Non-linear pharmacokinetics of rifampicin in healthy Asian Indian volunteers

OBJECTIVE: To characterise the pharmacokinetics of rifampicin (RMP) in heal thy Asian Indian volunteers after oral administration of commercially marke ted reference formulations. DESIGN: Tw separate studies were conducted. In Study 1, 12 volunteers were administered a single 450 mg sugar-coated tablet, and in Study 2, 11 volunt eers were administered a 30 mi 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 plasm a 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 C-max, T-max and AUC(0.infinity ), were 8.59 (53.66) mug/ml, 1.58 h and 43.54 (61.79) mug x h/ml, respectiv ely. The corresponding mean (%CV) values for the suspension were 14.76 (24. 14) mug/ml, 1.45 h and 119.12 (28.24) mug x h/ml. Two-compartment analysis indicated that the mean (%CV) values for Cl/F, P and t(1/2 beta) were respe ctively 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 resp ective 94.76 (33.36) (ml/h)/kg, 0.1210 (33.66) h(-1) and 5.34 (16.69) h at the 600 mg dose (suspension) (P < 0.05). In addition, there was a significa nt linear correlation (r 0.60, P < 0.005, n = 21) between C-max and the eli mination half-life, indicating a concentration-dependent increase in half-l ife. CONCLUSION: Rifampicin obeys two-compartment kinetics with zero order absor ption, and exhibits nonlinear saturable elimination kinetics as well as lar ge inter-individual variability.