Drug interaction potential of high-dose rifampicin in patients with pulmonary tuberculosis

Abstract

Accumulating evidence supports the use of higher doses of rifampicin for tuberculosis (TB) treatment. Rifampicin is a potent inducer of metabolic enzymes and drug transporters, resulting in clinically relevant drug interactions. To assess the drug interaction potential of higher doses of rifampicin, we compared the effect of high-dose rifampicin (40 mg/kg daily, RIF40) and standard-dose rifampicin (10 mg/kg daily, RIF10) on the activities of major cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp). In this open-label, single-arm, two-period, fixed-order phenotyping cocktail study, adult participants with pulmonary TB received RIF10 (days 1-15), followed by RIF40 (days 16-30). A single dose of selective substrates (probe drugs) was administered orally on days 15 and 30: caffeine (CYP1A2), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), midazolam (CYP3A), and digoxin (P-gp). Intensive pharmacokinetic blood sampling was performed over 24 hours after probe drug intake. In all, 25 participants completed the study. Geometric mean ratios (90% confidence interval) of the total exposure (area under the concentration versus time curve, RIF40 versus RIF10) for each of the probe drugs were as follows: caffeine, 105% (96%-115%); tolbutamide, 80% (74%-86%); omeprazole, 55% (47%-65%); dextromethorphan, 77% (68%-86%); midazolam, 62% (49%-78%), and 117% (105%-130%) for digoxin. In summary, high-dose rifampicin resulted in no additional effect on CYP1A2, mild additional induction of CYP2C9, CYP2C19, CYP2D6, and CYP3A, and marginal inhibition of P-gp. Existing recommendations on managing drug interactions with rifampicin can remain unchanged for the majority of co-administered drugs when using high-dose rifampicin. Clinical Trials registration number NCT04525235.

Keywords: drug interactions; high-dose rifampicin; metabolic phenotyping; tuberculosis.

Fig 1

Geometric mean ratios (%) of AUC values (RIF40 versus RIF10) with 90% CI for all the probe drugs. The solid line is the unity line (i.e., no difference between RIF10 and RIF40). The dashed lines represent the standard bioequivalence range of 80%–125% (20). GMR estimates with 90% CI entirely within this range were considered to indicate no significant additional interaction with RIF40. The dotted lines represent the range that indicates a mild additional interaction (≤twofold decrease or increase) (18, 19).

Fig 2

Comparison of midazolam and omeprazole PK with reference studies (with and without rifampicin). Figure A depicts GM AUC_0–∞ values (95% CI) of midazolam after an oral dose of 15 mg in healthy volunteers without and with rifampicin (A and B), as well as with RIF10 and RIF40 in our study (C and D). Figure B shows GM AUC values (95% CI) of omeprazole after an oral dose of 20 mg in healthy volunteers (AUC_0–∞) without and with rifampicin (A and B), as well as with RIF10 and RIF40 in our study (AUC_0–last, C and D). The AUC values from the reference studies were converted to h*ug/L for this figure (21, 22).

Fig 3

Schematic overview of the study design.