Atogepant

Non-clinical receptor binding studies and in vitro functional studies point to an involvement of more than one receptor type in the pharmacological effects of atogepant. Atogepant shows affinity to several receptors of the calcitonin/CGRP-receptor family. In view of the clinically relevant free plasma concentrations of atogepant (C_max >20 nM for a 60 mg dose) and the fact that CGRP and amylin-1 receptors are considered to be involved in the pathophysiology of migraine, inhibitory effects of atogepant at these receptors (Ki-value 26 pM and 2.4 nM, respectively) could be of clinical relevance. However, the precise mechanism of action of atogepant in the prophylaxis of migraine remains to be established.

Absorption

Following oral administration, atogepant is absorbed with peak plasma concentrations at approximately 1 to 2 hours. Following once daily dosing, atogepant displays dose-proportional pharmacokinetics up to 170 mg (approximately 3 times the highest recommended dose), with no accumulation.

Effect of food

When atogepant was administered with a high-fat meal, AUC and C_max were reduced by approximately 18% and 22%, respectively, with no effect on median time to maximum atogepant plasma concentration. Atogepant was administered without regard to food in clinical efficacy studies.

Distribution

Plasma protein binding of atogepant was not concentration-dependent in the range of 0.1 to 10 µM; the unbound fraction of atogepant was approximately 4.7% in human plasma. The mean apparent volume of distribution of atogepant (Vz/F) after oral administration is approximately 292 L.

Biotransformation

Atogepant is eliminated mainly through metabolism, primarily by CYP3A4. The parent compound (atogepant), and a glucuronide conjugate metabolite (M23) were the most prevalent circulating components in human plasma.

CYP3A4 inducers

Co-administration of atogepant with steady state rifampicin, a strong CYP3A4 inducer, resulted in a significant decrease in exposure (C_max by 30% and AUC by 60%) of atogepant in healthy subjects.

Co-administration of atogepant with steady-state topiramate, a mild CYP3A4 inducer, resulted in a decrease in exposure (C_max by 24% and AUC by 25%) of atogepant.

In vitro, atogepant is not an inhibitor for CYP3A4, 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, MAO-A, or UGT1A1 at clinically relevant concentrations. Atogepant also is not an inducer of CYP1A2, CYP2B6, or CYP3A4 at clinically relevant concentrations.

Elimination

The elimination half-life of atogepant is approximately 11 hours. The mean apparent oral clearance (CL/F) of atogepant is approximately 19 L/h. Following single oral dose of 50 mg ¹⁴C-atogepant to healthy male subjects, 42% and 5% of the dose was recovered as unchanged atogepant in faeces and urine, respectively.

Transporters

Atogepant is a substrate of P-gp, BCRP, OATP1B1, OATP1B3, and OAT1. Dose adjustment for concomitant use with strong inhibitors of OATP is recommended based on a clinical interaction study with a strong OATP inhibitor. Atogepant is not a substrate of OAT3, OCT2, or MATE1.

Atogepant is not an inhibitor of P-gp, BCRP, OAT1, OAT3, NTCP, BSEP, MRP3, or MRP4 at clinically relevant concentrations. Atogepant is a weak inhibitor of OATP1B1, OATP1B3, OCT1, and MATE1, but no clinically relevant interactions are expected.

Special populations

Renal impairment

The renal route of elimination plays a minor role in the clearance of atogepant. Based on population pharmacokinetic analysis, there is no significant difference in the pharmacokinetics of atogepant in patients with mild or moderate renal impairment (CLcr 30-89 mL/min) relative to those with normal renal function (CLcr ≥90 mL/min). As patients with severe renal impairment or end-stage renal disease (ESRD; CLcr <30 mL/min) have not been studied, use of atogepant 10 mg is recommended in those patients.

Hepatic impairment

In patients with pre-existing mild (Child-Pugh Class A), moderate (Child-Pugh Class B), or severe hepatic impairment (Child-Pugh Class C), total atogepant exposure was increased by 24%, 15% and 38%, respectively. However, unbound atogepant exposure was approximately 3-fold higher in patients with severe hepatic impairment. The use of atogepant in patients with severe hepatic impairment should be avoided.

Other special populations

Based on a population pharmacokinetic analysis, sex, race, and body weight did not have a significant effect on the pharmacokinetics (C_max and AUC) of atogepant. Therefore, no dose adjustments are warranted based on these factors.

Notwithstanding marked interspecies differences in CGRP-receptor affinity of atogepant, non-clinical data reveal no special hazard for atogepant in humans based on conventional studies of safety pharmacology, repeat dose toxicity, genotoxicity, phototoxicity or carcinogenic potential.

Impairment of fertility

Oral administration of atogepant to male and female rats prior to and during mating and continuing in females to gestation day 7 resulted in no adverse effects on fertility or reproductive performance. Plasma exposures (AUC) are up to approximately 15 times that in humans at the maximum recommended human dose (MRHD).

Reproductive and developmental toxicology

Oral administration of atogepant to pregnant rats and rabbits during the period of organogenesis resulted in decreased foetal body weight in rats and an increased incidence of foetal visceral and skeletal variations at doses associated with minimal maternal toxicity. At the no-effect dose for adverse effects on embryofoetal development, plasma exposure (AUC) was approximately 4 times in rats and 3 times in rabbits that in humans at the MRHD of 60 mg/day.

Oral administration of atogepant to rats throughout gestation and lactation resulted in non-adverse significant decreased pup body weight which persisted into adulthood. Plasma exposure (AUC) at the no-effect dose for pre- and postnatal development were approximately 5-times that in humans at the MRHD. In lactating rats, oral dosing with atogepant resulted in levels of atogepant in milk approximately 2-fold higher than those in maternal plasma.