Population-based meta-analysis of hydrochlorothiazide pharmacokinetics

Hydrochlorothiazide (HCTZ) is a thiazide diuretic used for the treatment of hypertension and edema associated with fluid overload conditions such as congestive heart failure (CHF). A population-based meta-analysis approach in NONMEM® was used to develop a PK model to characterize the time-course of HCTZ concentrations in plasma and excretion into the urine for healthy subjects and CHF patients. Data from healthy subjects receiving 100 mg of oral HCTZ were supplemented with additional plasma concentration and urinary excretion versus time data published in the literature following administration of oral HCTZ doses ranging from 10 to 500 mg to healthy subjects or patients with renal failure, CHF or hypertension. A two-compartment model with first-order oral absorption, using a Weibull function, and first-order elimination best described HCTZ PK. Creatinine clearance (CL_CR) was a statistically significant predictor of renal clearance (CL_R). Non-renal clearance was estimated to be 2.44 l/h, CL_R was 18.3 l/h and T _1/2,α was 1.6 h and T_1/2,β was 14.8 h for a typical individual with normal renal function (CL_CR = 120 ml/min). However, CL_R was reduced to 10.5, 5.47 and 2.70 l/h in mild (CL _CR = 80 ml/min), moderate (CL_CR = 50 ml/min) and severe (CL_CR = 30 ml/min) renal impairment, respectively. Model diagnostics helped to demonstrate that the population PK model reasonably predicts the rate of urinary HCTZ excretion over time using dosing history and estimated CL _CR, allowing for the convenient assessment of PK-PD relationships for HCTZ when given alone or in combination with other agents used to treat fluid overload conditions.