Physiologically Based Pharmacokinetic Modeling to Predict Transporter-Mediated Clearance and Distribution of Pravastatin in Humans

Abstract

Hepatobiliary excretion mediated by transporters, organic anion-transporting polypeptide (OATP) 1B1 and multidrug resistance-associated protein (MRP) 2, is the major elimination pathway of an HMG-CoA reductase inhibitor, pravastatin. The present study examined the effects of changes in the transporter activities on the systemic and liver exposure of pravastatin using a physiologically based pharmacokinetic model. Scaling factors, determined by comparing in vivo and in vitro parameters of pravastatin in rats for the hepatic uptake and canalicular efflux, were obtained. The simulated plasma and liver concentrations and biliary excretion profiles were very close to the observed data in rats under linear and nonlinear conditions. In vitro parameters, determined in human cryopreserved hepatocytes and canalicular membrane vesicles, were extrapolated to in vivo parameters using the scaling factors obtained in rats. The simulated plasma concentrations of pravastatin were close to the reported values in humans. Sensitivity analyses showed that changes in the hepatic uptake ability altered the plasma concentration of pravastatin markedly but had a minimal effect on the liver concentration, whereas changes in the ability of canalicular efflux altered the liver concentration of pravastatin markedly but had a small effect on the plasma concentration. In conclusion, the model allows the prediction of the disposition of pravastatin in humans. The present study suggests that changes in the OATP1B1 activities may have a small and a large impact on the therapeutic efficacy and side effect (myopathy) of pravastatin, respectively, whereas those in the MRP2 activities may have opposite impacts (i.e., large and small impacts on the therapeutic efficacy and side effect).

Prediction of the Pharmacokinetics of Pravastatin as an OATP Substrate Using Plateable Human Hepatocytes With Human Plasma Data and PBPK Modeling

“…For the other investigations, different in vitro assays have been explored to quantitatively assess the OATP uptake process for pravastatin. In the human suspended hepatocytes with an oil‐spin method, the Cl int,T was determined as 4.5 and 0.7 µL/min/million cells at 1 µM and 100 µM of pravastatin 5. The scaling factor obtained in rats between in vitro hepatic uptake and in vivo observation was applied to the model in order to predict the observed human PK.…”

“…In the Simcyp default compound profile, in order to describe the clinical data, the OATP Cl int,T input of hepatic uptake parameter for pravastatin was back calculated by fitting to the observed in vivo PK data. In the other studies,5, 7, 8, 9 the in vitro OATP Cl int,T data generated in the suspended hepatocytes and the sandwich cultured hepatocytes were used. Nevertheless, when the in vitro data were incorporated into the PBPK model, a scaling factor was found to be necessary in order to predict the observed pravastatin PK profile accurately.…”

Noninvasive Preclinical and Clinical Imaging of Liver Transporter Function Relevant to Drug-Induced Liver Injury

“…This modeling approach is extremely useful to improve our understanding of the ratedetermining process driving hepatic exposure of a drug, i.e., whether this is uptake, efflux/metabolism or a composite of multiple processes. It also provides mechanistic insight into in vivo consequences that arise when individual disposition processes are perturbed [81,82,[94][95][96][97]. For example, active uptake via OATPs from the blood into hepatocytes is the major process leading to high unbound liver-blood concentration ratio of many statins (e.g., simvastatin acid).…”

“…For example, inhibition of hepatobiliary efflux transporters at the apical plasma membrane domain of hepatocytes membrane may lead to changes in drug exposure in the hepatocyte that have potential toxicological significance, but result only in minor changes in drug plasma exposure [81] (see also next section).…”

“…3). For drugs predominantly eliminated via liver, the effect of reduced OATP activity on liver exposure (AUC liver ) is expected to be marginal, as this parameter is determined primarily by either metabolic clearance (in case of simvastatin acid) or biliary excretion (BCRP-rosuvastatin, MRP2-pravastatin) [81,82,[95][96][97][98]. In contrast, inhibition of biliary transporters (MRP2, BSEP) or metabolic enzymes (CYP3A4) may lead to changes in drug exposure in the liver and consequently even to hepatotoxicity, with only minor changes in drug plasma exposure.…”