Pharmacokinetics

Absorption Distribution Metabolism Excretion Special Population Other Details

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.

Absorption

Perampanel is readily absorbed after oral administration with no evidence of marked first-pass metabolism.Perampanel oral suspension is bioequivalent on a mg per mg basis to perampanel tablets under fasted conditions. When a single 12-mg dose of both formulations was administered with a high fat meal, perampanel oral suspension achieves equivalent AUC0-inf and approximately 23 % lower Cmax and 2 hours delay in time
to peak exposure (tmax) compared to the tablet formulation. However, population pharmacokinetic analysis demonstrated that under simulated steady state exposure conditions, Cmax and AUC, of perampanel oral suspension were bioequivalent to the tablet formulation under both fasted and fed conditions.

When coadministered with a high fat meal, Cmax and AUC0-inf of a single 12-mg dose of perampanel oral suspension were approximately 22% and 13%, respectively, lower compared to fasted conditions.


 

Distribution

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).


 

Metabolism

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.


 

Excretion

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.


 

Special Population

Hepatic impairment

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.

Renal impairment

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.

Gender

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.

Pediatric population

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.


 

Other details

Linearity/non-linearity

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.