Influence of Inflammation on the Pharmacokinetics of Perampanel.

ABSTRACT

BACKGROUND: It is well-known that the pharmacokinetics of various drugs are influenced by inflammation. This study evaluated the relationship between C-reactive protein (CRP; an inflammation marker) and the pharmacokinetics of perampanel. METHODS: Among 111 patients who underwent measurement of both CRP and perampanel, 23 patients had a serum CRP level exceeding 1.5 mg/dL (CRP-positive). We compared the concentration/dose ratio (CD ratio) of perampanel in these 23 patients between the times when they were CRP-positive and CRP-negative. To evaluate the effect of CRP on the CD ratio, multiple regression analysis was performed with the following covariates CRP-positive status, body weight, and use of phenytoin, carbamazepine, or phenobarbital, and combinations of these drugs. RESULTS: In 10 patients using enzyme-inducing antiepileptic drugs (AEDs), the mean CD ratio increased by 53.5% [from 1389 to 2132 (ng/mL)/(mg/kg)] when they were CRP-positive. In 13 patients without enzyme-inducing AEDs, the mean CD ratio increased by 100.8% [from 3826 ng/mL to 7683 (ng/mL)/(mg/kg)] when they were CRP-positive. By multiple regression analysis, the CRP level was a significant independent determinant of the CD ratio of perampanel. Despite a marked increase of the CD ratio, no adverse events were reported. CONCLUSIONS: Irrespective of concomitant administration of enzyme-inducing AEDs, the serum perampanel concentration showed a marked increase in patients with inflammation. However, this increase was not associated with central nervous system toxicity. Although it is unknown whether the concentration of free and/or bound perampanel was increased, it seems likely that dose reduction is unnecessary for elevation of the serum perampanel level in patients with inflammation.