Non-linear pharmacokinetics of rifampicin in healthy Asian Indian volunteers

Abstract

Objective: To characterise the pharmacokinetics of rifampicin (RMP) in healthy Asian Indian volunteers after oral administration of commercially marketed reference formulations.

Design: Two separate studies were conducted. In Study 1, 12 volunteers were administered a single 450 mg sugar-coated tablet, and in Study 2, 11 volunteers were administered a 30 ml suspension (100 mg/5 ml) equivalent to a 600 mg dose of RMP. Blood samples were collected at 0 hours and then at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 hours post dose, and plasma concentrations were assayed by high performance liquid chromatography.

Results: Non-compartmental analysis indicated that the mean (coefficient of variation [%CV]) values for the tablet for Cmax, Tmax and AUC(0-infinity) were 8.59 (53.66) microg/ml, 1.58 h and 49.54 (61.79) microg x h/ml, respectively. The corresponding mean (%CV) values for the suspension were 14.76 (24.14) microg/ml, 1.45 h and 119.12 (28.24) microg x h/ml. Two-compartment analysis indicated that the mean (%CV) values for Cl/F, beta and t(1/2beta) were respectively 197.51 (46.58) (ml/h)/kg, 0.2153 (32.01) h(-1) and 3.57 (34.85) h, at the 450 mg dose (tablet), and were significantly different from the respective 94.76 (33.96) (ml/h)/kg, 0.1210 (33.66) h(-1) and 5.44 (16.69) h at the 600 mg dose (suspension) (P < 0.05). In addition, there was a significant linear correlation (r = 0.60, P < 0.005, n = 21) between Cmax and the elimination half-life, indicating a concentration-dependent increase in half-life.

Conclusion: Rifampicin obeys two-compartment kinetics with zero order absorption, and exhibits non-linear saturable elimination kinetics as well as large inter-individual variability.