TABLE 3

Prediction of OATP1B-mediated DDIs for rifampin, diltiazem and itraconazole using R-value and endogenous biomarker methods

Data are expressed as mean ± S.D.

Drugs	Dose Regimen	C_max^{^a}	f_u^{^b}	OATP1B1		OATP1B3		Observed CPI and CPIII AUC_(0–24h) Changes^{^d}	Reported Rosuvastatin and Atorvastatin AUC Changes^{^e}
Drugs	Dose Regimen	C_max^{^a}	f_u^{^b}	IC₅₀^{^c}	R-Value	IC₅₀^{^c}	R-Value	Observed CPI and CPIII AUC_(0–24h) Changes^{^d}	Reported Rosuvastatin and Atorvastatin AUC Changes^{^e}
		μM		μM		μM
Rifampin	600 mg SD	30.6	0.15	1.1	6.50	0.49	13.34	2.84- to 4.11-fold and 2.42-to 3.61-fold, respectively	3.03- to 4.67-fold and 4.62- to 12-fold, respectively
Diltiazem	240 mg QD for 8 days	0.44	0.22	260	1.03	170	1.05	1.00 ± 0.10-fold and 1.17 ± 0.44-fold, respectively	No data
Itraconazole Hydroxylitraconazole Itraconazole + Hydroxylitraconazole	200 mg QD for 8 days	2.79	0.036	> 100	<1.01	> 30	<1.03	0.94 ± 0.10-fold and 0.95 ± 0.13-fold, respectively	1.78-fold and 5.58-fold, respectively; no increase of pitavastatin AUC
		2.85	0.005	0.23	1.06	0.10	1.14
					<1.07		<1.17

f_u, Unbound fraction; IC₅₀, concentration required to inhibit transport by 50%; R-value was calculated using the method recommended by FDA, and estimated maximal unbound concentration in hepatic inlet is used for R-value calculation.
↵^a Maximum inhibitor plasma concentration following administration of the proposed dose (Barone et al., 1998; Sista et al., 2003; Lai et al., 2016).
↵^b Plasma unbound fraction of inhibitors (Templeton et al., 2008; Prueksaritanont et al., 2014, 2017) and Hardman et al., 2001.
↵^c Concentrations required to inhibit OATP1B-mediated transport by 50% using statins and estradiol 17β-glucuronide (Yoshida et al., 2012; Shen et al., 2013; Nakakariya et al., 2016; Vermeer et al., 2016).
↵^d Data obtained from the present studies and previously reported (Lai et al., 2016).
↵^e Data obtained from University of Washington Metabolism and Transport Drug Interaction Database.