Assessing potential drug-drug interactions between clofazimine and other frequently used agents to treat drug-resistant tuberculosis.

Autor:	Kengo A; Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa., Nabeemeeah F; Perinatal HIV Research Unit (PHRU), University of the Witwatersrand, Johannesburg, South Africa., Denti P; Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa., Sabet R; Perinatal HIV Research Unit (PHRU), University of the Witwatersrand, Johannesburg, South Africa., Okyere-Manu G; Perinatal HIV Research Unit (PHRU), University of the Witwatersrand, Johannesburg, South Africa., Abraham P; Perinatal HIV Research Unit (PHRU), University of the Witwatersrand, Johannesburg, South Africa., Weisner L; Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa., Mosala MH; Perinatal HIV Research Unit (PHRU), University of the Witwatersrand, Johannesburg, South Africa., Tshabalala S; Bioengineering and Integrated Genomics Group, Council for Scientific and Industrial Research, Pretoria, South Africa., Scholefield J; Bioengineering and Integrated Genomics Group, Council for Scientific and Industrial Research, Pretoria, South Africa., Resendiz-Galvan JE; Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa., Martinson NA; Perinatal HIV Research Unit (PHRU), University of the Witwatersrand, Johannesburg, South Africa.; Johns Hopkins University Center for Tuberculosis Research, Division of Infectious Diseases, School of Medicine, Baltimore, Maryland, USA., Variava E; Perinatal HIV Research Unit (PHRU), University of the Witwatersrand, Johannesburg, South Africa.; Department of Internal Medicine, University of the Witwatersrand, Klerksdorp/Tshepong Hospital Complex North-West Province, Klerksdorp-Tshepong, South Africa.
Jazyk:	angličtina
Zdroj:	Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2024 May 02; Vol. 68 (5), pp. e0158323. Date of Electronic Publication: 2024 Apr 10.
DOI:	10.1128/aac.01583-23
Abstrakt:	Clofazimine is included in drug regimens to treat rifampicin/drug-resistant tuberculosis (DR-TB), but there is little information about its interaction with other drugs in DR-TB regimens. We evaluated the pharmacokinetic interaction between clofazimine and isoniazid, linezolid, levofloxacin, and cycloserine, dosed as terizidone. Newly diagnosed adults with DR-TB at Klerksdorp/Tshepong Hospital, South Africa, were started on the then-standard treatment with clofazimine temporarily excluded for the initial 2 weeks. Pharmacokinetic sampling was done immediately before and 3 weeks after starting clofazimine, and drug concentrations were determined using validated liquid chromatography-tandem mass spectrometry assays. The data were interpreted with population pharmacokinetics in NONMEM v7.5.1 to explore the impact of clofazimine co-administration and other relevant covariates on the pharmacokinetics of isoniazid, linezolid, levofloxacin, and cycloserine. Clofazimine, isoniazid, linezolid, levofloxacin, and cycloserine data were available for 16, 27, 21, 21, and 6 participants, respectively. The median age and weight for the full cohort were 39 years and 52 kg, respectively. Clofazimine exposures were in the expected range, and its addition to the regimen did not significantly affect the pharmacokinetics of the other drugs except levofloxacin, for which it caused a 15% reduction in clearance. A posteriori power size calculations predicted that our sample sizes had 97%, 90%, and 87% power at P < 0.05 to detect a 30% change in clearance of isoniazid, linezolid, and cycloserine, respectively. Although clofazimine increased the area under the curve of levofloxacin by 19%, this is unlikely to be of great clinical significance, and the lack of interaction with other drugs tested is reassuring. Competing Interests: The authors declare no conflict of interest.
Databáze:	MEDLINE
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