farmakokinetik
1
2.5. Pharmacokinetics and metabolism 2.5.1. Almorexant and its primary metabolites The PK parameters of almorexant and its primary metabolites were determined by non-compartmental PK analysis of plasma concentration–time data using WinNonlin_ (Version 5.2.1, Pharsight, Mountain View, CA, USA). The area under the plasma concentration–time curve (AUC) was calculated according to the linear trapezoidal rule. AUC0_t was calculated using the measured concentration–time values above the LLOQ. AUC0_1 was calculated by combining AUC0_t and AUCextra. AUCextra represents an extrapolated value obtained by Ct/kz, where Ct is the last plasma concentration measured above the LLOQ and kz represents the elimination rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal elimination phase. The half-lives of almorexant and its primary metabolites were calculated as t1/2 = ln2/kz. 2.6. Tolerability and safety Tolerability and safety were evaluated on the basis of reported AEs, and the results of physical examination, and the assessment of body weight, vital signs (blood pressure and pulse rate), 12- lead ECGs, and clinical laboratory tests (hematology, clinical chemistry, coagulation, and urinalysis). All subjects who received study drug and who had at least one valid post-treatment safety assessment were included in the safety evaluation. 2.7. Statistical analysis Cmax, AUC, and t1/2 values were assumed to be log-normally distributed (Julious and Debarnot, 2000). Pharmacokinetic variables were presented as geometric mean with 95% confidence interval (CI) and, for tmax, as median and range. The effect of hepatic impairment on the PK of almorexant and its metabolites, i.e., on AUC0_t, AUC0_1, Cmax, tmax, and t1/2 was explored based on analyses of variance (ANOVA) after log-transformation for Cmax, AUC, and t1/2 with fixed effect for group (mild and moderate hepatic impairment, healthy subjects, and healthy subjects matched to subjects in Groups A and B, respectively, defined as groups DA and DB). The residuals of the ANOVA were inspected for conformity with the normality assumption using the Shapiro–Wilk test. The ratios of geometric means and their 90% CI were derived for the comparison of mild or moderate impairment vs. the healthy subject groups. For plasma protein binding the ratio of free and total almorexant plasma concentration (Cf/C) was expressed as a percentage. Tolerability and safety endpoints were analyzed descriptively.
description
n
Transcript of farmakokinetik
2.5. Pharmacokinetics and metabolism2.5.1. Almorexant and its primary metabolitesThe PK parameters of almorexant and its primary metabolites were determined by non-compartmental PK analysis of plasma concentrationtime data using WinNonlin_ (Version 5.2.1, Pharsight, Mountain View, CA, USA). The area under the plasma concentrationtime curve (AUC) was calculated according to the linear trapezoidal rule. AUC0_t was calculated using the measured concentrationtime values above the LLOQ. AUC0_1 was calculated by combining AUC0_t and AUCextra. AUCextra represents an extrapolated value obtained by Ct/kz, where Ct is the last plasma concentration measured above the LLOQ and kz represents the elimination rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal elimination phase. The half-lives of almorexant and its primary metabolites were calculated as t1/2 = ln2/kz.
2.6. Tolerability and safetyTolerability and safety were evaluated on the basis of reported AEs, and the results of physical examination, and the assessment of body weight, vital signs (blood pressure and pulse rate), 12-lead ECGs, and clinical laboratory tests (hematology, clinical chemistry, coagulation, and urinalysis). All subjects who received study drug and who had at least one valid post-treatment safety assessment were included in the safety evaluation.
2.7. Statistical analysisCmax, AUC, and t1/2 values were assumed to be log-normally distributed (Julious and Debarnot, 2000). Pharmacokinetic variables were presented as geometric mean with 95% confidence interval (CI) and, for tmax, as median and range. The effect of hepatic impairment on the PK of almorexant and its metabolites, i.e., on AUC0_t, AUC0_1, Cmax, tmax, and t1/2 was explored based on analyses of variance (ANOVA) after log-transformation for Cmax, AUC, and t1/2 with fixed effect for group (mild and moderate hepatic impairment, healthy subjects, and healthy subjects matched to subjects in Groups A and B, respectively, defined as groups DA and DB). The residuals of the ANOVA were inspected for conformity with the normality assumption using the ShapiroWilk test. The ratios of geometric means and their 90% CI were derived for the comparison of mild or moderate impairment vs. the healthy subject groups. For plasma protein binding the ratio of free and total almorexant plasma concentration (Cf/C) was expressed as a percentage. Tolerability and safety endpoints were analyzed descriptively.
