Pharmacokinetics of standard versus high-dose isoniazid for treatment of multidrug-resistant tuberculosis

被引：7

作者：

Gausi, Kamunkhwala ^{[1
]}

Chirehwa, Maxwell ^{[1
]}

Ignatius, Elisa H. ^{[2
]}

Court, Richard ^{[1
,3
]}

Sun, Xin ^{[4
]}

Moran, Laura ^{[5
]}

Hafner, Richard ^{[6
]}

Wiesner, Lubbe ^{[1
]}

Rosenkranz, Susan L. ^{[7
]}

de Jager, Veronique ^{[8
]}

de Vries, Nihal ^{[9
]}

Harding, Joseph ^{[10
]}

Gumbo, Tawanda ^{[11
]}

Swindells, Susan ^{[12
]}

Diacon, Andreas ^{[8
]}

Dooley, Kelly E. ^{[2
]}

McIlleron, Helen ^{[1
,3
]}

Denti, Paolo ^{[1
]}

机构：

[1] Univ Cape Town, Div Clin Pharmacol, Cape Town, South Africa

[2] Johns Hopkins Univ, Sch Med, Baltimore, MD USA

[3] Univ Cape Town, Wellcome Ctr Infect Dis Res Africa CIDRI Africa, Inst Infect Dis & Mol Med, Cape Town, South Africa

[4] Harvard TH Chan Sch Publ Hlth, Boston, MA USA

[5] DLH Co, Social & Sci Syst, Silver Spring, MD USA

[6] Natl Inst Allergy & Infect Dis, Div AIDS, Bethesda, MD USA

[7] Frontier Sci Fdn, Brookline, MA USA

[8] Task Appl Sci, Cape Town, South Africa

[9] Brooklyn Chest Hosp, Cape Town, South Africa

[10] DP Marais Hosp, Cape Town, South Africa

[11] Baylor Univ, Med Ctr, Ctr Infect Dis Res & Expt Therapeut, Baylor Res Inst, Dallas, TX USA

[12] Univ Nebraska Med Ctr, Dept Internal Med, Omaha, NE USA

来源：

JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY | 2022年 / 77卷 / 09期

基金：

美国国家卫生研究院; 英国惠康基金;

关键词：

INCORPORATING AUTOINDUCTION; SEMIMECHANISTIC MODEL; DRUG; ETHIONAMIDE; METABOLISM; NEVIRAPINE; RIFAMPIN;

D O I：

10.1093/jac/dkac188

中图分类号：

R51 [传染病];

学科分类号：

100401 ;

摘要：

Background The WHO-endorsed shorter-course regimen for MDR-TB includes high-dose isoniazid. The pharmacokinetics of high-dose isoniazid within MDR-TB regimens has not been well described. Objectives To characterize isoniazid pharmacokinetics at 5-15 mg/kg as monotherapy or as part of the MDR-TB treatment regimen. Methods We used non-linear mixed-effects modelling to evaluate the combined data from INHindsight, a 7 day early bactericidal activity study with isoniazid monotherapy, and PODRtb, an observational study of patients on MDR-TB treatment including terizidone, pyrazinamide, moxifloxacin, kanamycin, ethionamide and/or isoniazid. Results A total of 58 and 103 participants from the INHindsight and PODRtb studies, respectively, were included in the analysis. A two-compartment model with hepatic elimination best described the data. N-acetyltransferase 2 (NAT2) genotype caused multi-modal clearance, and saturable first-pass was observed beyond 10 mg/kg dosing. Saturable isoniazid kinetics predicted an increased exposure of approximately 50% beyond linearity at 20 mg/kg dosing. Participants treated with the MDR-TB regimen had a 65.6% lower AUC compared with participants on monotherapy. Ethionamide co-administration was associated with a 29% increase in isoniazid AUC. Conclusions Markedly lower isoniazid exposures were observed in participants on combination MDR-TB treatment compared with monotherapy. Isoniazid displays saturable kinetics at doses >10 mg/kg. The safety implications of these phenomena remain unclear.

引用

页码：2489 / 2499

页数：11

共 43 条

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