4 Discussion

We successfully developed a pregnancy PBPK model to predict the disposition of the approved monthly and bimonthly dosing regimens of LAI CAB and LAI RPV in pregnancy without the oral lead-in components. An earlier study had shown that Ctrough after the first LAI CAB dose with or without an oral lead-in were comparable though the target Ctrough could be achieved faster with the LAI CAB dose if given with the oral lead-in component [53]. The pregnancy PBPK model was developed from a validated adult PBPK model by incorporating pregnancy-induced biological changes that are known to influence PK such as changes in body weight, relevant enzyme activities and cardiac output defined by gestational age [17]. The adult PBPK model was validated with PK data of LAI CAB and LAI RPV in adults [34]. Similarly, available clinical PK data of oral RPV in pregnancy were used to validate the pregnancy PBPK model for RPV PK and by extension, the CYP3A4 activity in pregnant women. The absence of clinical PK data for oral CAB in pregnancy led to the adoption of a probe substrate (RAL) to validate UGT1A1 activity in pregnancy. RAL was a suitable probe substrate in this instance as it is solely metabolised by UGT1A1 and clinical PK data of oral RAL in pregnancy are available [52]. The use of a probe substrate to validate enzyme activity for a different drug with inadequate data has been previously reported in another study [54].
The model predictions suggest that both dosing regimens of LAI CAB were predicted to maintain efficacy throughout pregnancy. In contrast, whilst the monthly dosing regimen of RPV could maintain antiviral efficacy throughout pregnancy for majority of the population, the model suggests the need for caution in introducing the bimonthly regimen of RPV to the pregnant population. Use of the bimonthly regimen therefore requires careful clinical evaluation, including viral load monitoring and potentially therapeutic drug monitoring.
In the PBPK model, a simple first-order equation was used to characterise the absorption/release rate of the drug into the systemic circulation from the IM depot in the muscle. The mathematical expression was independent of the size of the patient’s muscle mass which could explain why the predicted PK of LAI CAB did not vary significantly between virtual patients with different body mass indices (BMI). Unlike the predicted PK of LAI CAB, studies in humans have reported that BMI is a significant covariate for the PK of LAI CAB [55]. The size of muscle mass might affect the available depot space for the drug in the muscle which could lead to a faster release of the drug into the systematic circulation and contribute to a faster decline of the LAI CAB concentrations in patients with low BMI [55, 56]. Patel et al (2020) reported higher maximal levels of LAI CAB in the plasma of a study volunteer with lower BMI compared to two others with higher BMI [56]. However, the release rates of LAI CAB and LAI RPV used in this study were fitted into the model with available clinical data [33, 34]. Sensitivity analyses of the plasma concentrations of cabotegravir and rilpivirine to variations of their release rates are shown in Figure S1. The PK of monthly and bimonthly LAI CAB and LAI RPV were also simulated for non-pregnant adult females for comparison with the pregnant population because LAI CAB PK has been reported to differ between males and females [55].
Drug transporter activity was not incorporated into the PBPK model primarily due to lack of data. RPV is not a known substrate of any drug transporter. On the other hand, CAB is a substrate of Multidrug resistance protein 1 (P-glycoprotein 1) and breast cancer resistance protein (BCRP) in vitro [57]. Though pregnancy has been reported to influence the activity of P-glycoprotein 1 and BCRP in rodents [58, 59], data in humans are not available. Regardless, the influence of drug transporter activity on the PK of oral CAB appear to be minimal [57].
A fetal compartment was not included in the female reproductive of the pregnancy PBPK model. As such, fetal exposure to the LAI CAB and LAI RPV in pregnancy could not be evaluated. UGT1A is not likely expressed in fetal liver [60]. Though fetal liver has been reported to express CYP3A, however, the contribution of the fetal liver clearance to the overall drug clearance of LAI RPV in the mother are expected to be minimal [61].
The administration of LAI drugs in pregnancy is not a new paradigm. LAI antipsychotic drugs have been administered in pregnancy for over two decades. Despite this long duration, PK data on the use of LAI antipsychotics in pregnancy has been very limited [62]. Similarly, outcomes on the safety of LAI antipsychotics in pregnancy have been inconsistent. Where poor outcomes have been reported in pregnancy after the use of LAI antipsychotics, there have been insufficient data to determine if the poor outcomes are due to the illness, class of the drug or the long-acting formulation [63]. Nonetheless, there have been strong arguments for LAI antipsychotic use during pregnancy owing to improved adherence, reduced risk of overdose, and less psychiatric rehospitalisation compared to oral antipsychotics [64]. Adherence to antipsychotics is particularly important during pregnancy to prevent relapses which might lead to poor birth outcomes [64].
In a similar vein, adherence to antiretrovirals in pregnancy is highly necessary to reduce the risk of vertical transmission of HIV. LAI antiretrovirals might be a preferred choice throughout pregnancy to support adherence and to reduce psycho-social challenges relating to disclosure of HIV status. In addition, the new option of LAI antiretrovirals might be particularly important in early pregnancy for women living with HIV that may prefer a non-oral route of drug administration due to nausea and vomiting. However, there is a need to frequently monitor pregnant women on LAI antiretrovirals towards improving available data on safety and efficacy. PBPK modelling readily overcomes many ethical and logistic challenges associated with randomised clinical trials in complex populations. It could also prove useful in exploring PK in complex clinical scenarios and complex populations.
Since the approval of LAI RPV and LAI CAB for the general adult population, there have been limited clinical data to guide the dosing of both LAIs in pregnant women. In this study, we developed a pregnancy PBPK model to describe plasma concentrations of LAI CAB and LAI RPV in pregnancy. Based on the model predictions, both the monthly and bimonthly dosing regimen of LAI CAB could maintain antiviral efficacy throughout pregnancy without need for adjustments. However, bimonthly dosing regimen of LAI RPV might be introduced in pregnancy with caution and adequate monitoring. Future clinical studies in humans are needed to confirm these model predictions.
Acknowledgements
S.A. was supported by the Duncan Norman Charitable Trust. CW is funded by the Wellcome Trust [222075_Z_20_Z]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.
Conflict of interest statement
Marco Siccardi has received research grant funding from Janssen and ViiV unrelated to this work. M.S. is currently employed by Labcorp. All other authors have no potential conflicts of interest to declare.
Funding Information
Wellcome Trust (222075_Z_20_Z)
Data Availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.