Atogepant: Mechanism of action, clinical and translational science

Abstract Since the discovery of calcitonin gene‐related peptide (CGRP) in 1982, its integral role in migraine pathophysiology, specifically migraine pain, has been demonstrated through cumulative scientific discoveries that have led to the development and approval of migraine‐specific therapeutics. Today, eight drugs, including monoclonal antibodies and small molecule CGRP receptor antagonists, known as gepants, have received approval for acute or preventive treatment of migraine. The primary mechanism of these drugs is to block CGRP signaling, thus preventing CGRP‐mediated nociception and neurogenic inflammation. Here, we focus on atogepant, a highly potent and selective gepant and the first and only oral medication approved for the preventive treatment of both episodic and chronic migraine in adults. In this article, we summarize the role of CGRP in migraine pathophysiology and the mechanism of action of atogepant. In addition, we provide an overview of atogepant's pharmacology and the key clinical trials and outcomes that have demonstrated the safety and efficacy of atogepant

Mechanistic Analysis of the Inactivation of Cytochrome P450 2B6 by Phencyclidine: Effects on Substrate Binding, Electron Transfer, and Uncoupling

Phencyclidine (PCP) is a mechanism-based inactivator of cytochrome P450 (P450) 2B6. We have analyzed several steps in the P450 catalytic cycle to determine the mechanism of inactivation of P450 2B6 by PCP. Spectral binding studies show that binding of benzphetamine, a type I ligand, to P450 2B6 was significantly affected as a result of the inactivation, whereas binding of the inhibitor n-octylamine, a type II ligand, was not compromised. Binding of these ligands to P450 2B6 occurs in two phases. Stopped-flow spectral analysis of the binding kinetics of benzphetamine to PCP-inactivated 2B6 revealed a 15-fold decrease in the rate of binding during the second phase of the kinetics (k1 = 5.0 s–1, A1 = 30%; k2 = 0.02 s–1, A2 = 70%, where A2 indicates the fractional magnitude of the second phase) compared with the native enzyme (k1 = 8.0 s–1, A1 = 58%; k2 = 0.3 s–1, A2 = 42%). Analysis of benzphetamine metabolism by the inactivated protein using liquid chromatography/electrospray ionization/mass spectrometry showed that the rates of formation of nor-benzphetamine and hydroxylated nor-benzphetamine were decreased by 75 and 69%, respectively, whereas the rates of formation for amphetamine, hydroxybenzphetamine, and methamphetamine showed slight but statistically insignificant decreases after the inactivation. The rate of reduction of P450 2B6 by NADPH and reductase was decreased by 6-fold as a result of the modification by PCP. In addition, the extent of uncoupling of NADPH oxidation from product formation, a process leading to futile production of H2O2, increased significantly during the metabolism of ethylbenzene as a result of the inactivation

Title Page Mechanisms and Predictions of Drug-Drug Interactions of the Hepatitis C Virus 3-Direct Acting Antiviral (3D) DMD # 74518 2 Running Title Page Running Title: DDI mechanisms and predictions of the HCV 3D regimen

Number of references: 34 Number of words in Abstract: 250 words Number of words in Introduction: 396 words Number of words in Discussion: 1,900 words Abbreviations: 3D, AbbVie's three direct acting antiviral regimen; AUCR, AUC ratio of substrate with perpetrator relative to control; CYP, cytochrome P450; DAA, direct acting antiviral; DDI, drug-drug interaction; HCV, hepatitis C virus DMD # 74518 3 Abstract To assess drug-drug interaction (DDI) potential for the 3 direct-acting antiviral (3D) regimen of ombitasvir, dasabuvir and paritaprevir, in vitro studies profiled drug metabolizing enzyme and transporter interactions. Using mechanistic static and dynamic models, DDI potential was predicted for CYP3A, CYP2C8, UGT1A1, OATP1B1/1B3, BCRP and P-gp. Perpetrator static model DDI predictions for metabolizing enzymes were within 2-fold of the clinical observations but for drug transporters, additional PBPK modeling was necessary to achieve the same. When assessing perpetrator interactions, ritonavir is responsible for the strong increase in exposure of sensitive CYP3A substrates while paritaprevir (OATP1B1/1B3 inhibitor) increases greatly the exposure of sensitive OATP1B1/1B3 substrates. The 3D regimen drugs are UGT1A1 inhibitors and are predicted to increase moderately plasma exposure of sensitive UGT1A1 substrates. Paritaprevir, ritonavir and dasabuvir are BCRP inhibitors. Victim DDI predictions were qualitatively in line with the clinical observations. Plasma exposures of the 3D regimen were reduced by strong CYP3A inducers (paritaprevir and ritonavir; major CYP3A substrates), but not impacted by strong CYP3A4 inhibitors since ritonavir (CYP3A inhibitor) is already present in the regimen. Strong CYP2C8 inhibitors increase plasma exposure of dasabuvir (major CYP2C8 substrate), OATP1B1/1B3 inhibitors increase the plasma exposure of paritaprevir (OATP1B1/1B3 substrate), and Pgp or BCRP inhibitors (all compounds are substrates of P-gp and/or BCRP) increase plasma exposure of the 3D regimen. Overall, the comprehensive mechanistic assessment of compound disposition along with mechanistic and PBPK approaches to predict victim and perpetrator DDI liability, may enable better clinical management of non-studied drug combinations with the 3D regimen