MATE1 Deficiency Exacerbates Dofetilide-Induced Proarrhythmia.

Dofetilide is a rapid delayed rectifier potassium current inhibitor widely used to prevent the recurrence of atrial fibrillation and flutter. The clinical use of this drug is associated with increases in QTc interval, which predispose patients to ventricular cardiac arrhythmias. The mechanisms involved in the disposition of dofetilide, including its movement in and out of cardiomyocytes, remain unknown.

Evaluation of the Absorption, Metabolism, and Excretion of a Single Oral 1-mg Dose of Tropifexor in Healthy Male Subjects and the Concentration Dependence of Tropifexor Metabolism.

Tropifexor (NVP-LJN452) is a highly potent, selective, nonsteroidal, non-bile acid farnesoid X receptor agonist for the treatment of nonalcoholic steatohepatitis. Its absorption, metabolism, and excretion were studied after a 1-mg oral dose of [C]tropifexor was given to four healthy male subjects. Mass balance was achieved with ∼94% of the administered dose recovered in excreta through a 312-hour collection period.

Considerations from the Innovation and Quality Induction Working Group in Response to Drug-Drug Interaction Guidance from Regulatory Agencies: Guidelines on Model Fitting and Recommendations on Time Course for In Vitro Cytochrome P450 Induction Studies Including Impact on Drug Interaction Risk Assessment.

Translational and ADME Sciences Leadership Group Induction Working Group (IWG) presents an analysis on the time course for cytochrome P450 induction in primary human hepatocytes. Induction of CYP1A2, CYP2B6, and CYP3A4 was evaluated by seven IWG laboratories after incubation with prototypical inducers (omeprazole, phenobarbital, rifampicin, or efavirenz) for 6-72 hours. The effect of incubation duration and model-fitting approaches on induction parameters (E and EC) and drug-drug interaction (DDI) risk assessment was determined.

Model-Informed Drug Development for Everolimus Dosing Selection in Pediatric Infant Patients.

Everolimus is currently approved in Europe as an adjunctive therapy for patients aged ≥ 2 years with tuberous sclerosis complex (TSC)-associated treatment-refractory partial-onset seizures, based on the EXIST-3 study (NCT01713946) results. As TSC-associated seizures can also affect children aged between 6 months and 2 years, a modeling and simulation (M&S) approach was undertaken to extrapolate exposure (trough plasma concentration (C )) after a dose of 6 mg/m and reduction in seizure frequency (RSF). A physiologically based pharmacokinetic model using Simcyp was developed to predict C in adult and pediatric patients, which was then used by a population pharmacodynamic model and a linear mixed effect model to predict short-term and long-term efficacy in adults (for validation) and in children, respectively.

Recommendations for the Design of Clinical Drug-Drug Interaction Studies With Itraconazole Using a Mechanistic Physiologically-Based Pharmacokinetic Model.

Regulatory agencies currently recommend itraconazole (ITZ) as a strong cytochrome P450 3A (CYP3A) inhibitor for clinical drug-drug interaction (DDI) studies. This work by an International Consortium for Innovation and Quality in Pharmaceutical Development working group (WG) is to develop and verify a mechanistic ITZ physiologically-based pharmacokinetic model and provide recommendations for optimal DDI study design based on model simulations. To support model development and verification, in vitro and clinical PK data for ITZ and its metabolites were collected from WG member companies.

Disposition of asciminib, a potent BCR-ABL1 tyrosine kinase inhibitor, in healthy male subjects.

Asciminib is a potent, specific BCR-ABL1 inhibitor being developed for the treatment of patients with chronic myelogenous leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph + ALL).Here, we present the results of human oral absorption, distribution, metabolism, excretion (ADME) and studies that together provide an overall understanding of the metabolism, distribution and clearance of asciminib in humans.Asciminib was rapidly absorbed with a maximum plasma concentration at two hours post-dose.

Considerations from the Innovation and Quality Induction Working Group in Response to Drug-Drug Interaction Guidances from Regulatory Agencies: Focus on CYP3A4 mRNA In Vitro Response Thresholds, Variability, and Clinical Relevance.

The Innovation and Quality Induction Working Group presents an assessment of best practice for data interpretation of in vitro induction, specifically, response thresholds, variability, application of controls, and translation to clinical risk assessment with focus on CYP3A4 mRNA. Single concentration control data and Emax/EC data for prototypical CYP3A4 inducers were compiled from many human hepatocyte donors in different laboratories. Clinical CYP3A induction and in vitro data were gathered for 51 compounds, 16 of which were proprietary.

Physiologically Based Pharmacokinetic Model Qualification and Reporting Procedures for Regulatory Submissions: A Consortium Perspective.

This work provides a perspective on the qualification and verification of physiologically based pharmacokinetic (PBPK) platforms/models intended for regulatory submission based on the collective experience of the Simcyp Consortium members. Examples of regulatory submission of PBPK analyses across various intended applications are presented and discussed. European Medicines Agency (EMA) and US Food and Drug Administration (FDA) recent draft guidelines regarding PBPK analyses and reporting are encouraging, and to advance the use and acceptability of PBPK analyses, more clarity and flexibility are warranted.

Simultaneous Physiologically Based Pharmacokinetic (PBPK) Modeling of Parent and Active Metabolites to Investigate Complex CYP3A4 Drug-Drug Interaction Potential: A Case Example of Midostaurin.

Midostaurin (PKC412) is being investigated for the treatment of acute myeloid leukemia (AML) and advanced systemic mastocytosis (advSM). It is extensively metabolized by CYP3A4 to form two major active metabolites, CGP52421 and CGP62221. In vitro and clinical drug-drug interaction (DDI) studies indicated that midostaurin and its metabolites are substrates, reversible and time-dependent inhibitors, and inducers of CYP3A4.

Evaluation of Clinical Drug Interaction Potential of Clofazimine Using Static and Dynamic Modeling Approaches.

The 2016 World Health Organization treatment recommendations for drug-resistant tuberculosis (DR-TB) positioned clofazimine as a core second-line drug. Being identified as a cytochrome P450 (P450) inhibitor in vitro, a P450-mediated drug interaction may be likely when clofazimine is coadministered with substrates of these enzymes. The P450-mediated drug interaction potential of clofazimine was evaluated using both static [estimation of the and area under the plasma concentration-time curve ratio (AUCR) values] and dynamic [physiologically based pharmacokinetics (PBPK)] modeling approaches.

Physiologically Based Pharmacokinetic Model Predictions of Panobinostat (LBH589) as a Victim and Perpetrator of Drug-Drug Interactions.

Panobinostat (Farydak) is an orally active hydroxamic acid-derived histone deacetylase inhibitor used for the treatment of relapsed or refractory multiple myeloma. Based on recombinant cytochrome P450 (P450) kinetic analyses in vitro, panobinostat oxidative metabolism in human liver microsomes was mediated primarily by CYP3A4 with lower contributions by CYP2D6 and CYP2C19. Panobinostat was also an in vitro reversible and time-dependent inhibitor of CYP3A4/5 and a reversible inhibitor of CYP2D6 and CYP2C19.

Considerations from the IQ Induction Working Group in Response to Drug-Drug Interaction Guidance from Regulatory Agencies: Focus on Downregulation, CYP2C Induction, and CYP2B6 Positive Control.

The European Medicines Agency (EMA), the Pharmaceutical and Medical Devices Agency (PMDA), and the Food and Drug Administration (FDA) have issued guidelines for the conduct of drug-drug interaction studies. To examine the applicability of these regulatory recommendations specifically for induction, a group of scientists, under the auspices of the Drug Metabolism Leadership Group of the Innovation and Quality (IQ) Consortium, formed the Induction Working Group (IWG). A team of 19 scientists, from 16 of the 39 pharmaceutical companies that are members of the IQ Consortium and two Contract Research Organizations reviewed the recommendations, focusing initially on the current EMA guidelines.

Drug Interaction Potential of Osilodrostat (LCI699) Based on Its Effect on the Pharmacokinetics of Probe Drugs of Cytochrome P450 Enzymes in Healthy Adults.

Background And Objectives: Osilodrostat (LCI699) is an adrenal steroidogenesis inhibitor currently in late-phase clinical development as a potential treatment for Cushing's disease. This study evaluated the inhibitory effect of osilodrostat on the pharmacokinetics of probe substrates of the cytochrome P450 (CYP) enzymes CYP1A2, CYP2C19, CYP2D6, and CYP3A4.

Methods: Healthy adult volunteers received single-dose cocktail probe substrates [caffeine (100 mg), omeprazole (20 mg), dextromethorphan (30 mg), and midazolam (2 mg)] followed by a 6-day washout.

A Physiologically-Based Pharmacokinetic Modeling Approach To Predict Drug-Drug Interactions of Sonidegib (LDE225) with Perpetrators of CYP3A in Cancer Patients.

Sonidegib (Odomzo) is an orally available Smoothened inhibitor for the treatment of advanced basal cell carcinoma. Sonidegib was found to be metabolized primarily by cytochrome P450 (CYP)3A in vitro. The effect of multiple doses of the strong CYP3A perpetrators, ketoconazole (KTZ) and rifampin (RIF), on sonidegib pharmacokinetics (PK) after a single 800 mg dose in healthy subjects was therefore assessed.

Evaluation of Drug-Drug Interaction Potential Between Sacubitril/Valsartan (LCZ696) and Statins Using a Physiologically Based Pharmacokinetic Model.

Sacubitril/valsartan (LCZ696) has been approved for the treatment of heart failure. Sacubitril is an in vitro inhibitor of organic anion-transporting polypeptides (OATPs). In clinical studies, LCZ696 increased atorvastatin C by 1.

Pradigastat disposition in humans: in vivo and in vitro investigations.

1. Pradigastat is a potent and specific diacylglycerol acyltransferase-1 (DGAT1) inhibitor effective in lowering postprandial triglycerides (TG) in healthy human subjects and fasting TG in familial chylomicronemia syndrome (FCS) patients. 2.

Clinical disposition, metabolism and in vitro drug-drug interaction properties of omadacycline.

1. Absorption, distribution, metabolism, transport and elimination properties of omadacycline, an aminomethylcycline antibiotic, were investigated in vitro and in a study in healthy male subjects. 2.

Evaluation of CYP2B6 Induction and Prediction of Clinical Drug-Drug Interactions: Considerations from the IQ Consortium Induction Working Group-An Industry Perspective.

Drug-drug interactions (DDIs) due to CYP2B6 induction have recently gained prominence and clinical induction risk assessment is recommended by regulatory agencies. This work aimed to evaluate the potency of CYP2B6 versus CYP3A4 induction in vitro and from clinical studies and to assess the predictability of efavirenz versus bupropion as clinical probe substrates of CYP2B6 induction. The analysis indicates that the magnitude of CYP3A4 induction was higher than CYP2B6 both in vitro and in vivo.

Evaluation of a New Molecular Entity as a Victim of Metabolic Drug-Drug Interactions-an Industry Perspective.

Under the guidance of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ), scientists from 20 pharmaceutical companies formed a Victim Drug-Drug Interactions Working Group. This working group has conducted a review of the literature and the practices of each company on the approaches to clearance pathway identification (fCL), estimation of fractional contribution of metabolizing enzyme toward metabolism (fm), along with modeling and simulation-aided strategy in predicting the victim drug-drug interaction (DDI) liability due to modulation of drug metabolizing enzymes. Presented in this perspective are the recommendations from this working group on: 1) strategic and experimental approaches to identify fCL and fm, 2) whether those assessments may be quantitative for certain enzymes (e.

Disposition and metabolism of [(14)C] Sacubitril/Valsartan (formerly LCZ696) an angiotensin receptor neprilysin inhibitor, in healthy subjects.

1. Sacubitril/valsartan (LCZ696) is an angiotensin receptor neprilysin inhibitor (ARNI) providing simultaneous inhibition of neprilysin (neutral endopeptidase 24.11; NEP) and blockade of the angiotensin II type-1 (AT1) receptor.

Identification of Three Novel Ring Expansion Metabolites of KAE609, a New Spiroindolone Agent for the Treatment of Malaria, in Rats, Dogs, and Humans.

KAE609 [(1'R,3'S)-5,7'-dichloro-6'-fluoro-3'-methyl-2',3',4',9'-tetrahydrospiro[indoline-3,1'-pyridol[3,4-b]indol]-2-one] is a potent, fast-acting, schizonticidal agent being developed for the treatment of malaria. After oral dosing of KAE609 to rats and dogs, the major radioactive component in plasma was KAE609. An oxidative metabolite, M18, was the prominent metabolite in rat and dog plasma.

Physiologically based pharmacokinetic modeling for assessing the clinical drug-drug interaction of alisporivir.

Alisporivir is a novel cyclophilin-binding molecule with potent anti-hepatitis C virus (HCV) activity. In vitro data from human liver microsomes suggest that alisporivir is a substrate and a time-dependent inhibitor (TDI) of CYP3A4. The aim of the current work was to develop a novel physiologically based pharmacokinetic (PBPK) model to quantitatively assess the magnitude of CYP3A4 mediated drug-drug interactions with alisporivir as the substrate or victim drug.

Evaluation of calibration curve-based approaches to predict clinical inducers and noninducers of CYP3A4 with plated human hepatocytes.

Cytochrome P450 (P450) induction is often considered a liability in drug development. Using calibration curve-based approaches, we assessed the induction parameters R3 (a term indicating the amount of P450 induction in the liver, expressed as a ratio between 0 and 1), relative induction score, Cmax/EC50, and area under the curve (AUC)/F2 (the concentration causing 2-fold increase from baseline of the dose-response curve), derived from concentration-response curves of CYP3A4 mRNA and enzyme activity data in vitro, as predictors of CYP3A4 induction potential in vivo. Plated cryopreserved human hepatocytes from three donors were treated with 20 test compounds, including several clinical inducers and noninducers of CYP3A4.

Time-dependent inhibition and induction of human cytochrome P4503A4/5 by an oral IAP antagonist, LCL161, in vitro and in vivo in healthy subjects.

Tumor cells can evade programmed cell death via up-regulation of inhibitor of apoptosis proteins (IAPs). LCL161 is a small molecule oral IAP antagonist in development for use in combination with cytotoxic agents. The effect of LCL161 on CYP3A4/5 (CYP3A) activity was investigated in vitro and in a clinical study.