Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
Antimicrob Agents Chemother. 2018 Jan 25;62(2). doi: 10.1128/AAC.00420-17. Print 2018 Feb.
Lopinavir-ritonavir forms the backbone of current first-line antiretroviral regimens in young HIV-infected children. As multidrug-resistant (MDR) tuberculosis (TB) frequently occurs in young children in high-burden TB settings, it is important to identify potential interactions between MDR-TB treatment and lopinavir-ritonavir. We describe the pharmacokinetics of and potential drug-drug interactions between lopinavir-ritonavir and drugs routinely used for MDR-TB treatment in HIV-infected children. A combined population pharmacokinetic model was developed to jointly describe the pharmacokinetics of lopinavir and ritonavir in 32 HIV-infected children (16 with MDR-TB receiving treatment with combinations of high-dose isoniazid, pyrazinamide, ethambutol, ethionamide, terizidone, a fluoroquinolone, and amikacin and 16 without TB) who were established on a lopinavir-ritonavir-containing antiretroviral regimen. One-compartment models with first-order absorption and elimination for both lopinavir and ritonavir were combined into an integrated model. The dynamic inhibitory effect of the ritonavir concentration on lopinavir clearance was described using a maximum inhibition model. Even after adjustment for the effect of body weight with allometric scaling, a large variability in lopinavir and ritonavir exposure, together with strong correlations between the pharmacokinetic parameters of lopinavir and ritonavir, was detected. MDR-TB treatment did not have a significant effect on the bioavailability, clearance, or absorption rate constants of lopinavir or ritonavir. Most children (81% of children with MDR-TB, 88% of controls) achieved therapeutic lopinavir trough concentrations (>1 mg/liter). The coadministration of lopinavir-ritonavir with drugs routinely used for the treatment of MDR-TB was found to have no significant effect on the key pharmacokinetic parameters of lopinavir or ritonavir. These findings should be considered in the context of the large interpatient variability found in the present study and the study's modest sample size.
洛匹那韦利托那韦是目前儿童 HIV 感染者一线抗逆转录病毒治疗方案的基础。由于在高负担结核病环境中，儿童经常发生耐多药结核病（TB），因此确定耐多药-TB 治疗与洛匹那韦利托那韦之间的潜在相互作用非常重要。我们描述了 HIV 感染儿童中洛匹那韦利托那韦与常规用于耐多药-TB 治疗的药物之间的药代动力学和潜在药物相互作用。我们开发了一个联合人群药代动力学模型，以联合描述 32 名 HIV 感染儿童（16 名患有 MDR-TB，接受高剂量异烟肼、吡嗪酰胺、乙胺丁醇、乙硫异烟胺、特立齐酮、氟喹诺酮和阿米卡星联合治疗，16 名无结核病）中洛匹那韦利托那韦的药代动力学，他们接受了洛匹那韦利托那韦的抗逆转录病毒方案。洛匹那韦和利托那韦的一级吸收和消除的单室模型被合并到一个综合模型中。利托那韦浓度对洛匹那韦清除的动态抑制作用采用最大抑制模型进行描述。即使在考虑了体重对异速缩放的影响后，仍发现洛匹那韦和利托那韦的暴露存在很大的变异性，并且洛匹那韦和利托那韦的药代动力学参数之间存在强烈的相关性。MDR-TB 治疗对洛匹那韦或利托那韦的生物利用度、清除率或吸收速率常数没有显著影响。大多数儿童（MDR-TB 患儿的 81%，对照组的 88%）达到了治疗性洛匹那韦谷浓度（>1 毫克/升）。洛匹那韦利托那韦与常规用于治疗耐多药结核病的药物联合使用，对洛匹那韦或利托那韦的关键药代动力学参数没有显著影响。这些发现应考虑到本研究中发现的大个体间变异性和研究的适度样本量。
