The practical impact of altered dosing on perampanel plasma concentrations: pharmacokinetic modeling from clinical studies.
BACKGROUND
Perampanel is a selective AMPA receptor antagonist approved for adjunctive therapy in patients with refractory partial-onset seizures. Perampanel is metabolized primarily via CYP3A4, yet it has a relatively long half-life of 105h; it is, therefore, recommended that perampanel be given once daily (preferably at bedtime). Many patients occasionally have less-than-perfect adherence to their drug regimen, and given the known pharmacokinetic interactions of perampanel with commonly used enzyme-inducing antiepileptic drugs (EIAEDs), we explored the effects of a missed dose on steady-state perampanel plasma concentrations and the ramifications of "make up" doses in these patients. Although perampanel is approved for once-daily dosing, some clinicians may elect to give perampanel as a divided dose (i.e., twice daily), so we also sought to examine the pharmacokinetic impact of twice- versus once-daily dosing.


METHODS
Pharmacokinetic simulations were performed using validated perampanel pharmacokinetic parameters, derived from 19 phase I studies in 606 subjects, to investigate the effect on perampanel plasma concentration of (1) missing a dose of perampanel followed by delayed replacement of the missed dose, (2) missing a dose followed by resumption of scheduled therapy, and (3) missing a dose in the presence/absence of carbamazepine. Simulations were done for a typical patient receiving an 8-mg once-daily or a 4-mg twice-daily dose using the nonlinear mixed effects program, NONMEM v7.2, in conjunction with PDx-pop v5.


RESULTS
Our results corroborate that given the pharmacokinetic characteristics of perampanel, a missed dose is unlikely to cause as much fluctuation in plasma concentration as would be expected for a drug with a short half-life. Importantly, simulations suggest that supplementing a missed dose 6-12h later, followed by continuation of the regular schedule, may not result in any significant "spikes" in perampanel plasma concentrations. Simulations demonstrated that twice-daily dosing offered little advantage in further flattening the concentration-time profile of perampanel in the adherent patient. However, fluctuations in plasma concentrations are minimized by twice-daily dosing in patients receiving concomitant EIAEDs.


CONCLUSIONS
These pharmacokinetic simulations suggest that the long half-life of perampanel may be advantageous in conferring a relatively smooth concentration-time profile with a once-daily or twice-daily dosing, even in the presence of concomitant EIAEDs. However, the results of the present study suggest that perampanel replacement is recommended for patients taking an EIAED to mitigate the potential risks associated with reduced exposure. Confirmation of the ultimate clinical impact of these findings will require further study.
School of Pharmacy, University of Wisconsin, Madison, WI, USA. Electronic address: begidal@pharmacy.wisc.edu.
Barry E
BE
Gidal
Eisai Ltd, Hatfield, UK.
Oneeb
O
Majid
Eisai Neuroscience Product Creation Unit, Woodcliff Lake, NJ, USA.
Jim
J
Ferry
Eisai Ltd, Hatfield, UK.
Ziad
Z
Hussein
Eisai Neuroscience Product Creation Unit, Woodcliff Lake, NJ, USA.
Haichen
H
Yang
Eisai Neuroscience Product Creation Unit, Woodcliff Lake, NJ, USA.
Jin
J
Zhu
Eisai Medical and Scientific Affairs, Woodcliff Lake, NJ, USA.
Randi
R
Fain
Eisai Neuroscience Product Creation Unit, Woodcliff Lake, NJ, USA.
Antonio
A
Laurenza
D000927:Anticonvulsants / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D035843:Biomedical Research; D002220:Carbamazepine / Q000097:blood / Q000627:therapeutic use; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004828:Epilepsies, Partial / Q000097:blood* / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008297:Male; D055118:Medication Adherence; D008954:Models, Biological; D009570:Nitriles; D010599:Pharmacokinetics; D011728:Pyridones / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D013997:Time Factors
D000927:Anticonvulsants; D009570:Nitriles; D011728:Pyridones; D002220:Carbamazepine; C551441:perampanel
Adherence; Antiepileptic drugs; Dosing; Perampanel; Pharmacokinetics