltetrahydrofolate and total tetrahydrofolates; values were compared for A versus B, C versus D, A versus C, and B versus D in study 1 and A versus C and B versus D in study 2. Results from 35 men in study 1 and 33 in study 2 showed that 12.5-mg oral doses and 15-mg intravenous doses of levoleucovorin are bioequivalent to 25-mg oral doses and 30-mg intravenous doses of leucovorin, respectively. Equivalence was observed after oral and intravenous administration. The absolute bioavailability of levoleucovorin (74%) was not significantly different from that of leucovorin (65%).(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of food on the absorption of methotrexate sodium tablets in healthy volunteers.

OBJECTIVE: To examine the effect of food on the absorption and bioavailability of low-dose orally administered methotrexate sodium tablets. METHODS: In this randomized, 2-way crossover study, a 7.5-mg dose of methotrexate (three 2.5-mg tablets) was administered to 12 healthy male volunteers after an overnight fast or within 10 minutes of consuming a high fat-content breakfast. Serum methotrexate concentrations over the next 24 hours were used to determine the area under the concentration-time curve (AUC), the maximum concentration, the time to maximum concentration (tmax), and the serum half-life for each phase. RESULTS: Food delayed the tmax by approximately 30 minutes, but the extent of absorption, as measured by the AUC, for both phases was similar. CONCLUSION: These results demonstrate that the bioavailability of low-dose orally administered methotrexate sodium tablets is not influenced by food.

Bioequivalence of verapamil hydrochloride extended-release pellet-filled capsules when opened and sprinkled on food and when swallowed intact.

A study was performed to determine whether verapamil hydrochloride administered in extended-release pellet-filled capsules is bioequivalent to the same formulation administered by sprinkling the contents of the capsules onto food. Thirty-two healthy subjects participated in the randomized, two-way crossover study. In treatment A, the subjects swallowed the contents of a verapamil hydrochloride extended-release pellet-filled capsule, 240 mg, that had been sprinkled on applesauce. In treatment B, the subjects swallowed the same type of capsule intact. Blood samples were drawn at baseline, every hour for 10 hours, and at 12, 15, 24, 30, 36, and 48 hours after each dose administration. The plasma was analyzed for verapamil and norverapamil by high-performance liquid chromatography. The following calculations were performed: AUC0-48, AUC0-infinity, Cmax, tmax, and k. Results for the two treatments were compared by analysis of variance. There were no significant differences between the AUC0-48, AUC0-infinity, Cmax, tmax, and k for the two methods of dose administration. For verapamil the differences for all variables were less than 5%, and for norverapamil the differences were less than 4% for all variables except tmax (9.5%). The 90% confidence intervals were within acceptable limits for all variables except the norverapamil tmax comparison. Sprinkling the contents of extended-release pellet-filled capsules onto food provides verapamil hydrochloride that is bioequivalent to that obtained from the intact capsules.