Effects of hydrochlorothiazide and amlodipine on single oral dose pharmacokinetics of valsartan in healthy Korean subjects: Population model-based approach.

Fixed dose combination (FDC) of valsartan (VAL) and hydrochlorothiazide (HCT) or VAL and amlodipine (AML) has been available in many countries for the treatment of hypertension. Due to drug-drug interaction potentials, in the current study we aimed to evaluate potent effects of HCT and AML on pharmacokinetics (PKs) of VAL when they are orally co-administered as FDC (VAL/HCT at 80/12.5 mg or 160/12.5 mg; and VAL/AML at 160/5 mg or 160/10 mg) products in healthy Korean subjects. Population pharmacokinetic (PK) modeling and analysis were performed by the nonlinear mixed-effects modeling software. PKs of VAL was described by two-compartment disposition model, first-order elimination, four-sequential first-order absorption model, correlation between apparent clearances and volumes of distribution, and lag time. For all FDCs, there were no statistically significant differences in both maximum concentration and areas under the concentration-time curves (AUCs) of VAL in comparison to those when administered VAL alone, except the combination of VAL/AML at 160/10 mg, where AUC increased by 11.8% in mean and 6.86% in median. In addition, there was an increasing trend in time to reach peak (T) of VAL in FDCs, where it was increased by 0.22-0.34 h in mean and 0.40-0.44 h in median, except the combination of VAL/HCT at 160/12.5 mg. However, these differences in AUC and T might not be considered as clinically important. In conclusion, HCT or AML has no potent effect on PKs of VAL when they are co-administered as FDC products. No dose adjustment for VAL is recommended when co-administered with HCT or AML.