Evaluating pediatric tuberculosis dosing guidelines: A model-based individual data pooled analysis.
Evaluating pediatric tuberculosis dosing guidelines: A model-based individual data pooled analysis.
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DOI：
10.1371/journal.pmed.1004303
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发表时间：
2023-11
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影响因子：
15.8
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目前世界卫生组织（WHO）儿科结核病给药指南导致药物暴露不佳。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规模较小，导致研究之间的药代动力学结果具有较高的变异性和不确定性。我们汇总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，从而优化儿童结核病的剂量。我们使用非线性混合效应模型来表征利福平、异烟肼和吡嗪酰胺的药代动力学，并研究了人类免疫缺陷病毒（HIV）、抗逆转录病毒治疗（ART）、药物配方、年龄和体型与其药代动力学的关系。来自南非、赞比亚、马拉维和印度的387名儿童的数据可供分析; 47%为女性，39%感染艾滋病毒（95%接受抗逆转录病毒治疗）。中位（范围）年龄为2.2（0.2 - 15.0）岁，体重为10.9（3.2 - 59.3）kg。使用体型（异速生长）来衡量所有3种药物的清除率和分布容积。年龄影响利福平和异烟肼的生物利用度;在出生时，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），并且两种药物在2岁后达到完全的成人生物利用度。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%，并在3岁左右接近完全成熟。虽然艾滋病毒本身并不影响一线结核病药物的药代动力学，但利福平清除率降低了22（95% CI [13%，28%]; p < 0.001），吡嗪酰胺清除率高49%（95% CI [39%，57%]; p < 0.001）;异烟肼生物利用度降低39%（95% CI [32%，45%]; p < 0.001），依法韦仑组降低37%（95% CI [22%，52%]; p < 0.001）。对2010年世卫组织推荐的儿科结核病剂量的模拟显示，与成人值相比，大多数儿童的利福平暴露量较低，但3个月以下的儿童除外，由于清除不成熟，他们对所有药物的暴露量相对较高。对于体重25 kg的儿童，将3个月以上儿童的利福平剂量增加75 mg<25 kg and 150 mg for children weighing >可改善利福平暴露。我们的分析受到了汇总研究中协变量可用性差异的限制。3个月以上儿童的利福平暴露量低于成人，增加75或150 mg剂量可改善治疗。感染艾滋病毒的儿童暴露量的改变最有可能是由伴随的抗逆转录病毒疗法而不是艾滋病毒本身引起的。应进一步评价与洛匹那韦/利托那韦和依法韦仑的药物相互作用的重要性，并在未来的给药指南中予以考虑。ClinicalTrials.gov 注册号; NCT 02348177、NCT 01637558、ISRCTN 63579542 Lufina Galileya及其同事汇总了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，从而优化儿童结核病给药。最近对2010年世界卫生组织（WHO）推荐的结核病一线治疗的儿童药代动力学研究发现，利福平、异烟肼和吡嗪酰胺的暴露量不同，利福平是暴露量最低的药物。人类免疫缺陷病毒（HIV）与一线结核病药物暴露的相关性研究结果不一致，HIV、抗逆转录病毒药物、制剂、人口统计学以及不同样本处理和分析方法之间的关系尚不清楚。为了迅速缓解低利福平暴露，政策制定者一直在研究服用现有的固定剂量复方片剂沿着额外的75 mg或150 mg利福平片剂（补充）是否是优化儿童利福平剂量的好方法。我们汇总了来自3项大型研究的个体药代动力学数据，共收集了387名儿童，我们通过他们研究了HIV、抗逆转录病毒药物和制剂的相关性，并研究了利福平剂量增加75 mg或150 mg后的暴露量。年龄影响药物的生物利用度和清除率，并且体型与一线结核病药物的分布容积和药物清除率之间存在关联。HIV与一线结核病药物暴露无关;相反，抗逆转录病毒药物洛匹那韦/利托那韦增加了利福平暴露，减少了异烟肼和吡嗪酰胺暴露。增加利福平剂量可导致与成人中观察到的利福平暴露量相当的利福平暴露量，我们报告了利福平和异烟肼制剂之间的巨大差异，某些制剂的暴露量降低。有机会通过增加利福平剂量来迅速改善一线儿科结核病治疗，这可以通过利福平片剂补充到目前的固定剂量复方片剂来完成，作为世卫组织指南的一部分。未来的研究调查艾滋病毒与结核病药物暴露的关系，应探讨不同的抗逆转录病毒治疗与结核病药物暴露的关系，包括药物相互作用，由于管理的药物在同一时间。在可能的情况下，应密切监测接受艾滋病毒和结核病合并治疗的儿童是否存在药物相互作用引起的毒性或疗效降低。本研究的主要局限性是汇总研究之间的研究设计差异较小，这导致了一些不可归因的关联，我们将其归类为研究中心或研究关联。
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. 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. 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. ClinicalTrials.gov registration numbers; NCT02348177, NCT01637558, ISRCTN63579542 Lufina Galileya and colleagues pooled data from large pharmacokinetic studies to identify key covariates influencing drug exposure to optimize tuberculosis dosing in children. Recent pharmacokinetic studies in children on 2010 World Health Organization (WHO)-recommended first-line tuberculosis treatment found variable exposures of rifampicin, isoniazid, and pyrazinamide, with rifampicin being the drug achieving the lowest exposures. Findings of the association of human immunodeficiency virus (HIV) with the exposures of first-line tuberculosis drugs are inconsistent, and the relationships of HIV, antiretrovirals, formulation, demographics, and different sample processing and analysis methods are unclear. To rapidly mitigate the low rifampicin exposures, policymakers have been looking to investigate if taking the existing fixed dose combination tablet along with an additional 75 mg or 150 mg tablet of rifampicin alone (top-up) would be a good way to optimize rifampicin doses in children. We pooled individual pharmacokinetic data from 3 large studies, which gave us a total of 387 children through whom we investigated the association of HIV, antiretrovirals, and formulation, and investigated the exposures achieved after increasing rifampicin doses by 75 mg or 150 mg. Age affected drug bioavailability and clearance and there was an association between body size and both the volume of distribution and drug clearance of first-line tuberculosis drugs. HIV had no association with the exposures of first-line tuberculosis drugs; rather, the antiretroviral lopinavir/ritonavir increased rifampicin exposure and reduced isoniazid and pyrazinamide exposure. Increasing rifampicin doses can lead to rifampicin exposures comparable to those observed in adults, and we report large differences between rifampicin and isoniazid formulations with reduced exposures in some formulations. There are opportunities to rapidly improve first-line pediatric tuberculosis treatment through increasing rifampicin doses, which can be done through a rifampicin tablet top-up to the current fixed dose combination tablet as part of the WHO guidelines. Future studies investigating the association of HIV with tuberculosis drug exposures should explore the relationship of different antiretroviral therapies with tuberculosis-drug exposures, including drug–drug interactions due to administration of the drugs at the same time. Where possible, children on HIV and tuberculosis co-treatment should be closely monitored for possible toxicities or reduced efficacy arising from drug–drug interactions. The main limitation of our study is the small study design differences among the pooled studies, which led to some unattributable associations that we classified as site or study associations.