. 2022 May 22;10(3):e00959. doi: 10.1002/prp2.959

TABLE 2.

Evaluation of Fenfluramine (FFA) and norfenfluramine (nFFA) potential to induce CYP1A2, CYP2B6, or CYP3A4 mRNA in vivo

		FFA			nFFA
		HC10‐10	HC10‐8	HC7‐8	HC10‐10	HC10‐8	HC7‐8
CYP1A2
Fold‐change method	Fold change ^a	1.24	1.54	1.54	1.86	1.92	1.74
	% of control ^b	0.55	1.04	1.72	1.96	1.79	2.35
	Potential to induce	No	No	No	No	No	No
CYP2B6
Fold‐change method	Fold change	2.09	3.77	2.05	2.54	3.01	2.15
	% of control	15.3	29.10	9.66	21.60	21.20	10.60
	Potential to induce	Yes	Yes	Yes	Yes	Yes	Yes
Basic kinetic model	E_max (fold) ^c	1.21 ± 0.21	2.80 ± 0.20	0.94 ± 0.10	1.36 ± 0.11	2.08 ± 0.197	1.14 ± 0.083
	EC₅₀ (µM)	4.61 ± 3.3	13.6 ± 1.5	8.32 ± 2.1	8.81 ± 1.6	26.4 ± 2.9	10.8 ± 2.3
	R₃ ^d	0.76	0.77	0.87	0.88	0.93	0.92
	Potential to induce	Yes	Yes	No	No	No	No
Static mechanistic model	AUCR ^d	0.92	0.93	0.96	0.99	0.99	0.99
Static mechanistic model	Potential to induce	No	No	No	No	No	No
CYP3A4
Fold‐change method	Fold change	2.86	3.95	3.77	4.57	5.75	4.91
	% of control	2.53	9.50	2.60	4.85	15.30	3.68
	Potential to induce	Yes	Yes	Yes	Yes	Yes	Yes
Basic kinetic model	E_max (fold)	2.30 ± 0.43	3.02 ± 0.25	2.69 ± 0.52	3.61 ± 0.40	6.95 ± 1.0	3.92 ± 0.048
	EC₅₀ (µM)	9.05 ± 3.6	20.4 ± 1.9	8.53 ± 4.3	17.1 ± 3.9	37.8 ± 5.6	12.9 ± 0.38
	R₃	0.74	0.82	0.70	0.84	0.86	0.79
	Potential to induce	Yes	No	Yes	No	No	Yes
Static mechanistic model	AUCR	0.92	0.95	0.90	0.96	0.97	0.95
Static mechanistic model		No	No	No	No	No	No

Purple: data relating to the basic kinetic model.

Blue: data relating to the static mechanistic model.

^{^a}

Fold‐change in mRNA concentration at highest dose tested (40 µM fenfluramine and 50 µM norfenfluramine).

^{^b}

Percent of positive control induction of mRNA.

^{^c}

E_max and EC₅₀ and respective standard errors were calculated from the plot of drug concentrations vs fold‐change −1 values of drug effect with Sigmoid, 3‐paramether equation (SigmaPlot).

^{^d}

Calculated as per FDA Guidance (2020).