Introduction

As of 2021, the Joint United Nations Programme on HIV/AIDS (UNAIDS) reported that 38.4 million people were living with HIV across the world and about half of these were women and girls [1]. Many countries around the world have adopted the test-and-treat strategy for managing HIV treatment as recommended by WHO [2, 3]. This implementation has contributed to improvement of viral suppression and has been associated with a reduced risk of HIV transmission, better quality of life, and increased life expectancy in people living with HIV [4-7]. Despite this overwhelming evidence, UNAIDS estimates that only 81% of pregnant women accessed antiretroviral drugs in 2021 to prevent transmission of HIV to their children [1].
Pregnant women often experience nausea and vomiting and/or difficulty swallowing which could contribute to the challenges associated using oral antiretroviral drugs in this population [8, 9]. Frequent oral administration of drugs can also pose different pharmacological and psychosocial challenges when managing a chronic condition like HIV [10, 11]. Reduction in drug adherence is often observed over time with increased risk of therapeutic failure and development of drug resistance [10, 12]. In contrast, long-acting formulations have advantages including, significantly reducing pill burden, consequently improving drug adherence and by-passing various barriers associated with oral administration [11, 13]. These characteristics make them a potential suitable treatment option for pregnant women experiencing the difficulties regarding oral administration. Recently, long-acting injectable (LAI) cabotegravir (CAB) and LAI rilpivirine (RPV) were approved by the FDA and EMA [11]. Both LAI CAB and LAI RPV are co-packaged in separate vials with approved doses of 600 mg & 400 mg CAB and 900 mg & 600 mg RPV, prepared for intra-muscular injections.
Pregnancy is associated with anatomical, physiological, and metabolic changes that influence pharmacokinetics (PK) [14]. Though intramuscular (IM) administration of antiretrovirals might overcome some effects of pregnancy on oral drug absorption, it remains vulnerable to pregnancy effects on drug distribution, metabolism, and elimination [14, 15]. For instance, CAB and RPV are mainly metabolised by uridine diphosphate-glucuronosyltransferase (UGT) 1A1 and cytochrome P450 (CYP) 3A4 respectively, with minor contributions from UGT1A9 for CAB [13, 16] and studies have suggested that the activities of both enzymes are upregulated in pregnancy [17, 18]. Limited clinical PK data on LAI CAB and LAI RPV during pregnancy at the time of approval by regulatory agencies implies there is inadequate information to guide the dosing of the IM formulations of the drugs in pregnant women [16]. With LAI CAB and LAI RPV, pregnant women might benefit from the less frequent drug administration and as an alternative regimen unaffected by nausea and vomiting. However, the approved dosing regimen of these drugs in adults could be at risk of reduced drug concentrations in pregnancy which might fall below the effective plasma concentration thresholds associated with adequate viral suppression. The commonly adopted target Ctrough for CAB is 4 times the protein-adjusted-IC90 (4*PAIC90 = 0.664 μg/ml). For RPV, different Ctrough targets exist which include the protein binding-adjusted EC90 for RPV (PAEC90 = 12 ng/ml) and 50 ng/ml (an approximation of its 4*PAEC90 = 48 ng/ml) [19, 20]. Another higher target Ctrough of 70 ng/ml was recently recommended for clinical practice to reduce the risk of the development of viral resistance to RPV [19]. Inadequate viral suppression increases the risk of perinatal HIV transmission and potential development of viral drug resistance. Currently, there is insufficient clinical data on the PK of LAI CAB and LAI RPV in pregnancy. Moreover, a small amount of data suggests that plasma concentrations of oral RPV are reduced in pregnancy [20, 21]. The common exclusion of pregnant women from many clinical trials leads to limited clinical data available to guide drug dosing in the pregnant population [22]. However, computational tools are increasingly employed to predict the impact of pregnancy on PK [18, 23, 24].
Physiologically-based pharmacokinetic (PBPK) models are mechanistic tools capable of representing the mechanisms involved in drug disposition within biological systems. PBPK models employ mathematical equations to integrate biological system information of a population along with drug-specific parameters towards characterising the disposition of the drug within the system [25]. Usually, anatomical, physiological, and demographical data of a population are used to define the biological system parameters. Similarly, the drug-specific parameters are comprised of physicochemical properties of the drug (e.g. acid dissociation constant and lipophicility) and in vitro data on the drug (e.g. fraction of unbound drug in plasma and intrinsic enzymatic clearance of the drug) [25, 26]. In this study, we developed and qualified a pregnancy PBPK model to evaluate if the dosing regimens of LAI CAB and LAI RPV approved or us in adults could maintain the respective Ctrough targets for CAB and RPV during pregnancy.