TABLE 5

Simulated pharmacokinetic parameters for CYP2C9 and CYP3A4 substrates

Dose of diclofenac (50 mg), midazolam (7.5 mg), and dextromethorphan (30 mg) simulated for 24 h and (S)-warfarin (12.5 mg) simulated for 168 h. Geometric means reported with fold difference between simulation and baseline Sim_{pH 7.4} given in parentheses. AUC, area under the concentration-time profile curve CI, confidence interval; CL, clearance calculated as Dose/AUC; Cmax, maximum observed concentration. The 95% confidence interval of the model predictions is listed in brackets.

		Simulation
		Sim_{pH 7.4} [95% CI]	Sim_{pH 7.4, FI} [95% CI]	Sim_{pH 7.0, FI} [95% CI]	Observed
Diclofenac	CL (l/h)	31.53 [28.83–34.49]	13.83 (0.4) [12.72–15.04]	15.24 (0.5) [13.99–16.61]	29.9
	C_max (mg/l)	1.22 [1.13–1.32]	1.77 (1.4) [1.64–1.90]	1.69 (1.4) [1.57–1.82]	2.0^{^a}
	AUC (mg/l·h)	1.59 [1.45–1.73]	3.62 (3.0) [3.33–3.93]	3.28 (2.7) [3.01–3.57]	1.67^{^a}
(S)-warfarin	CL (l/h)	276.40 [248.47–307.47]	133.06 (0.5) [121.69–145.50]	222.10 (0.8) [200.49–246.03]	207.6
	C_max (mg/l)	1.30 [1.21–1.40]	1.36 (1.0) [1.26–1.46]	1.31 (1.0) [1.22–1.42]	1.84^{^b}
	AUC (mg/l·h)	45.22 [40.65–50.31]	93.94 (2.1) [85.91–102.72]	56.28 (1.2) [50.81–62.35]	60.22^{^b}
Midazolam	CL (l/h)	85.52 [74.40–98.30]	93.12 (1.1) [81.00–107.05]	93.12 (1.1) [81.00–107.05]	81.52
	C_max (mg/l)	23.15 [20.62–25.99]	22.08 (1.0) [19.64–24.82]	22.08 (1.0) [19.64–24.82]	34^{^c}
	AUC (mg/l·h)	87.70 [76.29–100.80]	80.54 (0.9)[81.00–107.05]	80.54 (0.9) [81.00–107.05]	92^{^c}
Dextromethorphan	CL (l/h)	500.48 [418.62–598.33]	1084.12 (2.2) [888.42–1322.93]	603.19 (1.2) [503.91–722.04]	845.1
	C_max (mg/l)	5.18 [4.41–6.09]	2.63 (0.5) [2.18–3.17]	4.45 (0.9) [3.77–5.26]	3.49^{^d}
	AUC (mg/l·h)	59.94 [50.14–71.66]	27.67 (0.5) [22.68–33.77]	49.74 (0.8) [41.55–59.53]	35.5^{^d}

↵^a Willis et al. (1979).
↵^b Braeckman et al. (2014), assuming 12.5 mg (S)-warfarin from racemic mixture dose of 25 mg.
↵^c Bornemann et al. (1985).
↵^d Chi et al. (2013).