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.

ABSTRACT

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.