. 2021 May 2;10(5):441–454. doi: 10.1002/psp4.12605

Table 3.

PBPK model‐predicted geometric mean ratios of C_max and AUC for zanubrutinib as a DDI victim or perpetrator compared with observed data from clinical DDI studies.

Parameter		Ratio
Parameter		Observed ^a (90% CI)	Prediction ^a (90% PI)	Observed/predicted ^b
Inhibitor (itraconazole)	AUC	3.86 (3.49–4.22)	3.47 (3.32–3.63)	1.11
Inhibitor (itraconazole)	C_max	2.57 (2.26–2.91)	3.20 (3.03–3.38)	0.80
Inducer (rifampicin)	AUC	0.071 (0.062–0.090) (↓14.1‐fold)	0.060 (0.053–0.068) (↓16.6‐fold)	1.18
Inducer (rifampicin)	C_max	0.079 (0.068–0.095) (↓12.6‐fold)	0.062 (0.054–0.072) (↓16.0‐fold)	1.27
Substrate (midazolam) ^c	AUC	0.53 (0.48–0.57)	0.51 (0.49–0.053)	1.02
Substrate (midazolam) ^c	C_max	0.70 (0.63–0.78)	0.53 (0.50–0.055)	0.74
Substrate (omeprazole) ^d	AUC	0.63 (0.5–0.70)	0.94 (0.93–0.95)	0.67
Substrate (omeprazole) ^d	C_max	0.79 (0.65–0.97)	0.97 (0.96–0.98)	0.81
Substrate (warfarin) ^e	AUC	1.00 (0.98–1.03)	0.97 (0.96–0.97)	1.03
Substrate (warfarin) ^e	C_max	0.95 (0.87–1.04)	1.00 (1.00–1.00)	0.95

Abbreviations; AUC, area under the plasma concentration–time curve; AUC_0‐24 h, area under the plasma concentration–time curve from time 0 to 24 hours; AUC_0‐inf, area under the plasma concentration–time curve from time 0 to infinity; AUC_0‐t, area under the plasma concentration–time curve from time 0 to last observation; CI, confidence interval; C_max, maximum plasma concentration; DDI, drug‐drug interaction; PBPK, physiologically based pharmacokinetics; PI, prediction interval.

^{^a}

Expressed by ratio = (substrate +interaction)/substrate.

^{^b}

AUC_0‐t was used to calculate the observed ratio; AUC_0‐24 h was used to calculate the predicted ratio on Day 4 for zanubrutinib 20 mg used with itraconazole. Observed clinical data were from a clinical DDI study of Mu S, et al. ³⁸

^{^c}

Predicted AUC_0‐24 h on Day 7 for midazolam (2 mg) with/without zanubrutinib co‐administration. AUC_0‐inf was used to calculate the predicted ratio.

^{^d}

Predicted AUC_0‐24 h on Day 12 for omeprazole (20 mg) with/without zanubrutinib co‐administration. AUC_0‐t was used to calculate the predicted ratio.

^{^e}

Predicted AUC_0‐24 h on Day 8 for warfarin (10 mg) with/without zanubrutinib co‐administration. AUC_0‐inf was used to calculate the predicted ratio.