Abstract:
Thai general population has become more “aged society” (>60 years old) and chronic kidney disease (CKD) is one of major public health problems in Thailand. Ageing and CKD are known to affect pharmacokinetics which generally determines drug exposure in plasma and site of action. Due to the related mechanisms are still unclear, cytochrome P450 (CYP)3A and drug transporters activity changes were investigated in Thai elderly with or without CKD compared to healthy adults using a microdose cocktail.
This study was conducted in 3 groups of subjects: Group 1, healthy young subjects; Group 2, healthy elderly subjects; Group 3; elderly with CKD. All subjects received single dose of microdose cocktail probe containing 30 µg midazolam, 750 µg dabigatran etexilate, 100 µg atorvastatin, 10 µg pitavastatin, and 50 µg rosuvastatin. After 14 days of washout period, Group 1 continued period 2 of study received microdose cocktail plus rifampicin. AUC0-last (area under the concentration-time curve from time zero to last quantifiable concentration), AUC0-inf (AUC time zero to infinity), and Cmax (maximum concentration) were mainly estimated. Genotype analysis for Organic anion transporting polypeptide (OATP) 1B1 and breast cancer resistance protein (BCRP) transporters was analyzed for excluding confounding factor.
AUC0-last and Cmax of midazolam, a CYP3A probe substrate, were increased ~2 to 3-fold in Group 2 and Group 3. Reduction in elimination rate constant and half-life prolongation were observed in both groups. AUC0-last and Cmax of another CYP3A4 probe substrate, atorvastatin, was increased 2-fold in Group 2 and 4-fold in Group 3. CYP3A4 activity was reduced by advanced age resulting in decreased in midazolam clearance and prolonged half-life. The association of pharmacokinetics changes in other probe drugs with drug transporters activity including OATP1B, intestinal P-glycoprotein (P-gp), and BCRP was still inconclusive.
Microdose cocktail indicates the reduction in CYP3A4 activity associated with advanced age, especially in Thai population. Although OATP1B, P-gp, and BCRP activity of the special population cannot be concluded in this study yet, there was a trend of pharmacokinetic alterations in microdose cocktail probe drugs.
