Pharmacokinetics of Racemic Eflornithine in Human Plasma and Cerebrospinal Fluid: Clinical Perspectives for L-eflornithine Against Human African Trypanosomiasis

Intravenous dosing of L- and D-eflornithine in a racemic mixture is a currently recommended late-stage gambiense human African trypanosomiasis (g-HAT) treatment, either as 14-day monotherapy or in combination with oral nifurtimox for seven days. However, an oral eflornithine treatment against late-stage g-HAT would be preferable. Pharmacokinetics of eflornithine are enantioselective with different oral absorption of the enantiomers. L-eflornithine has a greater in vitro antitrypanosomal potency than D-eflornithine. This study aimed to integrate knowledge about in vitro potency and literature data from the only clinical study with enantiospecific pharmacokinetic oral data to predict L-eflornithine concentrations in plasma and cerebrospinal fluid to estimate the probability of target attainment. L- and D-eflornithine concentrations in cerebrospinal fluid from the clinical study with enantiospecific data were described with a compartment model that was validated using external data with total eflornithine concentrations. Simulations were performed with oral L-eflornithine doses ranging between 125 to 1000 mg/kg/day administered twice to twelve times daily. The probability of target attainment analysis showed that oral L-eflornithine doses of 750 mg/kg/day administered four or twelve times daily (i.e., drinking a solution every 2nd hour) as monotherapy would be needed to acquire efficacious exposures. In combination with nifurtimox, L-eflornithine dosed at 375 mg/kg/day four or twelve times daily would give exposures over the threshold concentration in cerebrospinal fluid. The presented simulation framework may serve as a starting point to find a suitable oral dose regimen to assess the clinical potential for an oral L-eflornithine-based combination treatments against late-stage g-HAT.