Toxicokinetic and toxicodynamic (TK/TD) evaluation to determine and predict the neurotoxicity of artemisinins

Abstract

Studies with laboratory animals have demonstrated fatal neurotoxicity that is associated with administration of artemether (AM) and arteether (AE) intramuscularly or artelinic acid (AL) orally. Toxicokinetic studies showed oil-soluble artemisinins form a depot at the intramuscular injection sites, which is associated with fascia inflammation in muscles. Oral administration of AL induces a gastrointestinal toxicity that is linked with delayed gastric emptying. These effects suggest that the exposure time of artemisinins was extended due to drug accumulation in blood, and this in turn resulted in neurotoxicity. In the present report, the drug exposure time with a neurotoxic outcome (neurotoxic exposure time) was evaluated as a predictor of neurotoxicity in vivo. The neurotoxic exposure time represents a total time spent above a lowest observed neurotoxic effect levels (LONEL) in plasma. The dose of AE required to induce minimal neurotoxicity requires a 2-3 fold longer exposure time in rhesus monkeys (179.5 h) than in rats (67.1 h) and dogs (103.7 h) by using a daily dose of 6-12.5 mg/kg for 7-28 days, indicating that the safe dosing duration in monkeys should be longer than 7 days under the exposure. The neurotoxic exposure time of artemisinins could be longer in humans as the comparison of monkeys to humans is likely more relevant than from rodents or dogs. Oral AL required much longer exposure times (8-fold) than intramuscular AE to induce neurotoxicity, suggesting that water-soluble artemisinins appear to be much safer than oil-soluble artemisinins. Due to lower doses (2-4 mg/kg) used with current artemisinins and the more rare use of AE in treating humans the exposure time is much shorter in humans. Therefore, the current regimen of 3-5 days dosing duration should be quite safe. These findings support a recently published WHO guide for malaria treatment with artemisinin regimens, such as artemisinin-based combination therapies and injectable artesunate, to avoid neurotoxicity.

Pharmacokinetic (PK) and Pharmacodynamic Profiles of Artemisinin Derivatives Influence Drug Neurotoxicity in Animals

“…The AUC (53.10 µg·h/ml) of AE observed on the last dosing day was shown to be 60-fold higher than the AUC of AE observed after intramuscular dosing on the first day (0.88 µg·h/ml), indicating that the exposure concentration of AE was greatly increased. The total AUC of AE observed during the entire 14 days of treatment was 70.96 µg·h/ml (Li & Hickman, 2011). Fig.…”

“…AE dissolved in sesame oil formulation showed high plasma concentrations in rhesus monkeys after daily intramuscular administrations of AE at 16 mg/kg for 14 days (Li & Hickman, 2011). The concentration-time profile of monkeys dosed with AE at 16 mg/kg showed the C max of AE (1038 ng/ml) on day 14 was 19 fold higher than on day 1 (63 ng/ml).…”

“…2. Pharmacokinetic profiles measured by HPLC-ECD (markers) and computer fitted curves (solid line) of arteether (AE) in sesame oil in rats at daily dose of 12.5 mg/kg for 7 days (top, Li et al, 1999b), in beagle dogs at daily dose of 15 mg/kg for 14 days (middle, Li et al, 2000), and in rhesus monkeys at daily dose of 16 mg/kg for 14 days (bottom, Li & Hickman, 2011). The lowest observed neurotoxic effect level (LONEL, dashed line) from AE measurement was estimated 41.32 ng/ml in rats, 40.92 ng/ml in dogs, and 193.8 ng/ml in rhesus monkeys, respectively.…”

“…Following 7 days of daily intramuscular injections of AE (25 mg/kg), 91.4% of a single dose (25 mg/kg/day) was still left in the muscles from the injection sites 24 hr after the last dose (Li et al, 1999b Finding severity were grading as 0 = no significant lesions, 1 = minimal, 2 = mild, 3 = moderate, Table 3. Muscle injury severity in the injection site areas following repeated arteether (AE) and artemether (AM) injection with vehicle sesame oil by multiple daily intramuscular dosing at 25 mg/kg for 7 days (n = 3) in rats (Li & Hickman, 2011).…”

“…In a study of 3500 patients in Thailand, evidence of serious toxicity was not noticed (Price et al, 1999). From other reports, rare neurologic side effects have been noted in humans receiving ART drugs, however, these findings were difficult to dissect from the effects of malaria infection (Li & Hickman 2011).…”