Background Obesity is increasingly prevalent among people with HIV (PWH). Obesity can reduce drug exposure; however, limited data are available for long-acting (LA) antiretrovirals. We performed in-silico trials using physiologically based pharmacokinetic (PBPK) modelling to determine the effect of obesity on the exposure of LA cabotegravir and rilpivirine after the initial injection and after multiple injections. Methods Our PBPK model was verified against available clinical data for LA cabotegravir and rilpivirine in normal weight/overweight (body mass index (BMI) < 30 kg/m2) and in obese (BMI ≥30 kg/m2). Cohorts of virtual individuals were generated to simulate the exposure of LA cabotegravir/rilpivirine up to a BMI of 60 kg/m2. The fold change in LA cabotegravir and rilpivirine exposures (AUC) and trough concentrations (Cmin) for monthly and bimonthly administration were calculated for various BMI categories relative to normal weight (18.5-25 kg/m2). Results Obesity was predicted to impact more cabotegravir than rilpivirine with a decrease in cabotegravir AUC and Cmin of >35% for BMI >35 kg/m2 and in rilpivirine AUC and Cmin of >18% for BMI >40 kg/m2 at steady-state. A significant proportion of morbidly obese individuals were predicted to have both cabotegravir and rilpivirine Cmin below the target concentration at steady-state with the bimonthly administration but this was less frequent with the monthly administration. Conclusions Morbidly obese PWH are at risk of presenting suboptimal Cmin for cabotegravir/rilpivirine after the first injection but also at steady-state particularly with the bimonthly administration. Therapeutic drug monitoring is advised to guide dosing interval adjustment.

中文翻译：

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肥胖对长效卡博特韦和利匹韦林暴露的影响：模型研究

背景 肥胖在艾滋病毒感染者（PWH）中越来越普遍。肥胖可以减少药物暴露；然而，长效（LA）抗逆转录病毒药物的可用数据有限。我们使用基于生理学的药代动力学 (PBPK) 模型进行了计算机试验，以确定肥胖对初次注射和多次注射后 LA cabotegravir 和利匹韦林暴露的影响。方法 我们的 PBPK 模型根据 LA 卡博特韦和利匹韦林在正常体重/超重（体重指数 (BMI) < 30 kg/m2）和肥胖（BMI ≥ 30 kg/m2）的现有临床数据进行验证。生成虚拟个体队列来模拟 BMI 为 60 kg/m2 的 LA cabotegravir/rilpivirine 的暴露。计算不同BMI类别相对于正常体重(18.5-25 kg/m2)每月和每两个月给药的LA卡博特韦和利匹韦林暴露量(AUC)和谷浓度(Cmin)的倍数变化。结果 预计肥胖对卡博特韦的影响比利匹韦林更大，对于 BMI > 35 kg/m2 的卡博特韦林 AUC 和 Cmin 降低 > 35%，对于 BMI > 40 kg/m2 的利匹韦林 AUC 和 Cmin 降低 > 18%在稳态。预计每两个月一次给药时，很大一部分病态肥胖个体的卡博特韦和利匹韦林 Cmin 都低于稳态目标浓度，但每月一次给药时这种情况的频率较低。结论 病态肥胖的孕产妇在第一次注射后存在卡博特韦/利匹韦林 Cmin 不理想的风险，但也处于稳态，特别是每两个月一次注射时。建议进行治疗药物监测以指导给药间隔调整。