Abstract

Aim: Direct effect, indirect effect, and competitive antagonism models were evaluated to describe plasma tolvaptan concentration effect on urine flow rate (UFR), with consideration of water intake rate (WIR) and concurrent diuretic use. Tolvaptan is a vasopressin (V2) receptor antagonist under development for congestive heart failure (CHF) and hyponatremia (HYP).

Methods: Data (1956 timed urine collections from 101 subjects) were pooled from 3 Phase 1 studies in healthy adults given single oral doses of placebo or tolvaptan (30 to 480 mg). Serial blood samples were collected to determine tolvaptan and vasopressin concentrations in plasma. Urine output and water intake were recorded for 2 days prior to, and for up to 3 days after the tolvaptan dose. WIR was calculated using a 1 hour delay for the urine output lag after water consumption. Previous models were used for tolvaptan PK and the non-constant baseline UFR.

Results: A direct effect model, with UFR estimated as a linear function of plasma tolvaptan concentration (slope = 0.941 mL/hr per ng/mL) best described the data. E0 was estimated as a linear function of WIR (intercept = 52.6 mL/hr, slope = 0.42), with shifts for concurrent use of loop (483 mL/hr) or thiazide diuretics (88.4 mL/hr), for each urine collection. Urine volumes predicted by the model during each interval were generally unbiased (median PE% = –1.27%) and reasonably precise (median |PE|% = 30%).

Conclusions: This PK/PD model demonstrates the effect of tolvaptan concentrations on UFR in healthy subjects, and provides a basis for estimating net fluid loss in Phase 2 patients with CHF and HYP.

American Society for Clinical Pharmacology and Therapeutics (ASCPT), Baltimore, Maryland, March 2006

By Van Wart, S.A., Cirincione, B.B., Elizabeth A. Ludwig, Thaddeus H. Grasela, Chen, X., Shoaf, S., Mallikaarjun, S.