Physiologically-based pharmacokinetic predictions of intestinal BCRP-mediated drug interactions of rosuvastatin in Koreans

It was recently reported that the C(max) and AUC of rosuvastatin increases when it is coadministered with telmisartan and cyclosporine. Rosuvastatin is known to be a substrate of OATP1B1, OATP1B3, NTCP, and BCRP transporters. The aim of this study was to explore the mechanism of the interactions between rosuvastatin and two perpetrators, telmisartan and cyclosporine. Published (cyclosporine) or newly developed (telmisartan) PBPK models were used to this end. The rosuvastatin model in Simcyp (version 15)'s drug library was modified to reflect racial differences in rosuvastatin exposure. In the telmisartan–rosuvastatin case, simulated rosuvastatin C(maxI)/C(max) and AUC(I)/AUC (with/without telmisartan) ratios were 1.92 and 1.14, respectively, and the T(max) changed from 3.35 h to 1.40 h with coadministration of telmisartan, which were consistent with the aforementioned report (C(maxI)/C(max): 2.01, AUCI/AUC:1.18, T(max): 5 h → 0.75 h). In the next case of cyclosporine–rosuvastatin, the simulated rosuvastatin C(maxI)/C(max) and AUC(I)/AUC (with/without cyclosporine) ratios were 3.29 and 1.30, respectively. The decrease in the CL(int,BCRP,intestine) of rosuvastatin by telmisartan and cyclosporine in the PBPK model was pivotal to reproducing this finding in Simcyp. Our PBPK model demonstrated that the major causes of increase in rosuvastatin exposure are mediated by intestinal BCRP (rosuvastatin–telmisartan interaction) or by both of BCRP and OATP1B1/3 (rosuvastatin–cyclosporine interaction).

Population pharmacokinetics of imatinib mesylate in healthy Korean subjects

Imatinib (Gleevec™; Novartis Pharmaceuticals) is an orally administered protein-tyrosine kinase inhibitor. The goal of this study was to investigate the population pharmacokinetics (PK) of imatinib (as imatinib mesylate) in healthy male Koreans. A total of 1,773 plasma samples from 112 healthy male volunteers enrolled in three phase I clinical studies were used. Among the subjects, 76 received 400 mg and 36 received 100 mg as single oral doses. Peripheral blood sampling for PK analysis was done at 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 48, 60 and 72 (at 400 mg group) h after dosing. The firstorder conditional estimation with interaction method of NONMEM® (ver. 7.3) was used to build the population PK model. A two-compartment model with Weibull absorption and elimination gave the best fit to the data. The estimates of clearance (CL/F), volume of central compartment (Vc/F), intercompartmental clearance (Q/F), peripheral volume (Vp/F) and their interindividual variabily (%CV) were 13.6 L/h (23.4%), 153 L (29.2%), 8.64 L/h (35.9%) and 64 L (67%), respectively.

Population pharmacokinetics and inter-laboratory variability of sildenafil and its metabolite after oral administration in Korean healthy male volunteers

This study was to clarify population pharmacokinetics (PK) of sildenafil and its metabolite, N-desmethyl sildenafil (NDS) in Korean healthy male population using a pooled data from multiple clinical trials in consideration of inter-institution and inter-laboratory difference. A population PK analysis was performed with data of 243 healthy volunteers from five single-center (4 centers) comparative PK trials. The dataset included 7,376 sildenafil and NDS concentration (3,688 for each analyte) observed during 24 hours after the single dose of original sildenafil (either 50 mg or 100 mg of Viagra®). The plasma concentration was assayed in two laboratories. Various model structure was tested and the final model was evaluated using visual predictive checks. Demographic and clinical variables were assessed as potential covariates for PK parameters. A one-compartment first-order elimination model with proportional error was selected for the dispositional characteristics of sildenafil, and two-compartment model was chosen for NDS. Three transit compartments with Erlang-type absorption for fast absorption pathway and one compartment for slow absorption pathway constructed overall absorption model. The first-pass effect was rejected since it does not improve the model. The difference of NDS level by the bioanalysis laboratory was selected as the only covariate. Even though a direct comparison was difficult, the general trend in PK of sildenafil and NDS for Korean healthy male was considered similar to that of the other populations reported previously. It is recommended that the laboratory effect should be explored and evaluated when dataset is built using results from several laboratories.