Inadequate Lopinavir Concentrations With Modified 8-Hourly Lopinavir/Ritonavir 4:1 Dosing During Rifampicin-based Tuberculosis Treatment in Children Living With HIV.
Inadequate Lopinavir Concentrations With Modified 8-Hourly Lopinavir/Ritonavir 4:1 Dosing During Rifampicin-based Tuberculosis Treatment in Children Living With HIV.
复制标题
DOI：
10.1097/inf.0000000000004047
复制
发表时间：
2023-10-01
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
当与利福平联合给药时，洛匹那韦/利托那韦血浆浓度显著降低。洛匹那韦/利托那韦的超级加强受到利托那韦单药不可用的限制，而每日两次给予复方洛匹那韦/利托那韦的双倍剂量在幼儿中产生次优的洛匹那韦浓度。我们评估了在接受以利福平为基础的抗结核治疗的HIV感染儿童中，每日增加剂量（改良的8小时1次洛匹那韦/利托那韦4：1）是否能维持洛匹那韦的治疗血药浓度。体重为3.0 - 19.9 kg的HIV/结核病合并感染儿童，接受以利福平为基础的抗结核治疗，开始或改用8小时液体洛匹那韦/利托那韦4：1，使用体重带给药方法增加每日剂量。在完成抗结核治疗后2周，恢复洛匹那韦/利托那韦标准每日两次给药。在抗结核治疗期间和完成抗结核治疗后4周进行血浆采样。在入组的20例儿童中，15例（1-7岁）有药代动力学样本可用于分析。洛匹那韦浓度（中位数[范围]），8小时一次洛匹那韦/利托那韦与利福平联合给药（n = 15）0 -24的曲线下面积为55.32 mg/h/L [0.30-398.7 mg/h/L]，Cmax为3.04 mg/L [0.03-18.6 mg/L]; C8 hr 0.90 mg/L [0.01-13.7 mg/L]）低于不含利福平的标准给药（n = 12;曲线下面积24 121.63 mg/h/L [2.56-487.3 mg/h/L]; Cmax 9.45 mg/L [0.39-26.4 mg/L]; C12 hr 3.03 mg/L [0.01-17.7 mg/L]）。在利福平联合治疗期间和治疗后，分别只有7/15（44.7%）和8/12（66.7%）例儿童达到目标给药前洛匹那韦浓度≥ 1 mg/L。洛匹那韦/利托那韦的改良8小时给药在同时进行抗结核治疗时未能达到足够的洛匹那韦浓度。抗结核治疗后标准剂量的亚治疗洛匹那韦暴露值得关注，需要进一步评价。
Lopinavir/ritonavir plasma concentrations are profoundly reduced when co-administered with rifampicin. Super-boosting of lopinavir/ritonavir is limited by nonavailability of single-entity ritonavir, while double-dosing of co-formulated lopinavir/ritonavir given twice-daily produces suboptimal lopinavir concentrations in young children. We evaluated whether increased daily dosing with modified 8-hourly lopinavir/ritonavir 4:1 would maintain therapeutic plasma concentrations of lopinavir in children living with HIV receiving rifampicin-based antituberculosis treatment. Children with HIV/tuberculosis coinfection weighing 3.0 to 19.9 kg, on rifampicin-based antituberculosis treatment were commenced or switched to 8-hourly liquid lopinavir/ritonavir 4:1 with increased daily dosing using weight-band dosing approach. A standard twice-daily dosing of lopinavir/ritonavir was resumed 2 weeks after completing antituberculosis treatment. Plasma sampling was conducted during and 4 weeks after completing antituberculosis treatment. Of 20 children enrolled; 15, 1–7 years old, had pharmacokinetics sampling available for analysis. Lopinavir concentrations (median [range]) on 8-hourly lopinavir/ritonavir co-administered with rifampicin (n = 15; area under the curve0–24 55.32 mg/h/L [0.30–398.7 mg/h/L]; Cmax 3.04 mg/L [0.03–18.6 mg/L]; C8hr 0.90 mg/L [0.01–13.7 mg/L]) were lower than on standard dosing without rifampicin (n = 12; area under the curve24 121.63 mg/h/L [2.56–487.3 mg/h/L]; Cmax 9.45 mg/L [0.39–26.4 mg/L]; C12hr 3.03 mg/L [0.01–17.7 mg/L]). During and after rifampicin cotreatment, only 7 of 15 (44.7%) and 8 of 12 (66.7%) children, respectively, achieved targeted pre-dose lopinavir concentrations ≥1mg/L. Modified 8-hourly dosing of lopinavir/ritonavir failed to achieve adequate lopinavir concentrations with concurrent antituberculosis treatment. The subtherapeutic lopinavir exposures on standard dosing after antituberculosis treatment are of concern and requires further evaluation.