Physiologically based pharmacokinetic modelling to investigate the impact of aging on drug pharmacokinetics and drug-drug interaction magnitudes in aging people living with HIV

People living with HIV (PLWH) are aging but are often excluded from clinical studies because of pragmatical and ethical concerns. Therefore, the effect of aging on the pharmacokinetics and drug-drug interaction (DDI) magnitudes of antiretroviral drugs remain uncertain. Consequently, clinical guidance regarding dose adjustment for antiretroviral drugs and the clinical management of DDIs with advanced aging are missing.
Studies presented in this thesis combined clinically observed data with physiologically based pharmacokinetic (PBPK) modelling to investigate the continuous effect of aging on drug pharmacokinetics and DDI magnitudes. The PBPK model was developed in the mathematical programming language Matlab®. A virtual population considering age-related changes in demographics, physiology, and biology informed the model.
Clinically observed data of ten non-HIV drugs being commonly administered as comedications to aging PLWH were used to verify the predictive power of the PBPK model to simulate drug disposition in the elderly. Extrapolating the pharmacokinetics of all investigated ten drugs across adulthood (20 to 99 years) elucidated that the progressively decreasing drug clearance drove age-related pharmacokinetic changes, which itself was caused by the decline of the hepatic and renal blood flow and the glomerular filtration rate. Age-dependent pharmacokinetic alterations were independent of drug characteristics. Additional clinical data of 52 drugs obtained from young and elderly individuals verified this general model-based hypothesis.
Concentration-time profiles of ten antiretroviral drugs, belonging to the current first-line treatment, were obtained in two clinical studies including PLWH at least 55 years, who participated in the Swiss HIV Cohort Study. These clinically observed data were generally predicted within the 95% confidence interval of the PBPK model, demonstrating the ability of the used approach to predict real-life plasma concentrations from PLWH, who had a declined kidney function (e.g. the glomerular filtration rate was 65.6 ± 19.2 mL/min/1.73m²) and common comorbidities (e.g. hypertension). Age-related pharmacokinetic changes of antiretroviral drugs across adulthood were found to be similar to non-HIV drugs, indicating a marginal increase in antiretroviral drug exposure with advanced aging.
One of the conducted clinical studies in PLWH at least 55 years was designed to investigate DDI magnitudes between amlodipine, atorvastatin, or rosuvastatin and a dolutegravir (no interaction expected) or a boosted darunavir (high interaction potential) containing antiretroviral regimen. The comparison with historical data obtained in young PLWH aged 20 to 50 years yielded no changes in the DDI magnitudes between both investigated age groups. These clinically observed data were used to verify DDI simulations of the developed PBPK framework in the elderly and subsequently DDI magnitudes were predicted across the entire adult lifespan. The model indicated that DDI magnitudes were unchanged across adulthood regardless of the involved drugs, the DDI mechanism, or the sex of the investigated individual. This general model-based hypothesis was verified with independent clinically observed data from 17 DDIs.
As DDI magnitudes are not impacted by aging, static methods can be applied to predict DDI magnitudes in elderly patients, who receive two drugs with an uncharacterized DDI magnitude. Predictions are based on the fraction of metabolism by a specific enzyme and the strength of an inhibitor or inducer. In contrast to the PBPK approach, the static method provides a more straightforward supportive tool to rationalize dose adjustments to overcome a given DDI.
In conclusion, this thesis demonstrates marginal pharmacokinetic alterations of antiretroviral drugs and no age-related changes of DDI magnitudes. Therefore, a dose adjustment of antiretroviral drugs or a different management of DDIs in clinical practice are a priori not necessary when treating aging male and female PLWH in the absence of severe comorbidities. These general rules being broadly applicable to antiretroviral and non-HIV drugs support the overall care of elderly PLWH beyond HIV and therapies of future effective drugs.