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Effect of Obesity on the Exposure of Long-acting Cabotegravir and Rilpivirine: A Modeling Study
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Clinical Infectious Diseases 03 February 2024
Sara Bettonte,1,2 Mattia Berton,1,2 Felix Stader,3 Manuel Battegay,1,2 and Catia Marzolini1,2,4,5,
1Division of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical Research, University Hospital Basel, Basel, Switzerland; 2Faculty of Medicine, University of Basel, Basel, Switzerland; 3Certara UK Limited, Sheffield, United Kingdom; 4Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom; and 5Service and Laboratory of Clinical Pharmacology, Department of Laboratory Medicine and Pathology, University Hospital Lausanne and University of Lausanne, Lausanne, Switzerland
Abstract
Background
Obesity is increasingly prevalent among people with human immunodeficiency virus (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) modeling 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 (area under the curve [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.
The use of a longer needle (2-inch needle) in obese individuals was shown to significantly increase the trough concentration (Cmin) of LA cabotegravir after the initial injection, as it helps to reach the muscle rather than the subcutaneous adipose tissue, where blood flow is reduced which could result in lower initial concentrations [16]. Data from the FLAIR, ATLAS, and ATLAS-2 M studies have also shown that LA cabotegravir and rilpivirine could be impacted differently by obesity as, unlike cabotegravir, rilpivirine concentrations were comparable between normal weight/overweight and obese individuals after the initial injection [16], which could possibly be explained by differences in the physicochemical properties.
Importantly, our simulations indicate that morbidly obese individuals are at risk of presenting suboptimal trough concentrations for cabotegravir and rilpivirine not only after the first injection but also at steady-state particularly with the bimonthly administration. This finding is supported by the data of the Dutch ATHENA cohort reporting low cabotegravir or rilpivirine concentrations in two obese PWH (BMI: 31.5 and 45.5 kg/m2) who had a documented viral failure 8 and 13 months after the initiation of the LA treatment [31]. Long needles were used in these individuals and none of them had other risk factors for virological failure. Our findings and these real-life data suggest that caution is needed in obese and in morbidly obese individuals for whom TDM is advised to guide dosing interval adjustment. Our simulations suggest indeed that shortening the dosing interval from 8 to 4 weeks results in a lower proportion of morbidly individuals with concentrations predicted to be below the minimal thresholds at steady-state both for LA cabotegravir and rilpivirine.
Another limitation is that the PBPK model assumed that all the virtual subjects received the injection in the ventrogluteal muscles; however, real-life data have shown that the injected drug depot is not always deposited the muscle but sometimes also in the subcutaneous adipose tissue which can impact the drug release from the depot and thereby contribute to the variability in drug concentrations [33]. The probability of injecting LA cabotegravir/rilpivirine in the adipose tissue rather than the muscle is higher in obese PWH as the adipose layer is thicker compared to the one in normal weight individuals [34]. Thus, it is critical that injections are done with a longer needle in obese PWH.
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