Model-Informed Drug Development:Steps Toward Harmonized Guidance

Global alignment of expectations is required to achieve consistency in the planning, conduct, reporting, and regulatory review of modelinformed drug development (MIDD) applications. An International Council for Harmonization (ICH) MIDD general principles guideline has been positioned to provide a common standard of practice including a framework for risk-based assessment of MIDD-derived evidence within the context of global regulatory decision-making. This perspective provides the background, our viewpoints, and the next steps in the development of this guideline

Mechanism-based inactivation of human cytochrome P450 2B6 by phencyclidine: Metabolism, structural, and mechanistic studies.

This dissertation presents studies performed to elucidate the structure-function relationships of cytochrome P450 (P450) 2B6, the human 2B homologue responsible for the metabolism of several drugs, carcinogens, and some environmental chemicals. Phencyclidine (PCP), a psychomimetic drug of abuse, was shown to be metabolized by P450 2B6 and its metabolism results in mechanism-based inactivation of the enzyme. This study shows that P450 2B6 metabolizes phencyclidine via pathways different from the rat 2B1 and rabbit 2B4 homologues. Reactive intermediates of PCP were chemically trapped with glutathione (GSH) and N-acetylcysteine (NAC) during the metabolism and inactivation, and the resulting conjugates were identified. It appears that P450 2B6 favors oxygenation pathways that lead to the formation of a hydroxylated iminium or an epoxide intermediate of PCP, while a dehydrogenation pathway was favored by P450s 2B1 and 2B4, leading to the formation of the 2,3-dihydropyridinium metabolite of PCP. Studies with the P450 2B6 (K262R) mutant showed that this single residue mutation resulted in loss of inactivation of the enzyme by PCP, apparently because the mutant enzyme does not metabolize PCP to a reactive intermediate similar to that formed by the wild type enzyme. However, the K262R mutant retained the ability to reversibly bind PCP and metabolize it to all of the stable products. Mechanistic studies demonstrated that inactivation of P450 2B6 by PCP significantly decreased its benzphetamine binding affinity. The rate of benzphetamine binding was decreased by approximately 15 fold due to the inactivation. Analysis of benzphetamine metabolism showed that the rates of formation of two of the metabolites by the inactivated enzyme were significantly decreased, suggesting that benzphetamine binds with a different orientation in the active site of the inactivated protein. Furthermore, following inactivation by PCP the overall rate of the first electron transfer was decreased approximately 6 fold, with a concomitant increase in the uncoupling of the electron transfer from substrate turnover to increased hydrogen peroxide production. These studies show that the covalent modification of the P450 2B6 apo-protein by PCP may lead to dramatic changes in the chemistry of the enzyme catalysis.Ph.D.Health and Environmental SciencesPharmacologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/126819/2/3276292.pd

Ubrogepant: Mechanism of action, clinical and translational science

Abstract In recent years, the treatment of migraine has experienced a breakthrough in the development of drugs that target the calcitonin gene‐related peptide (CGRP) signaling pathway. Monoclonal antibodies against the receptor or ligand have been developed for the preventive treatment of migraine; whereas, orally administered small molecule CGRP receptor antagonists, called gepants, have been developed for both acute and/or preventive treatment. Both modalities have demonstrated safe and effective treatment of migraine, reducing the number of migraine days for patients as well as reducing symptoms and improving patient function and overall quality of life. Here, we provide an abridged review of ubrogepant, an oral CGRP receptor antagonist, approved for the acute treatment of migraine. We briefly summarize the role of CGRP in migraine pathophysiology, describing the mechanism of action of ubrogepant in the context of this pathway, the clinical pharmacology properties and the clinical development and outcomes, including safety, efficacy, pharmacokinetics, and pharmacodynamics, that supported ubrogepant's approval

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

Bone Mineral Density Changes Associated With Pregnancy, Lactation, and Medical Treatments in Premenopausal Women and Effects Later in Life.

Bone mineral density (BMD) changes during the life span, increasing rapidly during adolescence, plateauing in the third decade of life, and subsequently entering a phase of age-related decline. In women, menopause leads to accelerated bone loss and an increase in fracture risk. Between peak bone mass attainment and menopause, BMD is generally stable and the risk of fracture is typically low. This time period is marked by life events such as pregnancy and lactation, which transiently decrease BMD, yet their long-term effects on fracture risk are less certain. BMD may also be altered by exposure to medications that affect bone metabolism (e.g., contraceptives, glucocorticoids, antidiabetic medications, antiepileptic drugs). Although oral contraceptives are often believed to be neutral with regard to bone health, depot medroxyprogesterone acetate (DMPA) and gonadotropin-releasing hormone (GnRH) agonists have been associated with decreases in BMD. Development of newer medical therapies, principally GnRH antagonists (e.g., ASP1707, elagolix, linzagolix, relugolix), for treatment of endometriosis-associated pelvic pain and heavy menstrual bleeding due to uterine fibroids has renewed interest in the short- and long-term impacts of changes in BMD experienced by premenopausal women. It is important to understand how these drugs influence BMD and put the findings into context with regard to measurement variability and naturally occurring factors that influence bone health. This review summarizes what is known about the effects on bone health pregnancy, lactation, and use of DMPA, GnRH agonists, and GnRH antagonists in premenopausal women and potential consequences later in life. ClinicalTrials.gov identifier: NCT03213457

Assessing modeling methods for predicting clinical CYP3A induction: A collaborative effort among academic, government regulatory, and pharmaceutical industry scientists

Several drug-drug interaction (DDI) prediction models were evaluated for their capability of identifying drugs with cytochrome P450 (CYP) 3A induction liability based on in vitro mRNA data. These models included basic methods (e.g. Cmax/EC50, Relative Induction Score, and R3 approach) and mechanistic models (e.g. Net Effect and physiologically-based pharmacokinetic models). All methods performed with high fidelity with few, if any, false negatives or positives predicted for induction. The basic methods resulted in no false negatives when total Cmax was incorporated. Mechanistic models that include CYP inactivation had a slightly higher false negative rate, likely due to an over-prediction of the inactivation effect. Based upon this evaluation, a tiered approach using the basic R3 approach for initial DDI risk assessment followed by more mechanistic modeling is recommended. For compounds that are both CYP3A inducers and inactivators, DDI predictions of each mechanism should be considered separately for decisions of clinical trial initiation

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