The ASTRO-CM dose-finding pilot study investigated the role of adjunctive sertraline for the treatment of HIV-associated cryptococcal meningitis in HIV-infected Ugandan patients. The present study is a post hoc pharmacokinetic-pharmacodynamic analysis of the ASTRO-CM pilot study to provide insight into sertraline exposure–response–outcome relationships. We performed a population pharmacokinetic analysis using sertraline plasma concentration data and correlated various predicted PK-PD indices with the percentage change in log₁₀ CFU/mL from baseline. Sertraline clearance was 1.95-fold higher in patients receiving antiretroviral (ART), resulting in 49% lower drug exposure. To quantify the clinical benefit of sertraline, we estimated rates of fungal clearance from cerebrospinal fluid (CSF) of ASTRO-CM patients using Poisson model and compared the clearance rates to a historical control study (COAT) in which patients received standard Cryptococcus therapy of amphotericin B (0.7–1.0 mg/kg per day) and fluconazole (800 mg/day) without sertraline. Adjunctive sertraline significantly increased CSF fungal clearance rate compared to COAT trial and sertraline effect was dose-independent with no covariate found to affect fungal clearance including ART. Study findings suggest sertraline response could be mediated by different mechanisms than directly inhibiting the initiation of protein translation as previously suggested; this is supported by the prediction of unbound sertraline concentrations is unlikely to reach MIC concentrations in the brain. Study findings also recommend against the use of higher doses of sertraline, especially those greater than the maximum FDA-approved daily dose (200 mg/day), since they unlikely provide any additional benefits and come with greater costs and risk of adverse events.

中文翻译：

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舍曲林作为抗真菌药在感染艾滋病毒的乌干达隐球菌性脑膜炎患者中的药代动力学-药效学。


ASTRO-CM 剂量探索试点研究调查了辅助舍曲林治疗 HIV 感染乌干达患者的 HIV 相关隐球菌性脑膜炎的作用。本研究是 ASTRO-CM 试点研究的事后药代动力学-药效学分析，旨在深入了解舍曲林暴露-反应-结果关系。我们使用舍曲林血浆浓度数据进行群体药代动力学分析，并将各种预测的 PK-PD 指数与相对于基线的 log ₁₀ CFU/mL 的百分比变化相关联。接受抗逆转录病毒 (ART) 治疗的患者舍曲林清除率高出 1.95 倍，导致药物暴露量降低 49%。为了量化舍曲林的临床益处，我们使用泊松模型估计了 ASTRO-CM 患者脑脊液 (CSF) 中的真菌清除率，并将清除率与历史对照研究 (COAT) 进行比较，在该研究中，患者接受了两性霉素的标准隐球菌治疗B（每天 0.7–1.0 毫克/公斤）和氟康唑（800 毫克/天），不含舍曲林。与 COAT 试验相比，辅助舍曲林显着增加了脑脊液真菌清除率，并且舍曲林的效果与剂量无关，没有发现影响真菌清除率（包括 ART）的协变量。研究结果表明，舍曲林反应可能是通过不同的机制介导的，而不是像之前所建议的那样直接抑制蛋白质翻译的启动；未结合的舍曲林浓度不太可能达到大脑中的 MIC 浓度的预测支持了这一点。 研究结果还建议不要使用较高剂量的舍曲林，尤其是大于 FDA 批准的每日最大剂量（200 毫克/天）的舍曲林，因为它们不太可能提供任何额外的益处，并且会带来更大的成本和不良事件的风险。