Table 4.

Intravenous drug–drug interaction (DDI) studies with additional substrates (not cytochrome P450 [CYP] index substrates)

Victim	Perpetrator	Victim enzymes or transporters	Perpetrator enzymes or transporters	Population	N	$\frac{{\text{AUC}}^{\text{DDI}}}{{\text{AUC}}^{\text{Con}}}$	$\frac{{\text{CL}}^{\text{DDI}}}{{\text{CL}}^{\text{Con}}}$	$\frac{V_{\text{ss}}^{\text{DDI}}}{V_{\text{ss}}^{\text{Con}}}$	$\frac{{\text{MRT}}^{\text{DDI}}}{{\text{MRT}}^{\text{Con}}}$	$\frac{t_{1/2,z}^{\text{DDI}}}{t_{1/2,z}^{\text{Con}}}$	Percent AUC extrapolation	Refs.
Alfentanil	Fluconazole (100 mg; single dose)	CYP3A4	CYP3A4 CYP2C9 CYP2C19	Healthy subjects	12	1.2	0.84	0.93a	1.18a	1.18	2%/1%	[20]
	+ Ondansetron (4 mg; single dose)		Unknown
	+ Midazolam (1 mg; single dose)		Unknown
Alfentanil	Fluconazole (200 mg; single dose)	CYP3A4	CYP3A4 CYP2C9 CYP2C19	Healthy subjects	12	1.6	0.62	0.89a	1.45a	1.36	3%/1%	[20]
	+ Ondansetron (4 mg; single dose)		Unknown
	+ Midazolam (1 mg; single dose)		Unknown
Alfentanil	Fluconazole (400 mg; single dose)	CYP3A4	CYP3A4 CYP2C9 CYP2C19	Healthy subjects	12	2.2	0.46	0.90a	1.92a	1.73	5%/1%	[20]
	+ Ondansetron (4 mg; single dose)		Unknown
	+ Midazolam (1 mg; single dose)		Unknown
Antipyrine	Cimetidine (1000 mg BID; 7 days)	CYP enzymes	CYP enzymes OCT2 MATE1	Healthy subjects	7	1.33d	0.76b	1.05b	1.40f	1.30b	NR	[27]
Antipyrine	Ranitidine (150 mg BID; 7 days)	CYP enzymes	CYP3A CYP2C9 CYP2D6 OCT2	Healthy subjects	7	1.08d	0.93b	1.02b	1.09f	1.06b	NR	[27]
Lidocaine	Erythromycin (500 mg QID; 5 days)	CYP3A4 CYP1A2	CYP3A4 P-gp	Healthy subjects	8	1.19d	0.96b	1.14a	1.19a	1.37b	28%/23%a	[19]
	+ Midazolam (0.075 mg/kg; single dose)		Unknown

Pharmacokinetic values reported in the table are based on published average values, unless otherwise noted

AUC area under the curve, BID twice daily, CL clearance, Con control, MATE1 Multidrug and Toxic Extrusion 1, MRT mean residence time, NR, not reported, OCT organic cation transporter, P-gp P-glycoprotein, QID four times a day, Refs reference, t_1/2,z terminal half-life, V_ss volume of distribution at steady state

^aRatios are calculated by digitization of published average plasma concentration–time profiles and performing a non-compartmental analysis

^bRatios are calculated for each individual using published individual pharmacokinetic data; the reported value reflects the average of each individual ratio

^dAUC was calculated for each individual with the equation AUC = dose/CL using known dose and reported individual values of CL; the reported value reflects the average of each individual ratio

^fMRT was calculated for each individual with the equation V_ss = CL·MRT using reported individual values of CL and V_ss; the reported value reflects the average of each individual ratio