Accumulation of nifedipine after multiple doses

Abstract

The single and multiple dose pharmacokinetics of oral nifedipine capsules, 10 mg, have been examined in five patients with peripheral vasospasm. After a single dose, nifedipine was rapidly absorbed in three and slowly absorbed in two patients. Mean bioavailability parameters included a tmax of 2.9 h, a Cmax of 33.3 ng ml-1 and a AUC0-8 h of 113.3 ng h ml-1. After multiple dosing with either 10 or 20 mg every 8 h for 10 days the mean tmax at steady state was 2.1 h while the mean dose-corrected (to 10 mg) Cmax and AUC0-8 h were 51.9 ng ml-1 and 146.9 ng h ml-1, respectively. The mean elimination rate constant was 0.173 h-1 after both single and multiple doses. The mean extent of accumulation of nifedipine, defined as the ratio of AUC0-8 h (steady state)/AUC0-8 h (single dose), was 1.3; we concluded that nifedipine accumulates in the body when it is administered every 8 h. This should be taken into account when predicting steady state serum concentrations and haemodynamic effects of nifedipine from single dose kinetic data.

Biowaiver Monographs for Immediate-Release Solid Oral Dosage Forms: Nifedipine

“…The remaining dose is excreted in the feces as metabolites resulting from biliary excretion. The reported total body clearance ranges from 450 to 700 mL/min, which concurs with the mean elimination rate constant of 0.173 h −1 …”

“…The study results are in agreement with the conclusions derived independently from another study reported by Raemsch and Sommer However, the validity of results cannot be considered conclusive as the duration of pharmacokinetic studies was limited to 5 days that may not adequately reflect the conditions of chronic treatment. In a separate study reported by Lesko et al, accumulation of nifedipine following the multiple dosing was observed particularly when the dosage strength was increased from 10 to 20 mg per intake in 8 h intervals.…”

“…In a study reported by Lesko et al, nifedipine was well tolerated by subjects who received a maximum daily dose of 60 mg/day from the SGC formulation. The doses were continued for 5 days to achieve steady state.…”

“…However, no significant difference in C max or extent of absorption (AUC) was observed between the reported formulations. t max for the SGC ranged between 0.25 and 2.9 h . The average absolute BA for the oral to the intravenous (i.v.)…”

Factors affecting the absolute bioavailability of nifedipine.

“…When pharmacokinetic data were compared after oral administration of 20 mg nifedipine to healthy volunteers from Germany [9] and Japan [10], the Japanese subjects had significantly higher AUC and Cmax values [11]. Similarly, comparison of AUC data obtained in a number'of studies after the administration of either a single 10 mg capsule or a 20 mg slow release preparation to Caucasians [1, [12][13][14][15][16][17] and Mexican subjects [18][19][20] showed significantly higher AUC and Cmax values in the Mexicans.…”