Whole-Body Physiologically Based Pharmacokinetic Modeling of Trastuzumab and Prediction of Human Pharmacokinetics.

In the present study, we evaluated the pharmacokinetics (PK) of trastuzumab and sought to predict human PK based on animal studies, through the use of optical imaging and a whole-body physiologically based pharmacokinetic (WB-PBPK) modeling approach. The PK study was conducted in 24 mice, where serial blood samples were withdrawn and major organs were isolated after the last blood withdrawal. The drug concentrations in blood and major organs were measured via optical imaging. The WB-PBPK model was constructed using known physiological values including the volumes of major organs and blood/lymphatic flow. The NONMEM software (version 7.3) was used to determine tissue partition coefficients. Using the WB-PBPK model, a clinical trial simulation was performed with reference to human physiological values acquired from the literature. The simulated human PK was then compared with the actual PK observed in the previous study in which healthy male subjects received 6 mg/kg trastuzumab (Herceptin®) via intravenous route. The ratio of the simulated versus observed area under the concentration-time curve was 1.02 and that of maximal concentration was 0.72. The current study describes the potential synergistic applications of WB-PBPK and optical imaging in human PK prediction based on preclinical data obtained in early-stage drug development.

Prediction of the human in vivo antiplatelet effect of S- and R-indobufen using population pharmacodynamic modeling and simulation based on in vitro platelet aggregation test.

Indobufen (Ibustrin®), a reversible inhibitor of platelet aggregation, exists in two enantiomeric forms in 1:1 ratio. Here, we characterized the anti-platelet effect of S- and R-indobufen using response surface modeling using NONMEM® and predicted the therapeutic doses exerting the maximal efficacy of each enantioselective S- and R-indobufen formulation. S- and R-indobufen were added individually or together to 24 plasma samples from drug-naïve healthy subjects, generating 892 samples containing randomly selected concentrations of the drugs of 0-128 mg/L. Collagen-induced platelet aggregation in platelet-rich plasma was determined using a Chrono-log Lumi-Aggregometer. Inhibitory sigmoid Imax model adequately described the anti-platelet effect. The S-form was more potent, whereas the R-form showed less inter-individual variation. No significant interaction was observed between the two enantiomers. The anti-platelet effect of multiple treatments with 200 mg indobufen twice daily doses was predicted in the simulation study, and the effect of S- or R-indobufen alone at various doses was predicted to define optimal dosing regimen for each enantiomer. Simulation study predicted that 200 mg twice daily administration of S-indobufen alone will produce more treatment effect than S-and R-mixture formulation. S-indobufen produced treatment effect at lower concentration than R-indobufen. However, inter-individual variation of the pharmacodynamic response was smaller in R-indobufen. The present study suggests the optimal doses of R-and S-enantioselective indobufen formulations in terms of treatment efficacy for patients with thromboembolic problems. The proposed methodology in this study can be applied to the develop novel enantio-selective drugs more efficiently.

Predicting the efficacy of an oral paclitaxel formulation (DHP107) through modeling and simulation.

PURPOSE: DHP107 is an oral paclitaxel under development. The present study characterized the pharmacokinetic properties of DHP107 and predicted the efficacy in comparison to that of intravenous paclitaxel, using modeling and simulation of data from the early phase of clinical development. METHODS: In the first-in-human study of the pharmacokinetic characteristics of DHP107 and intravenous paclitaxel, patients received DHP107 60 to 600 mg/m(2), followed by intravenous paclitaxel 175 mg/m(2). Using the pharmacokinetic model of DHP107 from the present analysis and from a previously published pharmacodynamic analysis of the association between paclitaxel concentration and neutropenia, phase I clinical trial for DHP107, with a modified Fibonacci dose escalation scheme, were simulated to predict the maximal tolerated dose (MTD). Additional simulations of paclitaxel concentration over time were conducted to compare the efficacy of DHP107 with that of intravenous paclitaxel, based on time over minimum effective concentration. FINDINGS: In the clinical trial simulation, 480 mg/m(2) was the most frequently predicted MTD of DHP107. In the simulations for efficacy, the times over minimum effective concentration with DHP107 at the predicted MTD were greater than those of intravenous paclitaxel in weekly regimens. IMPLICATIONS: The findings from this analysis suggest the possibility of efficacy of DHP107 in weekly regimens and provides a scientific rationale for further development. Based on findings from modeling and simulation, DHP107 was predicted to be more efficacious compared with intravenous paclitaxel in weekly regimens, and this finding should be confirmed in further clinical trials.