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
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
收藏
页码:2489 / 2499
页数:11
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