Application of a Physiologically Based Pharmacokinetic Model to Predict OATP1B1-Related Variability in Pharmacodynamics of Rosuvastatin.

Typically, pharmacokinetic-pharmacodynamic (PK/PD) models use plasma concentration as the input that drives the PD model. However, interindividual variability in uptake transporter activity can lead to variable drug concentrations in plasma without discernible impact on the effect site organ concentration. A physiologically based PK/PD model for rosuvastatin was developed that linked the predicted liver concentration to the PD response model. The model was then applied to predict the effect of genotype-dependent uptake by the organic anion-transporting polypeptide 1B1 (OATP1B1) transporter on the pharmacological response. The area under the plasma concentration-time curve (AUC0-∞) was increased by 63 and 111% for the c.521TC and c.521CC genotypes vs. the c.521TT genotype, while the PD response remained relatively unchanged (3.1 and 5.8% reduction). Using local concentration at the effect site to drive the PD response enabled us to explain the observed disconnect between the effect of the OATP1B1 c521T>C polymorphism on rosuvastatin plasma concentration and the cholesterol synthesis response.

Physiologically-based pharmacokinetic (PBPK) models for assessing the kinetics of xenobiotics during pregnancy: achievements and shortcomings.

The physiological changes that occur in the maternal body and the placental-foetal unit during pregnancy influence the absorption, distribution, metabolism, and excretion (ADME) of xenobiotics. These include drugs that are prescribed for therapeutic reasons or chemicals to which women are exposed unintentionally from the surrounding environment. The pregnancy physiologically-based pharmacokinetic (p-PBPK) models developed for theoretical assessment of the kinetics of xenobiotics during pregnancy should take into account all the dynamic changes of the maternal and embryonic/foetal physiological functions. A number of p-PBPK models have been reported for pregnant animals and humans in the past 3 decades which have mainly been applied in the risk assessment of various environmental chemicals. The purpose of this review is to critically evaluate the current state of the art in p-PBPK modelling and to recommend potential steps that could be taken to improve model development and its application particularly in drug discovery and development for pregnant women, with potential implications for optimal drug treatment in pregnancy. The pregnancy-induced changes in physiology and pharmacokinetics, including metabolism, are reviewed to illustrate the basic alterations essential for pregnancy model development. A systemic search of the literature for existing p-PBPK models is carried out and the model structures, governing equations, methods of modelling growth, model validation/verification as well as model applications are highlighted. This review discusses benefits and limitations of the reported p-PBPK models so far and suggests areas for model improvement. The need for establishing databases on the system-related (biological, anatomical and physiological) and drug-related (physiochemical, affinity to enzymes and transpoorters) parameters for healthy and unhealthy pregnancies is particularly emphasized.

Assessment of activity levels for CYP2D6*1, CYP2D6*2, and CYP2D6*41 genes by population pharmacokinetics of dextromethorphan.

The pharmacokinetics of dextromethorphan (DM) is markedly influenced by cytochrome P450 2D6 (CYP2D6) enzyme polymorphisms. The aim of this study was to quantify the effects of the CYP2D6*1, *2, and *41 variants on DM metabolism in vivo and to identify other sources of pharmacokinetic variability. Concentrations of DM and dextrorphan (DO) in plasma and urine were evaluated in 36 healthy Caucasian men. These volunteers participated in three clinical studies and received a single oral dose of 30 mg DM-HBr. Data were modeled simultaneously using the population pharmacokinetics NONMEM software. A five-compartment model adequately described the data. The activity levels of the alleles assessed differed significantly. The clearance attributable to an individual CYP2D6*1 copy was 2.5-fold higher as compared with CYP2D6*2 (5,010 vs. 2,020 l/h), whereas the metabolic activity of CYP2D6*41 was very low (85 l/h). Urinary pH was confirmed as a significant covariate for DM renal clearance. These results refine genotype-based predictions of pharmacokinetics for DM and presumably for other CYP2D6 substrates as well.

Factors influencing pharmacokinetics of prophylactic posaconazole in patients undergoing allogeneic stem cell transplantation.

The objectives of the present study were to elucidate the factors influencing the pharmacokinetics of prophylactically administered posaconazole in allogeneic hematopoietic stem cell transplant (SCT) recipients. Between May 2007 and November 2008, clinical data were obtained from all SCT recipients at the University Hospital of Cologne undergoing therapeutic drug monitoring (TDM) of serum prophylactic posaconazole concentrations. The posaconazole concentrations were determined by high-performance liquid chromatography. We developed a population pharmacokinetic model using nonlinear mixed-effect modeling (NONMEM). The list of covariates tested included age; body weight; body height; gender; posaconazole dose; race; coadministration of antineoplastic chemotherapy; day of stem cell transplantation; concomitant ranitidine, pantoprazole, cyclosporine, or tacrolimus administration; coincident fever; diarrhea; and plasma gamma-glutamyltransferase activity. A total of 149 serum posaconazole concentrations from 32 patients were obtained. A one-compartment model with first-order absorption and elimination as the basic structural model appropriately described the data, with the apparent clearance being 75.8 liters/h (95% confidence interval [CI], 65.2 to 86.4 liters/h) and the apparent volume being distribution of 835 liters (95% CI, 559 to 1,111 liters). Among the covariates tested, significant effects were found for age (decrease in the volume of distribution of 123 liters per year of age) and the presence of diarrhea (59% loss of bioavailability). A basis for prediction of the mean posaconazole concentrations in allogeneic SCT recipients with hematological malignancies is provided for a given dose. Corresponding adjustments of the starting dose according to the presence of diarrhea and according to age appear to be justified before TDM results are available.