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Pharmacokinetic and Pharmacodynamic Modeling of a Copper-Selective Chelator (TETA) in Healthy Adults

From the Department of Pharmaceutical Sciences, School of Pharmacy, State University of New York at Buffalo (Dr Cho, Dr Jusko); the Buffalo Clinical Research Center, Buffalo, New York (Dr Blum); the School of Biological Sciences, University of Auckland, Auckland, New Zealand (Ms Sunderland); and the Department of Biochemistry, University of Oxford, UK (Dr Cooper).

The population pharmacokinetics (PK) and pharmacodynamics (PD) of triethylenetetramine (TETA) dihydrochloride (trientine, GC811007) administered orally as 100-, 300-, 600-, or 1800-mg twice-daily doses were assessed in healthy adult male and female volunteers. This study was a randomized, double-blind, placebo-controlled, group-sequential, dose-escalating design. Forty participants, 10 per dose level (8 receiving TETA, 2 receiving placebo), received twice-daily doses for 14 consecutive days. A 2-compartment model for the PK and a linear direct effect model for drug-induced copper excretion (PD) were employed. The population PK/PD model was applied using the NONMEM software. Covariates tested were glomerular filtration rate (GFR), body weight, and gender. Multiple daily doses of TETA were safe and generally well tolerated. The linear 2-compartment model with first-order absorption well characterized the serum concentration data. Although its role was small, GFR had a statistically significant (P < .05) influence on systemic clearance (CL/F). The augmentation of copper excretion was well described by a direct linear model in which the slope was related to GFR and gender (P < .001). The intersubject coefficient of variation was 22.2% for slope (SL) and 82.5% for intercept (ER₀). TETA has consistent single/multiple-dose pharmacokinetics and dose-proportional and serum concentration-proportional effects on enhancing copper excretion.

Key Words: Triethylenetetramine • copper • pharmacokinetics • pharmacodynamics • human subjects

Address for reprints: William J. Jusko, PhD, 565 Hochstetter Hall, Department of Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY 14260; e-mail: wjjusko{at}buffalo.edu.

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