Prediction of the pharmacokinetics of renally excreted antiretrovirals in older patients, using physiologically based pharmacokinetic (PBPK) modelling.
Manoranjenni Chetty, Mailys De Sousa Mendes, Karen Rowland-Yeo
Simcyp Ltd (a Certara company), Blades Enterprise Centre, John Street, Sheffield
Objectives: Despite our knowledge of diminishing renal function with advancing age, information on the impact of aging on the pharmacokinetics (PK) of antiretroviral drugs that are mainly excreted unchanged by the kidney is sparse. The objective of this study was to use PBPK modelling to determine whether changes in the exposure to antiretroviral drugs warrant dosage adjustments in older patients.
Methods: PBPK models for tenofovir, emtricitabine and lamivudine were developed previously [1]. These three drugs were selected on the basis that excretion via the kidney is >70%. The PBPK models for these drugs were verified initially in the Simcyp Simulator (v16) using available clinical data and then used to predict their pharmacokinetic profiles for standard doses in Caucasian population groups aged 20 to 49 years; 50 to 64 years and 65 to 75 years respectively. The Simcyp Geriatric Caucasian population was used for the 65 to 75 year age group. Since drug response has been associated with the area under the plasma concentration versus time curve (AUC) for these drugs, changes in exposure (AUC) were compared between the age groups.
Results: The PBPK models for tenofovir, emtricitabine and lamivudine showed good recovery of the clinical data, indicating the suitability of the models to be used in the prediction of PK. A decrease in CL and an increase in AUC with advancing age was observed for all three drugs. The mean increases in exposure (AUC) between the youngest and oldest age groups were about 40% for emtricitabine, lamivudine and tenofovir.
Conclusions: These results suggest that doses lower than the standard 200mg, 300mg and 300mg daily dose for emtricitabine, tenofovir and lamivudine respectively should be considered in patients aged between 65 and 75 years.
References:
[1] De Sousa Mendes M, Hirt D, Urien S, Valade E, Bouazza N, Foissac F, Blanche S, Treluyer JM, Benaboud S. Physiologically-based pharmacokinetic modeling of renally excreted antiretroviral drugs in pregnant women. Br J Clin Pharmacol. 2015;80(5):1031-41.