Armodafinil and modafinil in patients with excessive sleepiness associated with shift work disorder: a pharmacokinetic/pharmacodynamic model for predicting and comparing their concentration-effect relationships.
Armodafinil, the longer lasting R-isomer of racemic modafinil, improves wakefulness in patients with excessive sleepiness associated with shift work disorder (SWD). Pharmacokinetic studies suggest that armodafinil achieves higher plasma concentrations than modafinil late in a dose interval following equal oral doses. Pooled Multiple Sleep Latency Test (MSLT) data from 2 randomized, double-blind, placebo-controlled trials in 463 patients with SWD, 1 with armodafinil 150 mg/d and 1 with modafinil 200 mg/d (both administered around 2200 h before night shifts), were used to build a pharmacokinetic/pharmacodynamic model. Predicted plasma drug concentrations were obtained by developing and applying a population pharmacokinetic model using nonlinear mixed-effects modeling. Armodafinil 200 mg produced a plasma concentration above the EC(50) (4.6 µg/mL) for 9 hours, whereas modafinil 200 mg did not exceed the EC(50). Consequently, armodafinil produced greater increases in predicted placebo-subtracted MSLT times of 0.5-1 minute (up to 10 hours after dosing) compared with modafinil. On a milligram-to-milligram basis, armodafinil 200 mg consistently increased wakefulness more than modafinil 200 mg, including times late in the 8-hour shift.
Clinical Pharmacology Department, Cephalon, Inc., 41 Moores Road, Frazer, PA 19355, USA. mdarwish@cephalon.com
Mona
M
Darwish
Mary
M
Bond
Farkad
F
Ezzet
D001559:Benzhydryl Compounds / Q000097:blood / Q000494:pharmacology*; D000697:Central Nervous System Stimulants / Q000097:blood / Q000494:pharmacology*; D004311:Double-Blind Method; D006801:Humans; D000077408:Modafinil; D008954:Models, Biological; D020178:Sleep Disorders, Circadian Rhythm / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D014851:Wakefulness / Q000187:drug effects
D001559:Benzhydryl Compounds; D000697:Central Nervous System Stimulants; D000077408:Modafinil