REDUCTION OF SERUM LACTATE BY SODIUM DICHLOROACETATE, AND HUMAN PHARMACOKINETIC-PHARMACODYNAMIC RELATIONSHIPS

Sodium dichloroacetate (DCA) or placebo, two infusions 30 min in durat ion and 8 h apart, was administered to healthy subjects under double-b lind conditions. The objectives were to characterize accurately the to lerability of DCA, its pharmacokinetics, and the reduction of vesting serum lactate concentration by DCA. A hybrid, one-compartment pharmaco kinetic model fitted best, with zero-order elimination mean of 27.9 mu g/ml/h at concentrations above about 80 to 120 mu g/ml, and with firs t-order elimination (mean k(elim) = 0.54) at lower serum concentration s of DCA. Resting serum lactate was dose-independently, maximally redu ced within 15 min of the end of all active infusions. The duration of suppression of resting serum lactate was dose-dependent, from 4.5 h (3 0 mg/kg) to > 8 h (100 mg/kg). Second infusions (15-50 mg/kg) again pr omptly and maximally reduced resting serum lactate. Hysteresis loops w ere asymmetrical for all doses but exhibited change in shape that was dose-dependent; no good pharmacokinetic-pharmacodynamic model could be fitted that was consistent between doses. Infusions were well tolerat ed, 100 mg/kg + 50 mg/kg being the highest doses. Somnolence, the only dose-related adverse event, was reported by 3 of 37 subjects at times corresponding to the highest serum DCA concentrations. This study dem onstrates the tolerability of i.v. DCA, proposes a simple pharmacokine tic model for its elimination, characterizes the dose-response relatio nship in terms of time course of effect, shows the dissociation betwee n elimination of DCA and offset of response and will guide further stu dies of DCA in patients with head injury or stroke.