Table 3.

Predictions of fluconazole inhibition on siponimod pharmacokinetics using SimCYP ADME simulator version 9 (i, ii, iii) or version 16 (iv) and comparison with observed in vivo results

Trial no. (dose regimen)	Fluconazole		Siponimod	AUC/D (h ng/mL)/mg	AUC (h ng/mL)	CL/F (L/h)	AUCi/AUC	C max,i/C max
	Day 1	Day 2 till the last day
i	200 mg qd	200 mg qd	5 mg, day 4	249	1245	4.01	1.97	1.09
ii	200 mg bid	200 mg qd	5 mg, day 3	255	1273	3.93	2.43	1.10
iii	400 mg bid	400 mg qd	4 mg, day 3	257	1028	3.89	3.42	1.11
iv	200 mg bid	200 mg qd	4 mg, day 3	272	1089	3.71	2.15	1.07
in vivo*	200 mg bid	200 mg qd	4 mg, day 3	280	1110	3.59	1.97	1.10

Siponimod-predicted PK parameters are geometric mean of 70 virtual individuals; SimCYP version 9 was used for trials i to iii, and version 16 was used for trial iv. The CV% of the in vivo study is reported in detail in Table 2 of the companion manuscript (EJCP-17-D-17-00482). The CV ranges for the four simulations are C _max ratio (2–5%), AUC ratio (10–23%), CL/F (45–60%), AUC (41–59%) and AUC/D (41–59%), respectively

AUC area under the concentration–time curve, AUC _i area under the concentration–time curve under fluconazole inhibition, bid twice a day, CL/F apparent systemic clearance, C _max maximum plasma concentration, D dose, qd once a day, T _max time to maximum plasma concentration, T _1/2 terminal half-life