title: Population-based meta-analysis of hydrochlorothiazide pharmacokinetics.
abstract: 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 (CLCR ) was a statistically significant predictor of renal clearance (CLR ). Non-renal clearance was estimated to be 2.44 l/h, CLR was 18.3 l/h and T1/2,α was 1.6 h and T1/2,β was 14.8 h for a typical individual with normal renal function (CLCR  = 120 ml/min). However, CLR was reduced to 10.5, 5.47 and 2.70 l/h in mild (CLCR  = 80 ml/min), moderate (CLCR  = 50 ml/min) and severe (CLCR  = 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 CLCR , 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.
authors.affiliation: Institute for Clinical Pharmacodynamics, Latham, NY, USA; Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Van Wart
authors.forename: Susan E
authors.initials: SE
authors.lastname: Shoaf
authors.forename: Suresh
authors.initials: S
authors.lastname: Mallikaarjun
authors.forename: Donald E
authors.initials: DE
authors.lastname: Mager
mesh_terms: D000328:Adult; D000959:Antihypertensive Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D001552:Benzazepines / Q000494:pharmacology; D004232:Diuretics / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D006333:Heart Failure / Q000097:blood / Q000652:urine; D006801:Humans; D006852:Hydrochlorothiazide / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D006973:Hypertension / Q000097:blood / Q000652:urine; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D051437:Renal Insufficiency / Q000097:blood / Q000652:urine; D000077602:Tolvaptan; D055815:Young Adult
chemical_list: D000959:Antihypertensive Agents; D001552:Benzazepines; D004232:Diuretics; D006852:Hydrochlorothiazide; D000077602:Tolvaptan
keywords: heart failure; hydrochlorothiazide; population pharmacokinetics