Physiologically based pharmacokinetic modelling to guide drug delivery in older people

Abstract

Older patients are generally not included in Phase 1 clinical trials despite being the population group who use the largest number of prescription medicines. Physiologically based pharmacokinetic (PBPK) modelling provides an understanding of the absorption and disposition of drugs in older patients. In this review, PBPK models used for the prediction of absorption and exposure of drugs after parenteral, oral and transdermal administration are discussed. Comparisons between predicted drug pharmacokinetics (PK) and observed PK are presented to illustrate the accuracy of the predictions by the PBPK models and their potential use in informing clinical trial design and dosage adjustments in older patients. In addition, a case of PBPK modelling of a bioequivalence study on two controlled release products is described, where PBPK predictions reproduced the study showing bioequivalence in healthy volunteers but not in older subjects with achlorhydria, indicating further utility in prospectively identifying challenges in bioequivalence studies.

Development of a physiologically based pharmacokinetic (PBPK) population model for Chinese elderly subjects

“…To date, a few studies have been conducted on PBPK models to predict drug concentration in the geriatric population. In these models, alterations of certain physiological parameters with aging were considered, such as alveolar ventilation, cardiac output, different organs (e.g., liver, brain, heart, kidney, spleen, left and right lung) weights, and blood flows [9][10][11][12][13]. However, most models were developed in the Caucasian geriatric population whose physiological variables and PK characteristics were not necessarily same as Chinese geriatric population.…”

Are Standard Doses of Renally-Excreted Antiretrovirals in Older Patients Appropriate: A PBPK Study Comparing Exposures in the Elderly Population With Those in Renal Impairment

“…In the absence of adequate clinical trials in this special population, physiologically-based pharmacokinetic (PBPK) modelling can be used to predict the possible impact of changes associated with aging on the pharmacokinetics of specific drugs. The physiological, anatomical and biological changes in the elderly that are of relevance during PBPK modelling have recently been reviewed [2–4]. Some of the key changes described in these reviews include a trend towards a decrease in height and weight in the older patient, possible changes in gastric emptying time and intestinal transit time, a reduction in the size of some organs (including the liver), a reduction in cardiac output with a consequent reduction in blood flow to organs such as the liver and kidneys, possible changes in drug metabolising enzymes and a decline in renal function.…”

Implementation of a Physiologically Based Pharmacokinetic Modeling Approach to Guide Optimal Dosing Regimens for Imatinib and Potential Drug Interactions in Paediatrics

“…The observed trend of a higher interindividual variability of simulated C min in children aged between 2 and 5 years and middle-aged adults compared to other age groups (Figure 4) was likely attributed to a higher variability within these age bands due to maturational changes of CYP enzymes that have not attained adult levels of expression (Johnson et al, 2006) and a reduction of total hepatic clearance related to a decrease of liver weight and scaling factor (e.g., microsomal protein per gram of liver/ MPPGL) (Barter et al, 2007;Chetty et al, 2018), respectively.…”