Ranolazine Day 3

Mean plasma concentration-time profile for ranolazine, at steady state.

Mean plasma concentration-time profile for ranolazine, at steady state.

Abdallah H. et al. J Clin Pharmacol 2005; 45: 802-9.

Fig. 6.37. Hepatic Impairment (Reproduced with permission from Sage Publications, Thousand Oaks, CA.)

ranolazine and causes a higher C and AUC, but mild liver

disease has no impact on hepatic clearance.

Age and gender are the most common sources of variability for the pharmacokinetics and pharmacodynamics of a drug and can be determined in a standalone study or via population PK/PD analysis (Fig. 6.38). A typical phase I study uses 3 separate groups of 12 or higher number of males and females (preferably of equal proportions): young (18-45 years), elderly (65-75 years), and elderly (>75 years), which is demonstrated in the graph [22]. Single or multiple doses are employed. Measurement of both PK and PD includes urine

PK and creatinine clearance. Age and CLcr can be correlated. ANOVA is used to determine the effect of age and gender on the PK and or PD parameters. Blood samples are usually collected for pharmacokinetic analysis up to 24 hours post oral administration. It is possible that age and gender may affect the PK and not the PD or vice versa.

Children cannot simply be regarded as "miniature" adults: they differ from adults and even from other children in regard to drug absorption, distribution, metabolism, and elimination. Furthermore, age-related differences in receptor binding characteristics are also evident, resulting in different drug r Common source of variability r Study Design: Separate study o 3 groups of 12 or more, males and females

Young: 18-45 years Elderly (2): 65-75 & >75 years o Single or multiple doses O Measure both PK & PD including urine PK, CLCr and other covariates o ANOVA to determine effect of Age & gender on PK / PD parameters c Can be also determined via population PK / PD analysis r Age & gender may affect PK & not PD, or vice-versa

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