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Drug interaction potential of high-dose rifampicin in patients with pulmonary tuberculosis
Radboud Univ Nijmegen, Med Ctr, Dept Pharm, Nijmegen, Netherlands..ORCID iD: 0009-0008-6912-4163
TASK, Cape Town, South Africa..
Univ Cape Town, Div Pulmonol, Cape Town, South Africa.;Univ Cape Town, Dept Med, Cape Town, South Africa.;Univ Cape Town, Lung Inst, Cape Town, South Africa..
TASK, Cape Town, South Africa..
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2023 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 67, no 10, article id e0068323Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
American Society for Microbiology, 2023. Vol. 67, no 10, article id e0068323
Keywords [en]
tuberculosis, high-dose rifampicin, drug interactions, metabolic phenotyping
National Category
Pharmacology and Toxicology Pharmaceutical Sciences Respiratory Medicine and Allergy
Identifiers
URN: urn:nbn:se:uu:diva-522989DOI: 10.1128/aac.00683-23ISI: 001145398400001PubMedID: 37768317OAI: oai:DiVA.org:uu-522989DiVA, id: diva2:1837323
Funder
European Commission, TRIA2015-1102-PanACEAAvailable from: 2024-02-13 Created: 2024-02-13 Last updated: 2024-02-13Bibliographically approved

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Svensson, Elin M.

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