Population Pharmacokinetics and Pharmacodynamics of @entity35742 in @entity1 with XXXX .

@entity1 @entity5735 @entity6 @entity35742 @entity1011 @entity2449
BACKGROUND AND OBJECTIVES: @entity35742 is a @entity5735 inhibitor, used to treat @entity6 ( @entity6 ). Population pharmacokinetic and pharmacodynamic analyses were performed to characterize the impact of clinically relevant intrinsic/extrinsic factors (covariates) on @entity35742 exposure and @entity5735 inhibition in @entity1 with @entity6 . METHODS: @entity35742 plasma concentrations and @entity5735 activities were obtained from four studies (two phase 1, two phase 2b). Non-linear mixed-effects modelling techniques were implemented using NONMEM software. The covariates that were studied comprised demographic information and laboratory values, including liver enzyme levels and @entity1011 clearance, as well as study-related factors such as @entity2449 co-treatment. Covariate effects on parameters describing the pharmacokinetics and pharmacokinetic/pharmacodynamic relationship were investigated using stepwise forward inclusion/backward elimination. RESULTS: The pharmacokinetic analysis included 6,907 measurements of plasma @entity35742 concentrations from 462 @entity1 ; the pharmacokinetic/pharmacodynamic analysis included 9,674 measurements of plasma @entity5735 activity and @entity35742 plasma concentrations from 607 @entity1 . The non-linear pharmacokinetics were described by a target-mediated drug disposition model accounting for the concentration-dependent binding of @entity35742 to its target, @entity5735 . The difference in exposure between the 5th and 95th percentiles of the covariate distributions and median was <20 % for each single covariate. Likewise, the impact of the covariates on both the half-maximum effect (EC50) and the concentration leading to 80 % @entity5735 inhibition was <20 %. CONCLUSION: These analyses show that the investigated factors do not alter the pharmacokinetics and @entity5735 inhibitory activity of @entity35742 to a clinically relevant extent and that dose adjustment is not necessary on the basis of factors including age, sex and weight.
