Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.2   Pharmacodynamics
Cardiac Electrophysiology
At a dose 5 times the maximum recommended daily dose, QULIPTA does not prolong the QT interval to any clinically relevant extent.

Pharmacokinetic Properties

12.3   Pharmacokinetics
Absorption
Following oral administration of QULIPTA, atogepant is absorbed with peak plasma concentrations at approximately 1 to 2 hours. Atogepant displays dose-proportional pharmacokinetics up to 170 mg per day (approximately 3 times the highest recommended dosage), with no accumulation.
Effect of Food
When QULIPTA was administered with a high-fat meal, the food effect was not significant (AUC and Cmax were reduced by approximately 18% and 22%, respectively, with no effect on median time to maximum atogepant plasma concentration). QULIPTA 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.


Elimination
Metabolism
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.
Excretion
The elimination half-life of atogepant is approximately 11 hours. The mean apparent oral clearance (CL/F) of atogepant is approximately 19 L/hr. 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 feces and urine, respectively.
Specific Populations
Patients with Renal Impairment
The renal route of elimination plays a minor role in the clearance of atogepant. Based on a 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). Patients with severe renal impairment or end-stage renal disease (ESRD; CLcr <30 mL/min) have not been studied [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)].
Patients with Hepatic Impairment
In patients with pre-existing mild (Child-Pugh Class A), moderate (Child-Pugh Class B), or severe (Child-Pugh Class C) hepatic impairment, the total atogepant exposure was increased by 24%, 15%, and 38%, respectively.
Due to a potential for liver injury in patients with severe hepatic impairment, avoid use of QULIPTA in patients with severe hepatic impairment [see Use in Specific Populations (8.7)].
Other Specific Populations
Based on a population pharmacokinetic analysis, age, sex, race, and body weight did not have a significant effect on the pharmacokinetics (Cmax and AUC) of atogepant. Therefore, no dose adjustments are warranted based on these factors.
Drug Interactions
In Vitro Studies
Enzymes
In vitro, atogepant is not an inhibitor for CYPs 3A4, 1A2, 2B6, 2C8, 2C9, 2C19, or 2D6 at clinically relevant concentrations. Atogepant does not inhibit MAO-A or UGT1A1 at clinically relevant concentrations. Atogepant is not anticipated to be a clinically significant perpetrator of drug-drug interactions through CYP450s, MAO-A, or UGT1A1 inhibition.
Atogepant is not an inducer of CYP1A2, CYP2B6, or CYP3A4 at clinically relevant concentrations.
Transporters
Atogepant is a substrate of P-gp, BCRP, OATP1B1, OATP1B3, and OAT1. Dose adjustment for concomitant use of QULIPTA with inhibitors of OATP is recommended based on a clinical interaction study with a OATP inhibitor [see Dosage and Administration (2.2)].
Coadministration of atogepant with BCRP and/or P-gp inhibitors is not expected to increase the exposure of atogepant. 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. No clinical drug interactions are expected for atogepant as a perpetrator with these transporters.
In Vivo Studies
CYP3A4 Inhibitors
Co-administration of QULIPTA with itraconazole, a strong CYP3A4 inhibitor, resulted in a clinically significant increase (Cmax by 2.15-fold and AUC by 5.5-fold) in the exposure of atogepant in healthy subjects [see Drug Interactions (7.1)].
Physiologically based pharmacokinetic (PBPK) modeling suggested co-administration of QULIPTA with moderate or weak CYP3A4 inhibitors increase atogepant AUC by 1.7- and 1.1- fold, respectively. The changes in atogepant exposure when coadministered with weak or moderate CYP3A4 inhibitors are not expected to be clinically significant.
CYP3A4 Inducers
Co-administration of QULIPTA with rifampin, a strong CYP3A4 inducer, decreased atogepant AUC by 60% and Cmax by 30% in healthy subjects [see Drug Interactions (7.2)]. No dedicated drug interaction studies were conducted to assess concomitant use with moderate CYP3A4 inducers. Moderate inducers of CYP3A4 can decrease atogepant exposure [see Drug Interactions (7.2)]. Co-administration of QULIPTA with topiramate, a weak inducer of CYP3A4, decreased atogepant mean steady-state AUC 0-τ by 25% and mean steady-state Cmax by 24% in healthy subjects [see Drug Interactions (7.2)].
BCRP/OATP/P-gp Inhibitors
Co-administration of QULIPTA with single dose rifampin, an OATP inhibitor, increased atogepant AUC by 2.85-fold and Cmax by 2.23-fold in healthy subjects [see Drug Interactions (7.3)].
Co-administration of QULIPTA with quinidine, a P-gp inhibitor, increased atogepant AUC by 26% and Cmax by 4% in healthy subjects. The changes in atogepant exposure when co-administered with P-gp inhibitors are not expected to be clinically significant.
PBPK modeling suggests that co-administration of QULIPTA with BCRP inhibitors increases atogepant exposure by 1.2-fold. This increase is not expected to be clinically significant.
Other Drug Interaction Evaluations
Co-administration of QULIPTA with oral contraceptive components ethinyl estradiol and levonorgestrel, famotidine, esomeprazole, acetaminophen, naproxen, sumatriptan, or ubrogepant did not result in significant pharmacokinetic interactions for either atogepant or co-administered drugs. Co-administration of QULIPTA with topiramate did not result in clinically significant changes in the pharmacokinetics of topiramate.