Donald P R, Parkin D P, Seifart H I, Schaaf H S, van Helden P D, Werely C J, Sirgel F A, Venter A, Maritz J S
Paediatrics and Child Health, Faculty of Health Sciences, Stellenbosch University, PO Box 19063, Tygerberg 7505, South Africa.
Eur J Clin Pharmacol. 2007 Jul;63(7):633-9. doi: 10.1007/s00228-007-0305-5. Epub 2007 May 16.
This study evaluated the pharmacokinetics of isoniazid (INH) associated with optimal early bactericidal activity (EBA), defined as 90% of the maximum EBA (EBA(90)) and the influence of N-acetyltransferase-2 (NAT2) subtype on the ability of pulmonary tuberculosis (PTB) patients to reach the identified pharmacokinetic values after INH doses ranging from 0.2 to 10-12 mg/kg body weight.
INH serum concentrations and NAT2 subtype were determined during four studies of PTB patients in three of whom the EBA of INH was determined. The relationship of EBA to area under the curve (AUC) (AUC(0-infinity)) and 2-h serum concentrations was examined by exponential regression and fitted curves estimated the AUC(0-infinity) and 2-h serum concentrations at which EBA(90) was reached.
EBA(90) was reached at an AUC(0-infinity) of 10.52 microg/ml per hour and 2-h serum concentrations of 2.19 microg/ml. An AUC(0-infinity) of 10.52 microg/ml per hour was reached by all 66 patients receiving a 10-12 mg/kg INH dose and all 21 receiving 6 mg/kg, except 1 of 10 (10%) homozygous fast (FF) acetylators; however, at 5 mg/kg, 4 of 12 (33%) FF and 26 of 27 (96%) heterozygous fast (FS), but all 21 homozygous slow (SS) acetylators did so; and 1 of 3 (33%) FF, 2 of 6 (33%) FS, but all 4 SS acetylators at dose 3 mg/kg. An INH 2-h serum concentration of 2.19 microg/ml was reached by all 66 patients receiving 10-12 mg/kg and all 21 receiving 6 mg/kg, except for 2 (20%) FF acetylators at a dose of 5 mg/kg; however, only 3 (25%) of 12 FF acetylators, but 26 (96%) of 27 FS acetylators, and all 21 SS acetylators reached this concentration; and at a dose of 3 mg/kg, 1 (33%) of 3 FF acetylators, 2 (33%) of 6 FF, but all 4 SS acetylators.
At a 6 mg/kg dose, all except a minority of FF NAT2 acetylators, achieve an INH AUC(0-infinity) and 2-h INH serum concentrations associated with EBA(90), as did all 4 SS acetylators receiving 3 mg/kg. Any dose reduction below 6 mg/kg body weight will tend to disadvantage a significant proportion of faster acetylators, but, conversely, SS acetylators require only a 3 mg/kg dose to achieve a satisfactory exposure to INH.
本研究评估了与最佳早期杀菌活性（EBA）相关的异烟肼（INH）的药代动力学，最佳早期杀菌活性定义为最大EBA的90%（EBA(90)），并评估了N - 乙酰转移酶 - 2（NAT2）亚型对肺结核（PTB）患者在接受0.2至10 - 12mg/kg体重的INH剂量后达到确定药代动力学值能力的影响。
在四项针对PTB患者的研究中测定了INH血清浓度和NAT2亚型，其中三项研究测定了INH的EBA。通过指数回归研究EBA与曲线下面积（AUC）（AUC(0 - ∞)）和2小时血清浓度的关系，并通过拟合曲线估计达到EBA(90)时的AUC(0 - ∞)和2小时血清浓度。
当AUC(0 - ∞)为每小时10.52μg/ml且2小时血清浓度为2.19μg/ml时达到EBA(90)。所有接受10 - 12mg/kg INH剂量的66名患者以及所有接受6mg/kg剂量的21名患者，除了10名纯合快速（FF）乙酰化者中的1名（10%）外，均达到了每小时10.52μg/ml的AUC(0 - ∞)；然而，在5mg/kg剂量时，12名FF中的4名（33%）和27名杂合快速（FS）中的26名（96%）达到了，但所有21名纯合缓慢（SS）乙酰化者均达到；在3mg/kg剂量时，3名FF中的1名（33%）、6名FS中的2名（33%），但所有4名SS乙酰化者均达到。所有接受10 - 12mg/kg剂量的66名患者以及所有接受6mg/kg剂量的21名患者，除了5mg/kg剂量时2名（20%）FF乙酰化者外，均达到了2.19μg/ml的INH 2小时血清浓度；然而，12名FF乙酰化者中只有3名（25%），但27名FS乙酰化者中有26名（96%）以及所有21名SS乙酰化者达到了该浓度；在3mg/kg剂量时，3名FF乙酰化者中的1名（33%）、6名FF中的2名（33%），但所有4名SS乙酰化者均达到。
在6mg/kg剂量时，除少数FF NAT2乙酰化者外，所有患者均达到了与EBA(90)相关的INH AUC(0 - ∞)和2小时INH血清浓度，接受3mg/kg剂量的所有4名SS乙酰化者也是如此。体重低于6mg/kg的任何剂量降低都可能使相当一部分快速乙酰化者处于不利地位，但相反，SS乙酰化者只需3mg/kg剂量就能获得满意的INH暴露量。
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