Physiologically Based Pharmacokinetic Modeling and Simulation of Mavacamten Exposure with Drug-Drug Interactions from CYP Inducers and Inhibitors by CYP2C19 Phenotype.

Mavacamten is a first-in-class, oral, selective, allosteric, reversible cardiac myosin inhibitor approved by the US Food and Drug Administration for the treatment of adults with symptomatic New York Heart Association functional class II-III obstructive hypertrophic cardiomyopathy. Mavacamten is metabolized in the liver, predominantly via cytochrome P450 (CYP) enzymes CYP2C19 (74%), CYP3A4 (18%), and CYP2C9 (8%). A physiologically-based pharmacokinetic (PBPK) model was developed using Simcyp version 19 (Certara, Princeton, NJ). Following model verification, the PBPK model was used to explore the effects of strong CYP3A4 and CYP2C19 inducers, and strong, moderate, and weak CYP2C19 and CYP3A4 inhibitors on mavacamten pharmacokinetics (PK) in a healthy population, with the effect of CYP2C19 phenotype predicted for poor, intermediate, normal, and ultrarapid metabolizers. The PBPK model met the acceptance criteria for all verification simulations (> 80% of model-predicted PK parameters within 2-fold of those observed clinically). A weak induction effect was predicted when mavacamten was administered with a strong CYP3A4 inducer in poor metabolizers. Moderate reductions in mavacamten exposure were predicted with a strong CYP2C19/CYP3A4 inducer in all CYP2C19 phenotypes. Except for the effect of strong CYP2C19 inhibitors on ultrarapid metabolizers, steady-state area under plasma concentration-time curve and maximum plasma concentration values were weakly affected (< 2-fold) or not affected (< 1.25-fold), regardless of CYP2C19 phenotype. In conclusion, a fit-for-purpose PBPK model was developed and verified, which accurately predicted the available clinical data and was used to simulate the potential impact of CYP induction and inhibition on mavacamten PKs, stratified by CYP2C19 phenotype.

Emerging TACnology: Heterobifunctional Small Molecule Inducers of Targeted Posttranslational Protein Modifications.

Posttranslational modifications (PTMs) play an important role in cell signaling and they are often deregulated in disease. This review addresses recent advances in the development of heterobifunctional small molecules that enable targeting or hijacking PTMs. This emerging field is spearheaded by proteolysis-targeting chimeras (PROTACs), that induce ubiquitination of their targets and, thus, tag them for degradation by the proteasome. Within the last decade, several improvements have been made to enhance spatiotemporal control of PROTAC-induced degradation as well as cell permeability. Inspired by the success story of PROTACs, additional concepts based on chimeric small molecules have emerged such as phosphatase-recruiting chimeras (PhoRCs). Herein, an overview of strategies causing (de-)phosphorylation, deubiquitination as well as acetylation is provided, and the opportunities and challenges of heterobifunctional molecules for drug discovery are highlighted. Although significant progress has been achieved, a plethora of PTMs have not yet been covered and PTM-inducing chimeras will be helpful tools for chemical biology and could even find application in pharmacotherapy.

Pharmacokinetic Interaction of Chiglitazar with CYP3A4 Inducer or Inhibitor: An Open-Label, Sequential Crossover, Self-Control, 3-Period Study in Healthy Chinese Volunteers.

Chiglitazar, a pan agonist of non-thiazolidinedione peroxisome proliferator-activated receptor, has the potential to regulate blood sugar, improve lipid metabolism, and reduce cardiovascular complications. This study aimed to examine the effect of cytochrome P450 (CYP) 3A4 inhibitors/inducers on the in vivo metabolism of chiglitazar and provide a reference for the clinical combination use of chiglitazar. A single-center, open-label, sequential crossover, and self-control study was carried out in 24 healthy subjects to determine the pharmacokinetics of chiglitazar dosed with and without CYP3A4 inhibitors and inducers. The findings showed that the CYP3A4 inhibitor itraconazole had no apparent pharmacokinetic drug interaction with chiglitazar, whereas rifampicin did. When combined with rifampicin after continuous dosing, chiglitazar exposure was not theoretically reduced but increased compared to a single dose of chiglitazar. The possible explanation may be the transporters of bile salt export pump, but this needs to be confirmed. The safety of chiglitazar in single or combination doses was well tolerated. The findings of this study provide a basis for clinical combinations of chiglitazar with CYP3A4 inhibitors or inducers.

Current Perspective on Residual Knowledge Gaps in the Assessment of Transporter-Mediated Drug Interactions.

Assessment of transporter-mediated drug-drug interaction (DDI) is integral to drug development. A risk-based approach leveraging in vitro, in vivo, and in silico information is used to evaluate the DDI liability of drugs and inform the instructions of use. While tremendous advances have been made in recent decades, there are knowledge gaps warranting further research. Herein, we focus on select areas to advance assessment of DDI potential for drugs as substrates, inhibitors, or inducers of certain transporters.

Study of the metabolic stability profiles of perampanel, rufinamide and stiripentol and prediction of drug interactions using HepaRG cells as an in vitro human model.

New-generation antiepileptic drugs as perampanel, rufinamide and stiripentol emerged as alternatives in chronic epilepsy polytherapy. Hence, their metabolic stability and potential involvement in relevant drug-drug interactions (DDI) are of great clinical interest, being HepaRG cells herein used as an in vitro human model. To characterize their metabolic stability profiles, HepaRG cells were incubated with perampanel (1 µM), rufinamide (100 µM) or stiripentol (5 µM) for 12-h. HepaRG cells, pretreated with known CYP450 isoenzymes inducers (rifampicin, phenytoin, phenobarbital, omeprazole and carbamazepine), were also incubated with perampanel, rufinamide or stiripentol to assess possible DDI mediated by CYP450 induction. Results suggest a considerable decrease in perampanel and stiripentol concentrations over 12-h; contrary, rufinamide concentrations did not variated. Cells pretreatment with all inducers significantly decreased stiripentol concentrations (between 20.3% and 31.9%), suggesting a considerable potential for DDI. Rufinamide concentrations only decreased when preincubated with rifampicin and with the highest tested concentrations of the remaining inducers. Perampanel levels decreased with rifampicin, carbamazepine and phenobarbital, supporting the involvement of CYP3A4-mediated metabolism. Besides relevant information concerning the metabolic stability profile and potential DDIs of the new antiepileptics here studied, it was also reinforced the HepaRG cells suitability as a reliable in vitro model to foresee in vivo metabolism in humans.

A Phase 1 Pharmacokinetic Drug Interaction Study of Belumosudil Coadministered With CYP3A4 Inhibitors and Inducers and Proton Pump Inhibitors.

Belumosudil is a selective Rho-associated protein kinase 2 inhibitor. Inhibition of Rho-associated protein kinase 2 has emerged as a promising treatment for chronic graft-versus-host disease by restoring immune homeostasis and reducing fibrosis. In vitro assessments have suggested that metabolism of belumosudil is primarily dependent on cytochrome P450 (CYP) 3A4 activity and that the solubility of belumosudil is pH dependent. As such, this 2-part clinical drug-drug interaction study was conducted to assess the effect of itraconazole (a strong CYP3A4 inhibitor), rifampicin (a strong CYP3A4 inducer), rabeprazole, and omeprazole (both proton pump inhibitors) on the pharmacokinetics of belumosudil. No clinically relevant change in belumosudil exposure was observed following a 200-mg single oral dose of belumosudil with itraconazole; however, exposure of main metabolite, KD025m2, was decreased. Consistent with the proposed metabolic pathway of belumosudil, the strong CYP3A4 inducer rifampicin significantly decreased exposure of belumosudil and KD025m2 and increased KD025m1 exposure. When a 200-mg single oral dose of belumosudil was coadministered with both rabeprazole and omeprazole, parent and metabolite exposures were largely reduced, suggesting that belumosudil dosage should be increased when given with PPIs. Administration of belumosudil with and without perpetrator drugs was safe, and no notable adverse events were reported.

Translational aspects of cytochrome P450-mediated drug-drug interactions: A case study with clopidogrel.

Multimorbidity, polypharmacotherapy and drug interactions are increasingly common in the ageing population. Many drug-drug interactions (DDIs) are caused by perpetrator drugs inhibiting or inducing cytochrome P450 (CYP) enzymes, resulting in alterations of the plasma concentrations of a victim drug. DDIs can have a major negative health impact, and in the past, unrecognized DDIs have resulted in drug withdrawals from the market. Signals to investigate DDIs may emerge from a variety of sources. Nowadays, standard methods are widely available to identify and characterize the mechanisms of CYP-mediated DDIs in vitro. Clinical pharmacokinetic studies, in turn, provide experimental data on pharmacokinetic outcomes of DDIs. Physiologically based pharmacokinetic (PBPK) modelling utilizing both in vitro and in vivo data is a powerful tool to predict different DDI scenarios. Finally, epidemiological studies can provide estimates on the health outcomes of DDIs. Thus, to fully characterize the mechanisms, clinical effects and implications of CYP-mediated DDIs, translational research approaches are required. This minireview provides an overview of translational approaches to study CYP-mediated DDIs, going beyond regulatory DDI guidelines, and an illustrative case study of how the DDI potential of clopidogrel was unveiled by combining these different methods.

Evaluation of Nigerian Medicinal Plants Extract on Human P-glycoprotein and Cytochrome P450 Enzyme Induction: Implications for Herb-drug Interaction.

BACKGROUND: Herbal medicine represents a significant component of disease prevention and therapy in most African countries. Herb-drug interactions (HDI) can arise from the co-administration of herbal and orthodox medicines. OBJECTIVE: This study assessed the potential for HDI of V. amygdalina, O. gratissimum, M. oleifera, A. indica, and P. nitida extracts using in vitro assays. Little is known about these medicinal plants' potential for drug interaction despite their extensive use in Nigeria for several disease conditions. METHOD: The medicinal plant crude extracts were evaluated for Cytochrome P450 (CYP) enzyme induction using cryopreserved human hepatocytes. Enzyme activity was determined by quantifying probe substrate metabolism and metabolite formation using liquid chromatography-mass spectrometry/mass spectrometry. The extracts were evaluated for the potential to inhibit P-glycoprotein (P-gp) activity using human embryonic kidney membrane vesicles over-expressing human P-gp. The herbal extracts in vivo drug interaction potential was predicted based on the USFDA drug interaction guidance. RESULT: O. gratissimum and P. nitida methanol extracts induced CYP1A2 enzyme activity by greater than 3-fold. P. nitida methanol extracts showed over 2-fold induction of CYP1A2 mRNA expression. O. gratissimum methanol extract induced CYP2B6 mRNA expression over 2-fold. P. nitida and A. indica methanol extracts showed potent inhibition of P-gp activity (IC50: 3.8 and 5.4 µg/mL), respectively, while V. amygdalina and M. oleifera methanol extracts showed moderate P-gp inhibition (IC50: 12.1 and 37.2 µg/mL, respectively). CONCLUSION: Our studies suggested that the medicinal plants' extracts can modulate CYP enzymes and P-gp activity with the potential to cause herb-drug interaction in vivo.

Study on the effects of Zhuanggu Guanjie Pill, a modern Chinese medicine formula, on the activities and mRNA expression of seven CYP isozymes in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Zhuanggu Guanjie Pill (ZGGJP), a modern Chinese medicine formula, is composed of 12 herbs and has been used to treat osteoporosis in China for almost 30 years. However, no in vivo study of the influences of ZGGJP on the cytochrome P450 (CYP) activities have been reported. AIM OF THE STUDY: The aim of this study was to evaluate the effects of ZGGJP on the activities and the mRNA expression of CYP enzymes (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A) and their corresponding nuclear receptor levels in rats. MATERIALS AND METHODS: After 7 days oral treatment of ZGGJP at low- and high-dose, cocktail solution was given to rats. Blood samples were collected at series of time points. The plasma concentrations of probe drugs and their corresponding metabolites were determined by UPLC-MS/MS. The influence of ZGGJP on the activities of seven CYPs were evaluated the metabolic ratios (Cmax and AUC0-t) for metabolites/probe drugs. In addition, the effects of ZGGJP on the mRNA expression of CYPs and their corresponding nuclear receptors in rat liver were evaluated by real-time PCR. RESULTS: ZGGJP showed significant inductive effects on CYP1A2 and CYP2B6 of both male and female rats. The influence of ZGGJP on CYP2C9 and CYP3A showed gender difference. ZGGJP could induce the activities of CYP2C9 and CYP3A in female rats, but have no influence on the activities in male rats. ZGGJP had no effects on CYP2D6, CYP2C19 and CYP2E1. The mRNA expression results of CYPs were in accordance with the pharmacokinetic results. The mRNA expression levels of constitutive androstane receptor (CAR) and vitamin D receptor (VDR) were increased significantly in female rats at high dosage, but no significant changes were observed in male rats. CONCLUSION: ZGGJP had inductive effects on CYP1A2 and CYP2B6 in both male and female rats. The results showed that ZGGJP could induce the activities of CYP2C9 and CYP3A in female rats, but had no effect in male rats. This may suggest that the influence of ZGGJP on CYP2C9 and CYP3A exhibit gender difference. The inductive effects of ZGGJP on the activities of CYPs, exhibiting gender difference, may be regulated by CAR and VDR. Therefore, co-administration of ZGGJP with other drugs, especially using CYP2C9 and CYP3A substrates in females, may need dose adjustment to avoid herb-drug interaction.

Prediction of the drug-drug interaction potential of the α1-acid glycoprotein bound, CYP3A4/CYP2C9 metabolized oncology drug, erdafitinib.

Erdafitinib is a potent oral pan-fibroblast growth factor receptor inhibitor being developed as oncology drug for patients with alterations in the fibroblast growth factor receptor pathway. Erdafitinib binds preferentially to α1-acid glycoprotein (AGP) and is primarily metabolized by cytochrome P450 (CYP) 2C9 and 3A4. This article describes a physiologically based pharmacokinetic (PBPK) model for erdafitinib to assess the drug-drug interaction (DDI) potential of CYP3A4 and CYP2C9 inhibitors and CYP3A4/CYP2C9 inducers on erdafitinib pharmacokinetics (PK) in patients with cancer exhibiting higher AGP levels and in populations with different CYP2C9 genotypes. Erdafitinib's DDI potential as a perpetrator for transporter inhibition and for time-dependent inhibition and/or induction of CYP3A was also evaluated. The PBPK model incorporated input parameters from various in vitro and clinical PK studies, and the model was verified using a clinical DDI study with itraconazole and fluconazole. Erdafitinib clearance in the PBPK model consisted of multiple pathways (CYP2C9/3A4, renal, intestinal; additional hepatic clearance), making the compound less susceptible to DDIs. In poor-metabolizing CYP2C9 populations carrying the CYP2C9*3/*3 genotype, simulations shown clinically relevant increase in erdafitinib plasma concentrations. Simulated luminal and enterocyte concentration showed potential risk of P-glycoprotein inhibition with erdafitinib in the first 5 h after dosing, and simulations showed this interaction can be avoided by staggering erdafitinib and digoxin dosing. Other than a simulated ~ 60% exposure reduction with strong CYP3A/2C inducers such as rifampicin, other DDI liabilities were minimal and considered not clinically relevant.

Physiologically Based Pharmacokinetic Modeling for Selumetinib to Evaluate Drug-Drug Interactions and Pediatric Dose Regimens.

Selumetinib (ARRY-142886), an oral, potent and highly selective allosteric mitogen-activated protein kinase kinase 1/2 inhibitor, is approved by the US Food and Drug Administration for the treatment of pediatric patients aged ≥2 years with neurofibromatosis type 1 with symptomatic, inoperable plexiform neurofibromas. A physiologically based pharmacokinetic (PBPK) model was constructed to predict plasma concentration-time profiles of selumetinib, and to evaluate the impact of coadministering moderate cytochrome P450 (CYP) 3A4/2C19 inhibitors/inducers. The model was also used to extrapolate pharmacokinetic exposures from older children with different body surface area to guide dosing in younger children. This model was built based on physiochemical data and clinical in vivo drug-drug interaction (DDI) studies with itraconazole and fluconazole, and verified against data from an in vivo rifampicin DDI study and an absolute bioavailability study. The pediatric model was updated by changing system-specific input parameters using the Simcyp pediatric module. The model captured the observed selumetinib pharmacokinetic profiles and the interactions with CYP inhibitors/inducers. The predictions from the PBPK model showed a DDI effect of 30% to 40% increase or decrease in selumetinib exposure when coadministered with moderate CYP inhibitors or inducers, respectively, which was used to inform dose management and adjustments. The pediatric PBPK model was applied to simulate exposures in specific body surface area brackets that matched those achieved with a 25 mg/m2 dose in SPRINT clinical trials. The pediatric PBPK model was used to guide the dose for younger patients in a planned pediatric clinical study.

A Physiologically Based Pharmacokinetic and Drug-Drug Interaction Model for the CB2 Agonist Lenabasum.

BACKGROUND AND OBJECTIVES: Lenabasum is a synthetic agonist of the cannabinoid receptor type 2 (CB2) with anti-inflammatory and antifibrotic properties. Utilizing Simcyp, we developed a physiologically based pharmacokinetic (PBPK) model based on physicochemical properties, cell culture data, and cytochrome P450 (CYP) phenotyping, inhibition, and induction data. METHODS: Clinical data from healthy volunteers treated with 20 mg of lenabasum in a single ascending dose (SAD) study were used for model development. The model was verified using lenabasum SAD (10 and 40 mg) data as well as multiple dose (20 mg three times per day) data. Lenabasum is a CYP substrate, and the model predicted lenabasum clearance of 51% by CYP2C9, 37% by CYP2C8, and 12% by CYP3A4. Lenabasum is also an inhibitor of these isozymes. RESULTS: The model accurately described the area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) for lenabasum within 1.19-fold and 1.25-fold accuracy, respectively, of the observed clinical values. The simulations of CYP inducers predicted that the strongest interaction would occur with rifampin, with the AUC decreasing to 0.36 of the control value, whereas the simulations of CYP inhibitors predicted that the greatest effect would occur with fluconazole, with a 1.43-fold increase in AUC. CONCLUSIONS: Our model is a useful tool for predicting the pharmacokinetics of lenabasum and adjustments to its dosing in possible drug-drug interaction scenarios.

The Impact of Strong Inducers on Direct Oral Anticoagulant Levels.

PURPOSE: The concomitant use of direct oral anticoagulants (DOAC) and strong P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4) inducers may lead to reduced DOAC levels and therapeutic failure. This study aimed to describe DOAC concentrations in patients receiving strong P-gp and CYP3A4 inducers, in relation to individual risk factors for high or low DOAC levels. METHODS: We retrospectively identified hospitalized patients simultaneously receiving a DOAC and carbamazepine, phenobarbital, phenytoin, or rifampicin between 2016 and 2021. Among them, patients who underwent DOAC measurement at steady state were included. DOAC peak or trough levels were compared with on-therapy ranges observed in pivotal trials. Individual risk factors for high or low DOAC levels were identified. RESULTS: We included 17 patients (median age 75 years), mainly receiving apixaban and carbamazepine. For 5 patients (29%), DOAC trough or peak level was below the expected range. Among the remaining 12 patients, 8 had at least one measurement in the lower quartile of the range. The median number of risk factors for drug accumulation was 0 (range 0-1) in patients with ≥1 measurement below the range and 2 (range 0-3) in other patients. DOAC measurement led to treatment adjustments in 9 patients (DOAC dose increase or switch). CONCLUSION: Our data suggest a significant risk of reduced DOAC levels in patients taking strong P-gp and CYP3A4 inducers, especially those without risk factors for drug accumulation. DOAC measurement could help manage this relevant drug-drug interaction.

PBPK modeling to predict drug-drug interactions of ivosidenib as a perpetrator in cancer patients and qualification of the Simcyp platform for CYP3A4 induction.

Ivosidenib is a potent, targeted, orally active, small-molecule inhibitor of mutant isocitrate dehydrogenase 1 (IDH1) that has been approved in the United States for the treatment of adults with newly diagnosed acute myeloid leukemia (AML) who are greater than or equal to 75 years of age or ineligible for intensive chemotherapy, and those with relapsed or refractory AML, with a susceptible IDH1 mutation. Ivosidenib is an inducer of the CYP2B6, CYP2C8, CYP2C9, and CYP3A4 and an inhibitor of P-glycoprotein (P-gp), organic anion transporting polypeptide-1B1/1B3 (OATP1B1/1B3), and organic anion transporter-3 (OAT3) in vitro. A physiologically-based pharmacokinetic (PK) model was developed to predict drug-drug interactions (DDIs) of ivosidenib in patients with AML. The in vivo CYP3A4 induction effect of ivosidenib was quantified using 4ß-hydroxycholesterol and was subsequently verified with the PK data from an ivosidenib and venetoclax combination study. The verified model was prospectively applied to assess the effect of multiple doses of ivosidenib on a sensitive CYP3A4 substrate, midazolam. The simulated midazolam geometric mean area under the curve (AUC) and maximum plasma concentration (Cmax ) ratios were 0.18 and 0.27, respectively, suggesting ivosidenib is a strong inducer. The model was also used to predict the DDIs of ivosidenib with CYP2B6, CYP2C8, CYP2C9, P-gp, OATP1B1/1B3, and OAT3 substrates. The AUC ratios following multiple doses of ivosidenib and a single dose of CYP2B6 (bupropion), CYP2C8 (repaglinide), CYP2C9 (warfarin), P-gp (digoxin), OATP1B1/1B3 (rosuvastatin), and OAT3 (methotrexate) substrates were 0.90, 0.52, 0.84, 1.01, 1.02, and 1.27, respectively. Finally, in accordance with regulatory guidelines, the Simcyp modeling platform was qualified to predict CYP3A4 induction using known inducers and sensitive substrates.

Evaluation of the CYP3A and CYP2B6 Drug-Drug Interaction Potential of Lemborexant.

Lemborexant is approved for treating insomnia and is under investigation for treating irregular sleep-wake rhythm disorder. Based on in vitro drug-drug interaction (DDI) characteristics, phase 1, open-label DDI studies were conducted to evaluate lemborexant's cytochrome P450 3A (CYP3A) and CYP2B6 interaction potential. Interactions between lemborexant 10 mg and strong and moderate CYP3A inhibitors (itraconazole and fluconazole), a strong CYP3A inducer (rifampin), and CYP3A (midazolam) and CYP2B6 substrates (bupropion) were evaluated. Coadministration of lemborexant with itraconazole or fluconazole resulted in 1.4- to 1.6-fold and 3.7- to 4-fold increases in lemborexant maximum observed concentration (Cmax ) and area under the concentration-time curve from zero time extrapolated to infinity (AUC0-inf ), respectively. Coadministration of lemborexant with rifampin resulted in >90% decreases in lemborexant Cmax and AUC0-inf . Midazolam exposure was not affected. Coadministration of lemborexant with bupropion resulted in 49.9% and 45.5% decreases in S-bupropion Cmax and AUC0-inf , respectively.Comparison of estimated exposures for patients in phase 3 trials who were/were not receiving concomitant weak CYP3A inhibitors substantiated the DDI pharmacokinetic findings. Lemborexant was generally well tolerated in the phase 1 studies. In summary, lemborexant does not affect the pharmacokinetics of CYP3A substrates and has potential to induce CYP2B6. Consistent with in vitro findings, moderate and strong CYP3A inhibitors and inducers affected the pharmacokinetics of lemborexant; hence, patients taking lemborexant 5 or 10 mg should avoid coadministration with moderate and strong CYP3A inhibitors and inducers.

Primary care electronic medical records can be used to predict risk and identify potentially modifiable factors for early and late death in adult onset epilepsy.

OBJECTIVE: To use clinically informed machine learning to derive prediction models for early and late premature death in epilepsy. METHODS: This was a population-based primary care observational cohort study. All patients meeting a case definition for incident epilepsy in the Health Improvement Network database for inclusive years 2000-2012 were included. A modified Delphi process identified 30 potential risk factors. Outcome was early (within 4 years of epilepsy diagnosis) and late (4 years or more from diagnosis) mortality. We used regularized logistic regression, support vector machines, Gaussian naive Bayes, and random forest classifiers to predict outcomes. We assessed model calibration, discrimination, and generalizability using the Brier score, mean area under the receiver operating characteristic curve (AUC) derived from stratified fivefold cross-validation, plotted calibration curves, and extracted measures of association where possible. RESULTS: We identified 10 499 presumed incident cases from 11 194 182 patients. All models performed comparably well following stratified fivefold cross-validation, with AUCs ranging from 0.73 to 0.81 and from 0.71 to 0.79 for early and late death, respectively. In addition to comorbid disease, social habits (alcoholism odds ratio [OR] for early death = 1.54, 95% confidence interval [CI] = 1.12-2.11 and OR for late death = 2.62, 95% CI = 1.66-4.16) and treatment patterns (OR for early death when no antiseizure medication [ASM] was prescribed at baseline = 1.33, 95% CI = 1.07-1.64 and OR for late death after receipt of enzyme-inducing ASM at baseline = 1.32, 95% CI = 1.04-1.66) were significantly associated with increased risk of premature death. Baseline ASM polytherapy (OR = 0.55, 95% CI = 0.36-0.85) was associated with reduced risk of early death. SIGNIFICANCE: Clinically informed models using routine electronic medical records can be used to predict early and late mortality in epilepsy, with moderate to high accuracy and evidence of generalizability. Medical, social, and treatment-related risk factors, such as delayed ASM prescription and baseline prescription of enzyme-inducing ASMs, were important predictors.

An In Vitro and In Vivo Evaluation of the Effect of Relacorilant on the Activity of Cytochrome P450 Drug Metabolizing Enzymes.

Relacorilant is a selective modulator of the glucocorticoid receptor in development for the treatment of several serious diseases. The widely used cocktail method was employed to assess relacorilant's effect on various cytochrome P450 (CYP) drug metabolizing enzymes in vitro and in vivo. Inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2B6, CYP2C8, CYP3A4, and CYP3A5 as well as induction of CYP1A2, CYP2B6, and CYP3A4 were assessed in vitro (relacorilant concentrations up to 10 µM). A clinical study in healthy subjects (n = 27) evaluated the inhibition of CYP3A4, CYP2C8, and CYP2C9 in vivo by administering single doses of probe CYP substrates (midazolam, pioglitazone, and tolbutamide) alone and in combination with relacorilant (350 mg). Pharmacokinetic sampling was conducted, and safety was assessed throughout the study. Pharmacokinetic parameters were evaluated using 90% confidence intervals of the geometric least squares mean ratios of test (probe substrate with relacorilant) vs reference (probe substrate alone) using boundaries of 80% to 125%. In vitro, relacorilant inhibited CYP3A4, CYP2C8, and CYP2C9 but did not meaningfully affect the activity of the other CYP enzymes evaluated. Consistent with the in vitro data, relacorilant was shown to be a strong CYP3A inhibitor in vivo (>8-fold increase in midazolam area under the concentration versus time curve from time zero to the last quantifiable concentration and area under the concentration versus time curve from time zero extrapolated to infinity). Coadministration of relacorilant with drugs highly dependent on CYP3A for clearance is expected to increase the concentrations of these drugs. Importantly, clinical evaluation of relacorilant showed no inhibition of CYP2C8 or CYP2C9 in vivo. Accordingly, drugs that are substrates of only CYP2C8 and/or CYP2C9 can be coadministered with relacorilant without dose adjustment.