Clinically observed and Simcyp-predicted pharmacokinetic parameter estimates of midazolam in humans before and after 28-day repeated oral administration of crizotinib twice daily doses of 250 mg

CrizotinibCmaxAUC0-∞Fold Increase in Midazolam Oral Exposurea
Administrationng/mLng⋅h/mLCmaxR90% CIAUCR90% CI
ObservedPre13 (39)32 (41)
Post26 (44)117 (61)2.01.4––5.1
PredictedPre10 (58)27 (90)
P/O ratiob0.770.83
HLMcPost30 (39)547 (70)3.01.8–6.9214.7–72
P/O ratiob1.
HSPcPost19 (53)97 (109)1.91.4––8.8
P/O ratiob0.720.830.941.0
  • Data are expressed as geometric mean (% coefficient of variation) for pre- and post-doses of crizotinib (n = 14 and 8 patients, respectively).

  • a Fold increase in Cmax (CmaxR) and AUC0-∞ (AUCR) with coadministration of crizotinib with 90% CI.

  • b Calculated predicted to observed pharmacokinetic parameter ratio.

  • c Simcyp simulation was performed using TDI parameters from either HLM or HSP.