2011 - Athens - Greece

PAGE 2011: Other topics - Applications
Hyewon Jeon

A Population Pharmacokinetic/pharmacodynamic Approache of Drug X in Healthy Korean

Hyewon Jeon, SoJeong Yi, Sang-Goo Shin, In-Jin Jang, Kyung-Sang Yu

Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea

Objectives: Drug X is a selective arginine vasopressin (AVP) V2-receptor antagonist which is used for treatment of acute and chronic hyponatremia. The aim of this study was to develop the population pharmacokinetic (PK) and pharmacodynamic (PD) model of Drug X in healthy male Koreans.

Methods: A dose-block randomized, double-blinded, single-dose study was performed to evaluate pharmacokinetics and pharmacodynamics of 15, 30, and 60 mg of Drug X. Blood samples were collected up to 48 hours after drug administration. Free water clearance was estimated from 24-hour urine excretion rate (0-4, 4-8, 8-12, 12-24 hour interval), urine and plasma osmolality. Baseline for pharmacodynamic endpoints was the value of the predose sample. A non linear mixed-effect modeling approach, using NONMEM 7 (version 7.1.2) was implemented in modeling plasma Drug X concentration-time profiles and free water clearance of each timepoint.

Results: A total of 473 concentrations from 36 subjects were included in population analysis. Drug X concentrations were best described by a two-compartment model with first-order absorption and elimination. The estimate of pharmacokinetic parameters and inter-individual variability (IIV, % CV) for clearance (CL) was 15.5 L/h (30.3), central volume of distribution (V2) was 49.3 L (12.9), inter-compartment clearance (Q) was 15.3 L/h (31.8), absorption rate constant (KA) was 0.27 h-1 and peripheral volume of distribution (V3) was 1360 L. Posthoc Bayesian predicted concentrations of effect compartment were used for estimate PD using sigmoid Emax model. The estimated Emax and baseline of free water clearance were 7.99 and -0.63 mL/min, respectively. The exposure associated with a 50% increase (EC50) (IIV, % CV) was 48.6 µg/L (24.5) and Hill's coefficient was 1.1.

Conclusions: A PK/PD model was utilized to characterize the effect of Drug X on the free water clearance. Further studies will be needed to investigate the influence of subject's characteristics and mechanisms related to arginine vasopressin V2 receptor.

Acknowledgments: The clinical study was supported by funds from Korea Otsuka Pharmaceutical Co., Ltd.

[1] Robert W. Schrier, Peter Gross, Mihai Gheorghiade, Tomas Berl, Joseph G. Verbalis, Frank S. Czerwiec, and Cesare Orlandi for the SALT Investigators. Tolvaptan, a Selective Oral Vasopressin V2-Receptor Antagonist, for Hyponatremia, N Engl J Med 2006; 355:2099-2112
[2]  Susan E. Shoaf, Zhao Wang, Patricia Bricmont and Suresh Mallikaarjun. Pharmacokinetics, Pharmacodynamics, and Safety of Tolvaptan, a Nonpeptide AVP Antagonist, During Ascending Single-Dose Studies in Healthy Subjects J Clin Pharmacol 2007;47:1498-1507

Reference: PAGE 20 (2011) Abstr 2154 [www.page-meeting.org/?abstract=2154]
Poster: Other topics - Applications
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