TABLE 3

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

	Crizotinib	C_max	AUC_0-∞	Fold Increase in Midazolam Oral Exposure^{^a}
	Administration	ng/mL	ng⋅h/mL	C_maxR	90% CI	AUC_R	90% CI
Observed	Pre	13 (39)	32 (41)
	Post	26 (44)	117 (61)	2.0	1.4–2.9	3.7	2.6–5.1
Predicted	Pre	10 (58)	27 (90)
P/O ratio^{^b}		0.77	0.83
HLM^{^c}	Post	30 (39)	547 (70)	3.0	1.8–6.9	21	4.7–72
P/O ratio^{^b}		1.2	4.7	1.5		5.6
HSP^{^c}	Post	19 (53)	97 (109)	1.9	1.4–2.7	3.6	1.6–8.8
P/O ratio^{^b}		0.72	0.83	0.94		1.0

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 C_max (C_maxR) and AUC_0-∞ (AUC_R) 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.