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Clinical Pharmacology considerations and drug-drug interactions with long-acting cabotegravir and rilpivirine relevant to a sub-Saharan Africa
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  • Adrian Steulet,
  • Bonniface Obura,
  • Catriona Waitt,
  • Eva Laker,
  • Melanie Nicol,
  • Fiona Cresswell
Adrian Steulet
GHOL

Corresponding Author:adrian.steulet@bluewin.ch

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Bonniface Obura
University of Liverpool Department of Pharmacology and Therapeutics
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Catriona Waitt
University of Liverpool Department of Pharmacology and Therapeutics
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Eva Laker
Makerere University College of Health Sciences
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Melanie Nicol
University of Minnesota Twin Cities
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Fiona Cresswell
Brighton and Sussex Medical School
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Abstract

Long-acting injectable (LAI) cabotegravir and rilpivirine for HIV treatment and LAI cabotegravir for pre-exposure HIV prophylaxis are being rolled out in a multitude of countries worldwide. Due to the prolonged exposure, it can be challenging to undertake ‘traditional’ pharmacokinetic studies and current guidance is derived from their oral equivalents or physiologically-based pharmacokinetic studies. This review aims to consider pharmacokinetic characteristics of cabotegravir and rilpivirine and describe anticipated drug-drug interactions (DDIs) with frequent concomitant medications in African settings. Relevant comedications were identified from the WHO 2021 List of Essential Medicines. All original human and physiologically-based pharmacokinetic studies published in English on PubMed, discussing DDIs with LAI cabotegravir and rilpivirine prior to April 2023, were reviewed. The Liverpool HIV interaction database was also reviewed. LAI cabotegravir and rilpivirine have half-lives of 6-12 and 13-28 weeks, respectively. Cabotegravir is primarily metabolised by UDP-glucuronyltransferase (UGT)-1A1 and rilpivirine by cytochrome P450 (CYP)-3A4. LAI cabotegravir and rilpivirine themselves exhibit low risk of perpetrating interactions with comedications as they do not induce or inhibit the major drug metabolising enzymes. However, they are victims of DDIs relating to the induction of their metabolising enzymes by concomitantly administered medication. Noteworthy contraindicated comedications include rifamycins, carbamazepine, phenytoin, flucloxacillin and griseofulvin, which induce CYP3A4 and/or UGT1A1, causing clinically-significant reduced concentrations of rilpivirine and/or cabotegravir. In addition to virologic failure, subtherapeutic concentrations resulting from DDIs can lead to emergent drug resistance. Clinicians should be aware of potential DDIs and counsel people receiving LAI cabotegravir/rilpivirine appropriately to minimise risk.
Submitted to British Journal of Clinical Pharmacology
05 Feb 2024Review(s) Completed, Editorial Evaluation Pending
09 Feb 2024Editorial Decision: Revise Major
30 Mar 20241st Revision Received
04 Apr 2024Submission Checks Completed
04 Apr 2024Assigned to Editor
18 Apr 2024Reviewer(s) Assigned
29 Apr 2024Review(s) Completed, Editorial Evaluation Pending
09 May 2024Editorial Decision: Accept