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 .

Integrative Inducer Intervention and Transcriptomic Analyses Reveal the Metabolism of Paralytic Shellfish Toxins in Azumapecten farreri

“…Rifampicin mediation primarily occurs via its action on PXR . Studies have shown that rifampicin can induce dozens of genes in the CYP450 family, including CYP3A4, CYP2C9, CYP2D6, CYP2A13, and CYP24A1, among others. , There are also studies suggesting that rifampicin can induce ABCB1 (P-gp), but another study suggests that rifampicin may inhibit P-gp . There are important species differences in the ligand preferences of these xenobiotic-sensing receptors .…”

“…48,49 There are also studies suggesting that rifampicin can induce ABCB1 (P-gp), 50 but another study suggests that rifampicin may inhibit P-gp. 48 There are important species differences in the ligand preferences of these xenobiotic-sensing receptors. 51 In this study, it was found that the genes induced by rifampicin in A. farreri are quite distinct from those in human and other vertebrate experiments (Table S3).…”