OI-A-1Pharmacokinetic/pharmacodynamic (PK/PD) model for tolvaptan (TOL) in patients with congestive heart failure (CHF) and/or hyponatremia (HYP).

Abstract

AIM TOL is a oral vasopressin (V2) receptor antagonist under development for treatment of CHF and/or HYP. Direct and indirect effect PK/PD models were evaluated to characterize the effect of TOL concentration (Cp) on urine flow rate (UFR) and the influence of water intake rate (WIR), loop diuretic use, and patient covariates. METHODS Data (1650 timed urine collections from 103 patients) were pooled from 3 Phase 2 studies in CHF and/or HYP patients given placebo or TOL (5 to 120 mg) once daily. Urine output and water intake were recorded for 2 days prior and during the first 4 days of TOL therapy. Patient covariates were evaluated using stepwise forward (α=0.05) and backward (α=0.001) procedures. RESULTS A direct effect model, with UFR estimated as a linear function of TOL Cp (slope = 0.381 mL/hr per ng/mL) and as a function of time (slope declined 1.8% per hr after first dose) described the data. Baseline E0 (separate day and night estimates) was a linear function of WIR with a shift for loop diuretic use. Weight, vasopressin Cp, and presence of CHF also significantly impacted E0. The model slightly underpredicted (median PE% ranged from −3 to −9%) but provided reasonably precise (median |PE|% ranged from 13–16%) daily urine volumes. For a 30 mg dose (n = 12), the estimated net fluid loss due to TOL on the first treatment day was 1.3 L. CONCLUSION This PK/PD model relates TOL Cp to UFR with consideration of concurrent loop diuretic use, and provides individual estimates of daily net fluid loss for potential use in dose selection. Clinical Pharmacology & Therapeutics (2005) 79, P1–P1; doi: 10.1016/j.clpt.2005.12.002