Oral Pharmacokinetic Drug-drug Interactions between Amifampridine and Acetaminophen in Rats

Abstract

Amifampridine, the first-line medication for Lambert-Eaton myasthenic syndrome (LEMS), is extensivelymetabolized by N-acetyltransferase 2 (NAT2). Drug-drug interactions (DDIs) can occur when co-administered with a NAT2inhibitor and amifampridine. Acetaminophen is a widely used analgesic for mild to moderate pain, which is also known asa NAT2 inhibitor. In this work, we studied the effects of acetaminophen on the amifampridine pharmacokinetics in rats. Bothacetaminophen (300 mg/kg) and amifampridine (2 mg/kg) were administered orally. In acetaminophen-treated rats, thesystemic exposure to amifampridine significantly increased, and the ratio of the area under the plasma concentration-timecurve for 3-N-acetylamifampridine to amifampridine (AUCm/AUCp) decreased markedly, which is likely due to the inhibitionof NAT2 by acetaminophen. Also, the urinary amount excreted was increased in the acetaminophen-treated group, but therenal clearance remained unchanged. This oral pharmacokinetic drug-drug interaction study showed that orally administeredacetaminophen significantly inhibits the NAT2-based metabolism of amifampridine and may cause meaningful DDIs.