背景:目前的世界卫生组织(WHO)儿科结核病给药指南导致药物暴露次优。确定改变这些药物在儿童中暴露的因素对于剂量优化至关重要。儿科药代动力学研究通常很小,导致研究之间药代动力学结果的高度可变性和不确定性。我们汇集了来自大型药代动力学研究的数据,以确定影响药物暴露的关键协变量,以优化儿童结核病给药。
结果:我们使用非线性混合效应模型来表征利福平的药代动力学,异烟肼,还有吡嗪酰胺,并调查了人类免疫缺陷病毒(HIV)的关联,抗逆转录病毒疗法(ART),药物制剂,年龄,和身体大小及其药代动力学。来自南非的387名儿童的数据,赞比亚,马拉维,和印度可以进行分析;47%是女性,39%感染艾滋病毒(95%接受抗逆转录病毒疗法)。中位(范围)年龄为2.2(0.2至15.0)岁,体重为10.9(3.2至59.3)kg。使用身体大小(异形测量)来缩放所有3种药物的清除率和分布体积。年龄影响利福平和异烟肼的生物利用度;出生时,儿童有48.9%(95%置信区间(CI)[36.0%,61.8%];p<0.001)和64.5%(95%CI[52.1%,78.9%];p<0.001)成人利福平和异烟肼的生物利用度,分别,两种药物在2岁后达到完全成人生物利用度。年龄也影响所有药物的清除(成熟),儿童在出生后3个月左右达到成人药物清除能力的50%,在3岁左右接近完全成熟.虽然HIV本身并不影响一线结核病药物的药代动力学,利福平清除率降低22%(95%CI[13%,28%];p<0.001)和吡嗪酰胺清除率高出49%(95%CI[39%,57%];p<0.001)儿童服用洛匹那韦/利托那韦;异烟肼的生物利用度降低了39%(95%CI[32%,45%];p<0.001)当同时与洛匹那韦/利托那韦联合给药时,降低37%(95%CI[22%,52%];p<0.001)在儿童上使用依非韦仑。2010年世卫组织推荐的儿科结核病剂量模拟显示,与成人价值观相比,大多数儿童的利福平暴露率较低,除了三个月以下的人,他们对所有药物的暴露量相对较高,由于不成熟的间隙。对于体重<25kg的儿童,将3个月以上的儿童中的利福平剂量增加75mg,对于体重>25kg的儿童,增加150mg可以改善利福平暴露。我们的分析受到合并研究中协变量可用性差异的限制。
结论:3个月以上的儿童利福平暴露量低于成人,增加75或150mg的剂量可以改善治疗。感染艾滋病毒的儿童暴露的改变很可能是由伴随的ART引起的,而不是艾滋病毒本身。与洛匹那韦/利托那韦和法韦仑的药物-药物相互作用的重要性应进一步评估,并在未来的给药指导中予以考虑。
背景:ClinicalTrials.gov注册号;NCT02348177,NCT01637558,ISRCTN63579542。
BACKGROUND: The current World Health Organization (WHO) pediatric tuberculosis dosing
guidelines lead to suboptimal drug exposures. Identifying factors altering the exposure of these drugs in children is essential for dose optimization. Pediatric pharmacokinetic studies are usually small, leading to high variability and uncertainty in pharmacokinetic results between studies. We pooled data from large pharmacokinetic studies to identify key covariates influencing drug exposure to optimize tuberculosis dosing in children.
RESULTS: We used nonlinear mixed-effects modeling to characterize the pharmacokinetics of rifampicin, isoniazid, and pyrazinamide, and investigated the association of human immunodeficiency virus (HIV), antiretroviral therapy (ART), drug formulation, age, and body size with their pharmacokinetics. Data from 387 children from South Africa, Zambia, Malawi, and India were available for analysis; 47% were female and 39% living with HIV (95% on ART). Median (range) age was 2.2 (0.2 to 15.0) years and weight 10.9 (3.2 to 59.3) kg. Body size (allometry) was used to scale clearance and volume of distribution of all 3 drugs. Age affected the bioavailability of rifampicin and isoniazid; at birth, children had 48.9% (95% confidence interval (CI) [36.0%, 61.8%]; p < 0.001) and 64.5% (95% CI [52.1%, 78.9%]; p < 0.001) of adult rifampicin and isoniazid bioavailability, respectively, and reached full adult bioavailability after 2 years of age for both drugs. Age also affected the clearance of all drugs (maturation), children reached 50% adult drug clearing capacity at around 3 months after birth and neared full maturation around 3 years of age. While HIV per se did not affect the pharmacokinetics of first-line tuberculosis drugs, rifampicin clearance was 22% lower (95% CI [13%, 28%]; p < 0.001) and pyrazinamide clearance was 49% higher (95% CI [39%, 57%]; p < 0.001) in children on lopinavir/
ritonavir; isoniazid bioavailability was reduced by 39% (95% CI [32%, 45%]; p < 0.001) when simultaneously coadministered with lopinavir/
ritonavir and was 37% lower (95% CI [22%, 52%]; p < 0.001) in children on efavirenz. Simulations of 2010 WHO-recommended pediatric tuberculosis doses revealed that, compared to adult values, rifampicin exposures are lower in most children, except those younger than 3 months, who experience relatively higher exposure for all drugs, due to immature clearance. Increasing the rifampicin doses in children older than 3 months by 75 mg for children weighing <25 kg and 150 mg for children weighing >25 kg could improve rifampicin exposures. Our analysis was limited by the differences in availability of covariates among the pooled studies.
CONCLUSIONS: Children older than 3 months have lower rifampicin exposures than adults and increasing their dose by 75 or 150 mg could improve therapy. Altered exposures in children with HIV is most likely caused by concomitant ART and not HIV per se. The importance of the drug-drug interactions with lopinavir/
ritonavir and efavirenz should be evaluated further and considered in future dosing guidance.
BACKGROUND: ClinicalTrials.gov registration numbers; NCT02348177, NCT01637558, ISRCTN63579542.