The pharmacokinetics of perampanel have been studied in healthy adult subjects (age range 18 to 79), adults, adolescents, and paediatric patients with partial-onset seizures and primary generalized tonic-clonic seizures, adults with Parkinson’s disease, adults with diabetic neuropathy, adults with multiple sclerosis, and patients with hepatic impairment.
Perampanel is readily absorbed after oral administration with no evidence of marked first-pass metabolism. Co-administration of perampanel tablets with a high fat meal had no impact on the peak plasma exposure (Cmax) or total exposure (AUC0-inf) of perampanel. The tmax was delayed by approximately 1 hour compared to that under fasted conditions.
Data from in vitro studies indicate that perampanel is approximately 95% bound to plasma proteins.
In vitro studies show that perampanel is not a substrate or significant inhibitor of organic anion transporting polypeptides (OATP) 1B1 and 1B3, organic anion transporters (OAT) 1, 2, 3, and 4, organic cation transporters (OCT) 1, 2, and 3, and the efflux transporters P-glycoprotein and Breast Cancer Resistance Protein (BCRP).
Perampanel is extensively metabolized via primary oxidation and sequential glucuronidation. The metabolism of perampanel is mediated primarily by CYP3A based on clinical study results in healthy subjects administered radiolabeled perampanel and supported by in vitro studies using recombinant human CYPs and human liver microsomes.
Following administration of radiolabeled perampanel, only trace amounts of perampanel metabolites were observed in plasma.
Following administration of a radiolabeled perampanel dose to 8 healthy adults or elderly subjects, 30% of recovered radioactivity was found in the urine and 70% in the feces. In urine and feces, recovered radioactivity was primarily composed of a mixture of oxidative and conjugated metabolites. In a population pharmacokinetic analysis of pooled data from 19 Phase 1 studies, the average t1/2 of perampanel was 105 hours. When dosed in combination with the strong CYP3A inducer carbamazepine, the average t1/2 was 25 hours.
The pharmacokinetics of perampanel following a single 1 mg dose were evaluated in 12 patients with mild and moderate hepatic impairment (Child-Pugh A and B, respectively) compared with 12 healthy, demographically matched subjects.
The mean apparent clearance of unbound perampanel in mildly impaired patients was 188 mL/min vs. 338 ml/min in matched controls, and in moderately impaired patients was 120 mL/min vs. 392 mL/min in matched controls. The t1/2 was longer in mildly impaired (306 h vs 125 h) and moderately impaired (295 h vs 139 h) patients compared to matched healthy subjects.
The pharmacokinetics of perampanel has not been formally evaluated in patients with renal impairment. Perampanel is eliminated almost exclusively by metabolism followed by rapid excretion of metabolites; only trace amounts of perampanel metabolites are observed in plasma. In a population pharmacokinetic analysis of patients with partial-onset seizures having creatinine clearances ranging from 39 to 160 mL/min and receiving perampanel up to 12 mg/day in placebo-controlled clinical trials, perampanel clearance was not influenced by creatinine clearance.
In a population pharmacokinetic analysis of patients with primary generalized tonic-clonic seizures receiving perampanel up to 8 mg/day in a placebo-controlled clinical study, perampanel clearance was not influenced by baseline creatinine clearance.
In a population pharmacokinetic analysis of patients with partial-onset seizures receiving perampanel up to 12 mg/day and patients with primary generalized tonic-clonic seizures receiving perampanel up to 8 mg/day in placebo-controlled clinical trials, perampanel clearance in females (0.54 l/h) was 18% lower than in males (0.66 l/h).
Elderly (65 years of age and above)
In a population pharmacokinetic analysis of patients with partial-onset seizures (age range 12 to 74 years) and primary generalized tonic-clonic seizures (age range 12 to 58 years), and receiving perampanel up to 8 or 12 mg/day in placebo-controlled clinical trials, no significant effect of age on perampanel clearance was found. A dose adjustment in the elderly is not considered to be necessary.
In a population pharmacokinetic analysis on pooled data from children aged 4 to 11 years, adolescent patients aged ≥12 years, and adults, perampanel clearance increased with an increase in body weight. Hence, dose adjustment in children aged 4 to 11 years with a body weight < 30 kg is necessary.
In a population PK analysis on pooled data from twenty Phase 1 studies in healthy subjects receiving perampanel between 0.2 and 36 mg either as single or multiple doses, one Phase 2 and five Phase 3 studies in patients with partial‑onset seizure receiving perampanel between 2 and 16 mg/day and two Phase 3 studies in patients with primary generalised tonic‑clonic seizures receiving perampanel between 2 and 14 mg/day a linear relationship was found between dose and perampanel plasma concentrations.
Drug Interaction Studies
In Vitro Assessment of Drug Interactions
Drug Metabolizing Enzyme Inhibition
In human liver microsomes, perampanel (30 μmol/L) had a weak inhibitory effect on CYP2C8 and UGT1A9 among major hepatic CYPs and UGTs.
Drug Metabolizing Enzyme Induction
Compared with positive controls (including phenobarbital, rifampicin), perampanel was found to weakly induce CYP2B6 (30 μmol/L) and CYP3A4/5 (≥3 μmol/L) among major hepatic CYPs and UGTs in cultured human hepatocytes.