A pharmacokinetic model for aprepitant has been developed that incorporates body weight, age, ALT, BUN and aprepitant dose to predict the CL/F. The results of population pharmacokinetic analysis of dexamethasone support dose adjustment of dexamethasone in the case of co-administration with aprepitant.

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The absolute bioavailability of imidafenacin in rats and dogs is 5.6% and 36.1%, respectively.• The pharmacokinetic profiles of imidafenacin after oral administration have been revealed. • Imidafenacin is primarily metabolized to metabolites by CYP3A4 and UGT1A4. WHAT THIS STUDY ADDS• The absolute bioavailability of imidafenacin in human is 57.8%.• The pharmacokinetic profiles of imidafenacin after intravenous administration are revealed.• The formation of metabolites in the plasma is caused mainly by first-pass effects. AIMSTo investigate the absolute bioavailability of imidafenacin, a new muscarinic receptor antagonist, a single oral dose of 0.1 mg imidafenacin was compared with an intravenous (i.v.) infusion dose of 0.028 mg of the drug in healthy subjects. METHODSFourteen healthy male subjects, aged 21-45 years, received a single oral dose of 0.1 mg imidafenacin or an i.v. infusion dose of 0.028 mg imidafenacin over 15 min at two treatment sessions separated by a 1-week wash-out period. Plasma concentrations of imidafenacin and the major metabolites M-2 and imidafenacin-N-glucuronide (N-Glu) were determined. The urinary excretion of imidafenacin was also evaluated. Analytes in biological samples were measured by liquid chromatography tandem mass spectrometry. RESULTSThe absolute oral bioavailability of imidafenacin was 57.8% (95% confidence interval 54.1, 61.4) with a total clearance of 29.5 Ϯ 6.3 l h -1 . The steady-state volume of distribution was 122 Ϯ 28 l, suggesting that imidafenacin distributes to tissues. Renal clearance after i.v. infusion was 3.44 Ϯ 1.08 l h -1 , demonstrating that renal clearance plays only a minor role in the elimination of imidafenacin. The ratio of AUCt of both M-2 and N-Glu to that of imidafenacin was reduced after i.v. infusion from that seen after oral administration, suggesting that M-2 and N-Glu in plasma after oral administration were generated primarily due to first-pass metabolism. No serious adverse events were reported during the study.

The pharmacokinetic (PK) and pharmacodynamic (PD) parameters of ONO-4641 in humans were estimated using preclinical data in order to provide essential information to better design future clinical studies. The characterization of PK/PD was measured in terms of decreased lymphocyte counts in blood after administration of ONO-4641, a sphingosine 1-phosphate receptor modulator. Using a two-compartment model, human PK parameters were estimated from preclinical PK data of cynomolgus monkey and in vitro human metabolism data. To estimate human PD parameters, the relationship between lymphocyte counts and plasma concentrations of ONO-4641 in cynomolgus monkeys was determined. The relationship between lymphocyte counts and plasma concentrations of ONO-4641 was described by an indirect-response model. The indirect-response model had an I(max) value of 0.828 and an IC(50) value of 1.29 ng/ml based on the cynomolgus monkey data. These parameters were used to represent human PD parameters for the simulation of lymphocyte counts. Other human PD parameters such as input and output rate constants for lymphocytes were obtained from the literature. Based on these estimated human PK and PD parameters, human lymphocyte counts after administration of ONO-4641 were simulated. In conclusion, the simulation of human lymphocyte counts based on preclinical data led to the acquisition of useful information for designing future clinical studies.

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