Quantitative prediction of the impact of chronic kidney disease (CKD) on drug disposition has become important for the optimal design of clinical studies in patients. In this study, clinical data of 151 compounds under CKD conditions were extensively surveyed, and alterations in pharmacokinetic parameters were evaluated. In CKD patients, the unbound hepatic intrinsic clearance decreased to a similar extent for drugs eliminated via hepatic metabolism by cytochrome P450, UDP-glucuronosyltransferase, and other mechanisms. Renal clearance showed a similar decrease to glomerular filtration rate, irrespective of the contribution of tubular secretion. The scaling factor (SF) obtained from the interquartile range of the relative change in each parameter was applied to the well-stirred model to predict clearance in patients. Hepatic and renal clearance could be successfully predicted for approximately half and two-thirds, respectively, of the applied compounds, showing the high utility of SFs. SFs were also introduced to a physiologically based pharmacokinetic (PBPK) model, and the plasma concentration profiles of 12 model compounds with different elimination pathways were predicted for CKD patients. The PBPK model combined with SFs provided good predictability for plasma concentration. The developed PBPK model with information on SFs would accelerate translational research in drug development by predicting pharmacokinetics in CKD patients.

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1. The pharmacokinetics and metabolism of dalcetrapib (JTT-705/RO4607381), a novel cholesteryl ester transfer protein inhibitor, were investigated in rats and monkeys. 2. In in vitro stability studies, dalcetrapib was extremely unstable in plasma, liver S9 and small intestinal mucosa, and the pharmacologically active form (dalcetrapib thiol) was detected as major component. Most of the active form in plasma was covalently bound to plasma proteins via mixed disulfide bond formation. 3. Following oral administration of (14)C-dalcetrapib to rats and monkeys, active form was detected in plasma. The active form was mainly metabolized to the glucuronide conjugate and the methyl conjugate at the thiol group. Several minor metabolites including mono- and di-oxidized forms of the glucuronide are also detected in the plasma and urine. 4. The administered radioactivity was widely distributed to all tissues and mainly excreted into the feces (85.7 and 62.7% of the dose in rats and monkeys, respectively). Most of the radioactivity was recovered by 168 h. Although the absorbed dalcetrapib was hydrolyzed to the active form and was bound to endogenous thiol via formation of disulfide bond, it was relatively rapidly eliminated from the body and was not retained.

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In this study, total body clearance (CL), volume of distribution at steady state (V) and plasma concentration-time profiles in humans of model compounds were predicted using chimeric mice with humanized livers. On the basis of assumption that unbound intrinsic clearance (CL) per liver weight in chimeric mice was equal to those in humans, CL were predicted by substituting human liver blood flow and liver weights in well-stirred model. V were predicted by Rodgers equation using scaling factors of tissue-plasma concentration ratios (SF) in chimeric mice estimated from a difference between the observed and predicted V. These physiological approaches showed high prediction accuracy for CL and V values in humans. We compared the predictability of CL and V determined by the physiologically based predictive approach using chimeric mice with those from predictive methods reported by Pharmaceutical Research Manufacturers of America. The physiological approach using chimeric mice indicated the best prediction accuracy in each predictive method. Simulation of human plasma concentration-time profiles were generally successful with physiologically based pharmacokinetic (PBPK) model incorporating CL and SF obtained from chimeric mice. Combined application of chimeric mice and PBPK modeling is effective for prediction of human PK in various compounds.