A guide to developing population files for physiologically-based pharmacokinetic modeling in the Simcyp Simulator.

The Simcyp Simulator is a software platform widely used in the pharmaceutical industry to conduct stochastic physiologically-based pharmacokinetic (PBPK) modeling. This approach has the advantage of combining routinely generated in vitro data on drugs and drug products with knowledge of biology and physiology parameters to predict a priori potential pharmacokinetic changes in absorption, distribution, metabolism, and excretion for populations of interest. Combining such information with pharmacodynamic knowledge of drugs enables planning for potential dosage adjustment when clinical studies are feasible. Although the conduct of dedicated clinical studies in some patient groups (e.g., with hepatic or renal diseases) is part of the regulatory path for drug development, clinical studies for all permutations of covariates potentially affecting pharmacokinetics are impossible to perform. The role of PBPK in filling the latter gap is becoming more appreciated. This tutorial describes the different input parameters required for the creation of a virtual population giving robust predictions of likely changes in pharmacokinetics. It also highlights the considerations needed to qualify the models for such contexts of use. Two case studies showing the step-by-step development and application of population files for obese or morbidly obese patients and individuals with Crohn's disease are provided as the backbone of our tutorial to give some hands-on and real-world examples.

Exploring the impact of ethnicity on drug pharmacokinetics using PBPK models: A case study with lansoprazole in Japanese subjects.

AIMS: The aim of this study is to demonstrate the use of PBPK modelling to explore the impact of ethnic differences on drug PK. METHODS: A PBPK model developed for lansoprazole was used to predict the clinical PK of lansoprazole in Japanese subjects by incorporating the physiological parameters of a Japanese population into the model. Further verification of the developed Japanese population with clinical studies involving eight other CYP substrates-omeprazole, ticlopidine, alprazolam, midazolam, nifedipine, cinacalcet, paroxetine and dextromethorphan-was also carried out. RESULTS: The PK of lansoprazole in both Caucasian and Japanese subjects was well predicted by the model as the observed data were within the 5th and 95th percentiles across all the clinical studies. In age- and sex-matched simulations in both the Caucasian and Japanese populations, the predicted PK (mean ± SD) of a single oral dose of 30-mg lansoprazole was higher in the Japanese population in all cases, with more than twofold higher AUC of 5.98 ± 6.43 mg/L.h (95% CI: 4.72, 7.24) vs. 2.46 ± 2.45 mg/L.h (95% CI: 1.98, 2.94) in one scenario. In addition, in two out of the nine clinical DDIs of lansoprazole and the additional CYP substrates simulated using the Japanese population, the predicted DDI in Japanese was more than 1.25-fold that in Caucasians, indicating an increased DDI liability. CONCLUSIONS: By accounting for various physiological parameters that characterize a population in a PBPK model, the impact of the different identified interethnic differences on the drug's PK can be explored, which can inform the adoption of drugs from one region to another.

Simvastatin Inhibits L-Type Ca2+-Channel Activity Through Impairment of Mitochondrial Function.

Plasma membrane ion channels and mitochondrial electron transport complexes (mETC) are recognized "off targets" for certain drugs. Simvastatin is one such drug, a lipophilic statin used to treat hypercholesterolemia, but which is also associated with adverse effects like myopathy and increased risk of glucose intolerance. Such myopathy is thought to arise through adverse actions of simvastatin on skeletal muscle mETC and mitochondrial respiration. In this study, we investigated whether the glucose intolerance associated with simvastatin is also mediated via adverse effects on mETC in pancreatic beta-cells because mitochondrial respiration underlies insulin secretion from these cells, an effect in part mediated by promotion of Ca2+ influx via opening of voltage-gated Ca2+ channels (VGCCs). We used murine pancreatic beta-cells to investigate these ideas. Mitochondrial membrane potential, oxygen consumption, and ATP-sensitive-K+-channel activity were monitored as markers of mETC activity, respiration, and cellular ATP/ADP ratio respectively; Ca2+ channel activity and Ca2+ influx were also measured. In intact beta-cells, simvastatin inhibited oxidative respiration (IC50 approximately 3 µM) and mETC (1 < IC50 < 10 µM), effects expected to impair VGCC opening. Consistent with this idea simvastatin > 0.1 µM reversed activation of VGCCs by glucose but had no significant effect in the sugar's absence. The VGCC effects were mimicked by rotenone which also decreased respiration and ATP/ADP. This study demonstrates modulation of beta-cell VGCC activity by mitochondrial respiration and their sensitivity to mETC inhibitors. This reveals a novel outcome for the action of drugs like simvastatin for which mETC is an "off target".