Physiologically based pharmacokinetic modelling to investigate the pharmacokinetics of antiretrovirals in special populations

The demographics of the HIV population has considerably evolved since the first described cases of AIDS in 1981. To date, clinicians have to treat a heterogeneous population including, for instance, obese people with HIV (PWH) or pregnant women, who are often excluded from clinical trials leading to a knowledge gap on the effect of obesity or pregnancy/postpartum on antiretrovirals pharmacokinetics.
This PhD project aimed at determining the effect of obesity and pregnancy/postpartum on the pharmacokinetics of antiretroviral drugs using physiologically based pharmacokinetic (PBPK) modelling together with observed clinical data from the Swiss HIV Cohort Study or collected from the literature.
Virtual populations were developed to inform the PBPK model with the physiological changes occurring throughout obesity and pregnancy/postpartum. Thorough literature searches were carried out to collect physiological, anatomical, and biological data. Successively, regression analyses were performed to derive continuous functions to implement in our in-house PBPK model.
The obese population was verified by comparing the PBPK model simulation results against clinical observed data of ten commonly prescribed drugs in obese. Afterwards, the continuous effect of obesity (from a body mass index (BMI) of 18.5 up to 60 kg/m2) was studied. Simulations results identified the increase in hepatic blood flow and renal blood flow as the main drivers of the increase in clearance and the related reduction in drug exposure in obese. The volume of distribution was found to increase with BMI however different trend were observed which were explained by the combined effect of the drug properties (i.e., logP and pKa) responsible for the drug lipophilicity and ionization.
The obese population was leveraged to study the exposure and response of 11 antiretroviral drugs in obese and morbidly obese PWH. Observed clinical data obtained from the Swiss HIV Cohort Study and complemented with the few data available in the literature were nicely predicted by the PBPK model, demonstrating its ability to predict real life concentrations in obese PWH. The extrapolation of the pharmacokinetics across different BMI classes showed that obesity lowers the exposure of antiretrovirals. Nevertheless, trough concentrations are less impacted so that a dose adjustment is not required in obese PWH (BMI 30-40 kg/m2), but therapeutic drug monitoring is advised for etravirine and rilpivirine in morbidly obese PWH (BMI > 40 kg/m2).
The literature is lacking of drug-drug interaction studies in obese, therefore the newly developed population was used to investigate the combined effect of obesity and induction by rifampicin on the exposure of dolutegravir. This interaction can be overcome by administering dolutegravir twice daily instead of once daily, however given that obesity, per se, lowers dolutegravir exposure, it was important to verify that the currently recommended dose adjustment applies also in obese and morbidly obese PWH. Simulations results indicated that even if rifampicin exposure was lower in obese and morbidly obese, the magnitude of the induction was comparable to nonobese individuals. While, when taking into account the combined effect of induction and obesity, dolutegravir exposure was further reduced in obese and morbidly obese compared to nonobese individuals, however the trough concentrations were minimally impacted. Therefore, doubling dolutegravir dose is still sufficient to overcome the drug-drug interaction with rifampicin in obese and morbidly obese PWH.
The pregnant population was verified against clinical observed data collected from the literature. The pharmacokinetics during the second and third trimester as well as during the postpartum period were successfully predicted by the PBPK model. The pharmacokinetics of seven antiretroviral drugs across pregnancy and postpartum were simulated and the results showed that the physiological changes and therefore the major reduction exposure peaked during the third trimester of pregnancy; while, a 4-week time window is needed after delivery for these physiological changes to return to baseline and to have a negligible effect on the pharmacokinetics. This finding is essential when planning a pharmacokinetic study in pregnant and postpartum women because if pharmacokinetic investigations are conducted too early after delivery the physiological changes may still be present leading to an underestimation of the pregnancy effect on the pharmacokinetics.
In conclusion, this thesis demonstrates that PBPK modelling can be applied to study drug pharmacokinetics in special populations. The exposure of several antiretrovirals was successfully characterized in obese and morbidly obese but also drug-drug interactions providing important information to guide prescription in obese and morbidly obese PWH. Furthermore, this PhD project provides also guidance on when to conduct pharmacokinetic investigations during the postpartum period in order to fully characterize the effect of pregnancy on drug pharmacokinetics.