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.