Drug Exposure of Long-Acting Cabotegravir and Rilpivirine in Older People With Human Immunodeficiency Virus: A Pharmacokinetic Modeling Study

Sara Bettonte; Mattia Berton; Felix Stader; Manuel Battegay; Catia Marzolini

doi:10.1093/ofid/ofae171

Drug Exposure of Long-Acting Cabotegravir and Rilpivirine in Older People With Human Immunodeficiency Virus: A Pharmacokinetic Modeling Study

Open Forum Infect Dis. 2024 Mar 21;11(4):ofae171. doi: 10.1093/ofid/ofae171. eCollection 2024 Apr.

Authors

Sara Bettonte^{1

2}, Mattia Berton^{1

2}, Felix Stader³, Manuel Battegay^{1

2}, Catia Marzolini^{1

2

4

5}

Affiliations

¹ Division of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical Research, University Hospital Basel, Basel, Switzerland.
² Faculty of Medicine, University of Basel, Basel, Switzerland.
³ Certara UK Limited, Sheffield, United Kingdom.
⁴ Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
⁵ Service and Laboratory of Clinical Pharmacology, Department of Laboratory Medicine and Pathology, University Hospital Lausanne and University of Lausanne, Lausanne, Switzerland.

Abstract

Background: The life expectancy of people with human immunodeficiency virus (PWH) has significantly increased, thanks to combined antiretrovirals with improved potency and tolerability. One further step has been achieved with the development of long-acting (LA) injectable antiretrovirals, which allow for infrequent dosing. However, the pharmacokinetics of LA antiretrovirals has been poorly characterized in older PWH, as they are generally excluded from trials. We performed virtual studies using physiologically based pharmacokinetic (PBPK) modeling to determine the anticipated exposure of LA cabotegravir/rilpivirine in older individuals.

Methods: Our PBPK model was verified against available observed data for LA cabotegravir and rilpivirine. Cohorts of virtual individuals aged 20-50, 50-65, or 65-85 years were generated to simulate the exposure of LA cabotegravir/rilpivirine for each age group. The fold changes in trough concentration (C_min) and in drug exposure (area under the time-concentration curve [AUC]) were determined for older relative to young individuals.

Results: The verified PBPK models predicted an increase in exposure within the 0.8-1.25 fold range for monthly LA cabotegravir/rilpivirine. The C_min and AUC were predicted to be 29% and 26% higher in older compared with young adults for LA cabotegravir administered bimonthly (every 2 months) and 46% and 41% higher for LA rilpivirine bimonthly. The C_min and AUC of LA cabotegravir and rilpivirine were predicted to be modestly increased in female compared with male individuals for all age groups.

Conclusions: LA cabotegravir/rilpivirine exposure and trough concentrations are predicted to be higher in older than in young PWH; thus, older adults could have a lower risk to present suboptimal concentrations during the dosing interval.

Keywords: PBPK modeling; cabotegravir; long acting; older adults; rilpivirine.