Use of physiologically based pharmacokinetic modelling to simulate dosing requirements of long-acting intramuscular antiretroviral drugs in special populations and to manage drug-drug interactions

Since the emergence of HIV in 1970-1980, the life expectancy and health of people with HIV (PWH) have significantly improved thanks to the combined use of highly active antiretrovirals (ARVs). A novel milestone has been reached with the approval of the first long-acting intramuscular ARVs regimen, containing cabotegravir and rilpivirine, for the treatment and prevention of HIV. Upon administration, long-acting injectables maintain sustained drug concentration over an extended dosing interval; thereby allowing infrequent drug administration with the potential to improve adherence to the treatment. However, their long elimination half-life makes the conduct of clinical trials with long-acting ARVs challenging; therefore, several clinical questions remain to be addressed. Physiologically based pharmacokinetic (PBPK) modelling is a mathematical tool that can be used to simulate unstudied clinical scenarios and guide dose adjustment. In this thesis, we aimed to address several unstudied clinical questions related to the use of long-acting cabotegravir and rilpivirine. Specifically, we used PBPK modelling to investigate the magnitude of the drug-drug interactions (DDIs) and to evaluate effective strategies to overcome DDIs with long-acting drugs. Additionally, we looked at the impact of aging and obesity on cabotegravir and rilpivirine exposures to guide the use of injectable agents in these special populations generally excluded from clinical trials. To address these questions, we developed the first mechanistic framework describing the release of intramuscular LA drugs, considering both the physiology of the injection site and the physicochemical properties of the drug of interest. Several strategies to overcome DDIs in presence of a moderate inducer (i.e., rifabutin) were evaluated: specifically, a reduction of the dosing interval of LA cabotegravir and rilpivirine from bimonthly to monthly administration and the addition of an oral dose (25 mg) of rilpivirine. These strategies could be applied in clinical practice in PWH with tuberculosis or in presence of comorbidities requiring the administration of moderate inducers. Furthermore, switching from an inducer-containing ARV regimen to intramuscular cabotegravir and rilpivirine was shown to be feasible with low risk of having suboptimal drug exposure during the switch window. Elderly PWH were predicted to have higher exposure of LA cabotegravir and rilpivirine; conversely, lower exposure was predicted in obese and morbidly obese individuals, for whom therapeutic drug monitoring is recommended to guide dosing interval adjustment. Clinical studies need to be conducted to confirm our simulation results and to further position PBPK modelling as a powerful tool to inform drug labelling.