Study objectives: Determine the intrasubject and
intersubject variability in, and the effects of food or antacids on,
the pharmacokinetics of rifampin (RIF).
Randomized, four-period crossover phase I study.
Subjects: Fourteen healthy male and female volunteers.
Interventions: Subjects ingested single doses of RIF, 600
mg, under fasting conditions twice, with a high-fat meal, and with
aluminum-magnesium antacid. They also received standard doses of
isoniazid, pyrazinamide, and ethambutol.
and main results: Serum was collected for 48 h and assayed
by high-pressure liquid chromatography. Data were analyzed using
noncompartmental methods and a compartmental analysis using
nonparametric expectation maximization. Both fasting conditions
produced similar results: a mean RIF maximal serum concentration (Cmax)
of 10.54 ± 3.18 μg/mL, the time at which it occurred (Tmax) of
2.42 ± 1.32 h, and the area under the curve from time zero to
infinity (AUC0–∞) of 57.15 ± 13.41 μg ·
h/mL. These findings are similar to those reported previously. Antacids
did not alter these parameters (Cmax of 10.89 ± 5.22 μg/mL, Tmax
of 2.36 ± 1.28 h, and AUC0–∞ of 58.37 ± 18.49μ
g · h/mL). In contrast, the Food and Drug Administration
high-fat meal reduced RIF Cmax by 36% (7.27 ± 2.29 μg/mL), nearly
doubled Tmax (4.43 ± 1.09 h), but reduced AUC0–∞ by
only 6% (55.20 ± 14.48 μg · h/mL).
Conclusions: These changes in Cmax, Tmax, and
AUC0–∞ can be avoided by giving RIF on an empty stomach
Abbreviations: ANOVA = analysis of
variance; AUC = area under the curve; AUC0–∞ = area
under curve from time zero to infinity; C = clearance;
CI = confidence interval; ClCr = creatine clearance; Clr = renal
clearance; Cmax = maximal serum concentration; CV = coefficient of
variation; EMB = ethambutol; HPLC = high-pressure liquid
chromatography; INH = isoniazid; K = elimination rate constant;
ka = absorption rate constant; MIC = minimal inhibitory
concentration; NPEM = nonparametric expectation maximization;
PZA = pyrazinamide; QC = quality control; RIF = rifampin;
Tmax = time at which maximal serum concentration occurred;
V = volume of distribution