Rilpivirine (RPV) is a second generation antiretroviral (ARV) drug to treat patients with human immunodeficiency virus-1 (HIV-1) infection. In pivotal phase III trials, combinations of long-acting RPV (RPV LA) and cabotegravir LA (CAB) showed non-inferiority to the conventional oral three drug regimen. RPV LA is also being investigated alone for application in pre-exposure prophylaxis. Genetic polymorphisms and/or drug-drug interactions are known to influence the clearance of conventionally administered drugs but little is known about their influence on the pharmacokinetics of long-acting medicines. This work aimed to simulate the putative impact clearance changes on the pharmacokinetics of LAI RPV using physiologically-based pharmacokinetic modelling (PBPK)