Comparison of gepant effects at therapeutic plasma concentrations: connecting pharmacodynamics and pharmacokinetics

Table 1 Calculated pEC₅₀ of CGRP and clinical pharmacokinetics used for calculations

Gepant	Clinical dose	MW (g/mol)	Plasma-protein binding	Free fraction	Reported C_max	Total		Free fraction
Gepant	Clinical dose	MW (g/mol)	Plasma-protein binding	Free fraction	Reported C_max	C_max (nM)	Calculated pEC₅₀ of CGRP	C_max (>nM)	Calculated pEC₅₀ of CGRP
Rimegepant	75 mg, oral^a	534.56 (or 610.63^d)	96% [10]	4%	75 mg: 759.2 ± 23.0 ng/mL (mean ± SD)^b [6]	1,420	4.48	56.8	5.87
					75 mg: 862.9 ng/mL (43) (GM, CV%) [8]	1,614	4.42	64.5	5.82
Atogepant	10, 30, 60 mg, oral	603.5	98.2% [11]	1.8%	60 mg: 589 ± 248 ng/mL (mean ± SD)^b [11]	976	3.43	17.6	5.18
Ubrogepant	50 or 100 mg, oral	549.5	89.3% [12]	10.7%	100 mg: 344, 241–491 (median, 95% CI)^b [4]	344	5.14	36.8	6.11
					100 mg: 316, 250–400 nM (median, 95% CI)^c [4]	316	5.18	33.8	6.15
					100 mg: 405.76 ± 218.9 ng/mL (mean ± SD)^b [12]	738	4.81	79.0	5.78
Zavegepant	10 mg, intranasal	638.8 (or 675.28^d)	90% [24]	10%	10 mg: 13.40 ng/mL (52.87) (GM, CV%)^b [9]	21	6.06	2.1	7.04
					10 mg: 16.31 ng/mL (72.06) (GM, CV%)^c [9]	26	5.97	2.6	6.95
CGRP (Control)	-		-		-	-	8.4 (8.2 – 8.7)	-	8.4 (8.2 – 8.7)

CI Confidence interval, C_max maximum plasma concentration, CV Coefficient of variation, GM Geometric mean, MW molecular weight, pEC₅₀ negative log concentration of CGRP that would induce half of the maximum response in the presence of the gepant, SD Standard deviation
^a75 mg per day (acute). Dose used in phase 2/3 clinical trials for prophylaxis: 75 mg every other day
^bBased on a group receiving a single dose
^cBased on day 1 of a group receiving QD treatment
^dIn case of the form with sulphate attached

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