CYP3A4 Induction Research Articles

Clinical and Physiologically Based Pharmacokinetic Model Evaluations of Adagrasib Drug-Drug Interactions.

Adagrasib is a potent, highly selective, orally available, small molecule, covalent inhibitor of G12C mutated KRAS. As both a substrate and strong inhibitor of cytochrome P450 (CYP) 3A4, adagrasib inhibits its own CYP3A4-mediated metabolism following multiple dosing, resulting in time-dependent drug-drug interaction (DDI) liabilities. A physiologically-based pharmacokinetic (PBPK) model was developed and verified using a combination of physicochemical, in vitro and clinical pharmacokinetic (PK) data from healthy volunteers and cancer patients. The PBPK model well-described the single and multiple-dose adagrasib PK data as well as DDI data with itraconazole, rifampin, midazolam, warfarin, dextromethorphan, and digoxin, with model predictions within 1.5-fold of the observed clinical data. The PBPK model was used to predict untested scenarios including the clinical victim and perpetrator DDI liabilities at the approved dosing regimen of 600 mg twice daily (b.i.d.) in cancer patients. Strong, moderate, and weak inhibitors of CYP3A4 are predicted to have a negligible effect on the steady-state exposure of adagrasib 600 mg b.i.d. resulting from the significant inactivation of CYP3A4 by adagrasib. Additionally, strong and moderate inducers of CYP3A4 are predicted to decrease adagrasib exposure by 68% and 22%, respectively. As a perpetrator, adagrasib 600 mg b.i.d. is predicted to be a strong inhibitor of CYP3A4, a moderate inhibitor of CYP2C9 and CYP2D6, and an inhibitor of P-glycoprotein (P-gp). These results successfully supported regulatory interactions with the United States Food and Drug Administration regarding dosing recommendations for when adagrasib is used concomitantly with other medications, supporting a range of label claims in lieu of clinical trials.

In Vitro Evaluation of CYP-Mediated Metabolism of Fezolinetant and Pharmacokinetic Interaction Between Fezolinetant and Fluvoxamine in Healthy Postmenopausal Smokers and Nonsmokers.

Fezolinetant is an oral, nonhormonal, neurokinin 3 receptor antagonist treatment option for moderate to severe vasomotor symptoms associated with menopause. An in vitro study using human recombinant cytochrome P450 (CYP) enzymes and human liver microsomes showed that fezolinetant is metabolized to its major but inactive metabolite, ES259564, predominantly through CYP1A2, with minor contributions from CYP2C9 and CYP2C19. The clinical impact of CYP1A2 inhibition and induction on single-dose pharmacokinetics of fezolinetant was assessed in an open-label, single-sequence, phase 1 study in healthy postmenopausal women, where the impact of fluvoxamine, a strong CYP1A2 inhibitor, and smoking, a moderate CYP1A2 inducer, were evaluated. In total, 18 participants, 9 of whom were smokers, were enrolled. Fezolinetant pharmacokinetics were evaluated after a single 30-mg dose on Day 1 and Day 7. Fluvoxamine 50 mg was administered as a single dose on Days 3 and 10 and twice daily from Days 4 to 9. Fluvoxamine increased geometric mean ratio of fezolinetant maximum plasma concentrations (Cmax) and area under the curve from time of dosing extrapolated to infinity (AUCinf) to 182% and 939%, respectively, while ES259564 Cmax decreased to 20.1% with no significant change in AUC. In smokers versus nonsmokers, when fezolinetant was administered alone, fezolinetant Cmax and AUCinf decreased to 71.7% and 48.3%, respectively, while ES259564 Cmax increased to 130.2% and AUCinf decreased to 81.8%. A single oral 30-mg dose of fezolinetant was considered safe and well tolerated when co-administered with fluvoxamine in healthy postmenopausal women.

Responses in organs, sperm, steroid hormones and CYP450 enzyme in male mice treated by quinestrol only or in conjunction with clarithromycin

Pest rodents persistently undermine crop yields and food security. Fertility control could be a viable alternative for managing rodent populations. This study investigates the antifertility effects of various concentrations of clarithromycin combined with 1.0 mg/kg quinestrol on male rodents to determine an effective contraceptive dose that minimizes quinestrol usage, addressing key concerns such as potential environmental residue, which may impact ecological balance, and poor palatability, which could reduce ingestion and limit the sterilant’s effectiveness. Male mice were divided into five groups and administered different doses of clarithromycin or clarithromycin and quinestrol for three consecutive days, while the control group received sunflower seed oil only. After seven days, organ weights, reproductive organ weights, sperm density, serum hormone levels, and CYP3A4 content in small intestinal and liver tissues were measured to assess persistent effects. Compared with the control group, all treatment groups had significant reductions in epididymal weight, seminal vesicle weight, and serum T and LH levels. Higher concentrations of clarithromycin (2 mg/kg and 10 mg/kg) significantly impacted reproductive metrics, including sperm density, organ weights, and serum LH and testosterone levels, though complete sterilization was not achieved, with more than 60 million cauda epididymal spermatozoa remaining. However, the combination demonstrated potential as an effective strategy for male fertility control. The combination of 2.0 mg/kg clarithromycin and quinestrol can mitigate organ enlargement seen with quinestrol alone. This combination also decreased total enzyme content, thereby diminishing quinestrol’s induction of CYP3A4, which may increase the sterilization effectiveness of the treatment.

Clozapine Toxicity Predictor: Deep neural network model predicting clozapine toxicity and its therapeutic dose range

Clozapine is the gold standard for treatment-resistant schizophrenia; however, its superior efficacy is accompanied by potentially serious adverse events (neutropenia, seizures, constipations, pneumonia), many of which are also concentration-dependent. As such, clozapine dose titration should be guided by therapeutic drug monitoring (TDM). However, access to TDM is often limited. The present study describes a new deep neural network that can predict the concentrations, toxicity and therapeutic dose range for clozapine and norclozapine. The model was trained on basic clinical data (biological sex, age, clozapine daily dose, BMI, CRP and number of CYP 1A2 and 3A4 substrates, inhibitors and inducers) from 69 patients with treatment-refractory patients treated with different clozapine doses. Our findings provide the training efficacy data for the model, as well as an analysis of clozapine and norclozapine blood concentrations in a test group of three additional patients, to demonstrate its practical capabilities. The model is licensed on a free and permissive 2-Clause BSD license and is available to all clinicians; it can be accessed as a web application, available at https://csk.umed.pl/clotop.

Evaluation of drug-drug interactions of a novel potent FLT3 inhibitor SKLB1028 in healthy subjects.

SKLB1028 is a novel multi-target protein kinase inhibitor under investigation for the treatment of FLT3-ITD mutated acute myeloid leukemia. Based on the preclinical characterization of SKLB1028 metabolism, three drug-drug interaction clinical studies were performed to investigate the effects of itraconazole, rifampin (CYP3A4 inhibitor and inducer, respectively), and gemfibrozil (CYP2C8 inhibitor) on the metabolism of SKLB1028. Fourteen healthy Chinese male subjects were enrolled in each study. In Study 1, subjects were administered a single dose of SKLB1028 (100 mg on days 1 and 11) and multiple doses of itraconazole (200 mg twice daily on day 8 and 200 mg once daily from days 9 to 18). Itraconazole was given with a loading dose on Day 8 and the total administration of itraconazole was 11 days. In Study 2, subjects were administered a single dose of SKLB1028 (100 mg on days 1 and 12) and multiple doses of gemfibrozil (600 mg twice daily from days 8 to 19). In Study 3, subjects were administered a single dose of SKLB1028 (150 mg on days 1 and 15) and multiple doses of rifampin (600 mg once daily from day 8 to 22). Itraconazole increased the AUC and Cmax of SKLB1028 by approximately 28% and 41%, respectively. Compared to the single drug, co-administration with gemfibrozil increased the AUC of SKLB1028 by ~26% and the Cmax by ~21%. Co-administration with rifampin reduced the AUC of SKLB1028 by ~30%, while the Cmax did not change significantly. All treatments were well tolerated in all three studies.

Changes in Plasma Clearance of CYP450 Probe Drugs May Not be Specific for Altered In Vivo Enzyme Activity Under (Patho)Physiological Conditions: How to Interpret Findings of Probe Cocktail Studies.

CYP450 (CYP) phenotyping involves quantifying an individual's plasma clearance of CYP-specific probe drugs, as a proxy for in vivo CYP enzyme activity. It is increasingly applied to study alterations in CYP enzyme activity under various (patho)physiological conditions, such as inflammation, obesity, or pregnancy. The phenotyping approach assumes that changes in plasma clearance of probe drugs are driven by changes in CYP enzyme activity. However, plasma clearance is also influenced by protein binding, blood-to-plasma ratio, and hepatic blood flow, all of which may change under (patho)physiological conditions. Using a physiologically based pharmacokinetic (PBPK) workflow, we aimed to evaluate whether the plasma clearance of commonly used CYP probe drugs is indeed directly proportional to alterations in CYP enzyme activity (sensitivity), and to what extent alterations in protein binding, blood-to-plasma ratio, and hepatic blood flow observed under (patho)physiological conditions impact plasma clearance (specificity). Plasma clearance of CYP probe drugs is sensitive to alterations in CYP enzyme activity, since alterations in intrinsic clearance between - 90% and + 150% resulted in near-proportional changes in plasma clearance, except for midazolam in the case of > 50% CYP3A4 induction. However, plasma clearance also changed near-proportionally with alterations in the unbound drug fraction, diminishing probe specificity. This was particularly relevant for high protein-bound probe drugs, as alterations in plasma protein binding resulted in larger relative changes in the unbound drug fraction. Alterations in the blood-to-plasma ratio and hepatic blood flow of ± 50% resulted in plasma clearance changes of less than ± 16%, meaning they limitedly impacted plasma clearance of CYP probe drugs, except for midazolam. In order to correct for the impact of non-metabolic determinants on probe drug plasma clearance, an R script was developed to calculate how much the CYP enzyme activity is actually altered under (patho)physiological conditions, when alterations in the unbound drug fraction, blood-to-plasma ratio, and/or hepatic blood flow also impact probe drug plasma clearance. As plasma protein binding can change under (patho)physiological conditions, alterations in unbound drug fraction should be accounted for when using CYP probe drug plasma clearance as a proxy for CYP enzyme activity in patient populations. The tool developed in this study can support researchers in determining alterations in CYP enzyme activity in patients with (patho)physiological conditions.

Effect of CYP3A5*3 genotype on exposure and efficacy of quetiapine: A retrospective, cohort study

BackgroundThe involvement of cytochrome P450 3A5 (CYP3A5) in the metabolism of quetiapine has been proposed, though conclusive evidence is lacking. This study aimed to quantitatively assess the impact of CYP3A5 genetic variability on quetiapine exposure in a Chinese patient population. MethodsPatient data were retrospectively collected from the database of the Mental Health Centre at the First Hospital of Hebei Medical University, covering the period from September 1, 2019, to July 1, 2023. The study included patients genotyped for CYP3A5 who were treated with quetiapine. Inclusion criteria for the analysis of pharmacokinetic parameters, such as serum concentrations of the drug and its metabolites, included oral administration of quetiapine, availability of information on the prescribed daily dose and concomitant medications, and the determination of steady-state blood levels at the time of sampling (after at least 3 days of continuous administration at the same dose). Exclusion criteria comprised polypharmacy with known CYP3A4 inducers or inhibitors, as well as patients with hepatic or renal insufficiency. The primary endpoint was the exposure to quetiapine and N-dealkylquetiapine, measured using dose-corrected concentrations (C/D). The secondary endpoint was the metabolism of quetiapine to N-dealkylquetiapine, assessed by the ratio of metabolite to parent drug concentrations. The third endpoint is the differences in adverse reactions, QTc intervals, and biochemical parameters among patients with different CYP3A5 genotypes. ResultBased on the inclusion and exclusion criteria, clinical data from 207 patients were ultimately included in the study. Of these, 20 patients had the CYP3A5*1/*1 genotype, 78 had the CYP3A5*1/*3 genotype, and 109 had the CYP3A5*3/*3 genotype. The CYP3A5*3 variant was found to significantly impact the metabolism of quetiapine. The C/D values for both quetiapine and N-dealkyl quetiapine were notably higher in individuals with the *3/*3 genotype compared to those with the *1/*1 and *1/*3 genotypes (P1 < 0.001 and P2 = 0.002, respectively). A comparison of the variability in metabolic ratios among different genotype groups revealed no significant difference (P = 0.067). However, a post hoc analysis indicated that the metabolic ratio in poor metabolizers was significantly lower than that in intermediate metabolizers (P = 0.021). The analysis of adverse reaction incidence and QTc intervals among different genotypes showed no statistically significant differences (P = 0.652, P = 0.486). However, comparison of biochemical parameters across different genotype groups revealed that alanine aminotransferase, uric acid, hemoglobin, and gamma-glutamyl transferase levels were significantly higher in patients with the CYP3A5*3/*3 genotype compared to those with the CYP3A5*1/*1 and CYP3A5*1/*3 genotypes. ConclusionThe results indicated that the genetic polymorphism of CYP3A5*3 significantly influences the metabolism of quetiapine. Specifically, carriers of the CYP3A5*3/*3 genotype exhibited higher blood levels of quetiapine, with a greater likelihood of these levels exceeding the therapeutic range. This finding underscores the need for clinicians to pay special attention to the efficacy and occurrence of adverse reactions when prescribing quetiapine to patients carrying the CYP3A5*3/*3 genotype.

Building Confidence in Physiologically Based Pharmacokinetic Modeling of CYP3A Induction Mediated by Rifampin: An Industry Perspective.

Physiologically-based pharmacokinetic (PBPK) modeling offers a viable approach to predict induction drug-drug interactions (DDIs) with the potential to streamline or reduce clinical trial burden if predictions can be made with sufficient confidence. In the current work, the ability to predict the effect of rifampin, a well-characterized strong CYP3A4 inducer, on 20 CYP3A probes with publicly available PBPK models (often developed using a workflow with optimization following a strong inhibitor DDI study to gain confidence in fraction metabolized by CYP3A4, fm,CYP3A4, and fraction available after intestinal metabolism, Fg), was assessed. Substrates with a range of fm,CYP3A4 (0.086-1.0), Fg (0.11-1.0) and hepatic availability (0.09-0.96) were included. Predictions were most often accurate for compounds that are not P-gp substrates or that are P-gp substrates but that have high permeability. Case studies for three challenging DDI predictions (i.e., for eliglustat, tofacitinib, and ribociclib) are presented. Along with parameter sensitivity analysis to understand key parameters impacting DDI simulations, alternative model structures should be considered, for example, a mechanistic absorption model instead of a first-order absorption model might be more appropriate for a P-gp substrate with low permeability. Any mechanisms pertinent to the CYP3A substrate that rifampin might impact (e.g., induction of other enzymes or P-gp) should be considered for inclusion in the model. PBPK modeling was shown to be an effective tool to predict induction DDIs with rifampin for CYP3A substrates with limited mechanistic complications, increasing confidence in the rifampin model. While this analysis focused on rifampin, the learnings may apply to other inducers.

Quantitative Prediction of Drug-Drug Interactions Caused by CYP3A Induction Using Endogenous Biomarker 4β-Hydroxycholesterol.

Evaluation of the CYP3A induction risk is important in early drug development stages. This study focused on 4β-hydroxycholesterol (4β-HC) as an endogenous biomarker of drug-drug interactions (DDIs) caused by CYP3A induction. We investigated a new approach using 4β-HC for quantitative prediction of DDIs caused by CYP3A induction based on the mechanistic static pharmacokinetic (MSPK) model. The induction ratio, i.e., the ratio of plasma 4β-HC or 4β-HC/cholesterol (4β-HC/C) with and without a coadministered CYP3A inducer, and the ratio of the area under the plasma concentration-time curve (AUCR), i.e., the ratio of the AUC of plasma CYP3A substrate drugs with and without a coadministered CYP3A inducer, were collected. The scaling factor (d) in the MSPK model was calculated from the induction ratio of 4β-HC or 4β-HC/C based on the systemic term in the MSPK model. The AUCR of 18 CYP3A substrates with and without coadministration of seven CYP3A inducers were then predicted by substituting the calculated d value into the MSPK model. This approach showed that approximately 84% of the predicted AUCR values were within a twofold range of the observed values, showing that this approach can be a good tool to quantitatively predict DDIs caused by CYP3A induction. SIGNIFICANCE STATEMENT: A concise approach to predict drug interactions with adequate accuracy is preferable in the early drug development stage. In this study, a new approach using 4β-hydroxycholesterol for quantitative prediction of drug-drug interactions caused by CYP3A induction was investigated. The predictability was verified using seven CYP3A inducers and 18 substrates.

Characterization of rimegepant drug-drug interactions using the cytochrome P450 probe drugs, itraconazole, rifampin, fluconazole, and midazolam.

Reported here are the results of four rimegepant phase I studies, in healthy participants, aimed at determining the invivo potential of rimegepant (75 mg) for cytochrome P450 (CYP) 3A4-related drug-drug interactions (DDIs). Rimegepant orally disintegrating tablet (Pfizer Inc., New York, NY, USA) is a calcitonin gene-related peptide receptor antagonist approved for acute treatment of migraine and preventive treatment of episodic migraine. People with migraine commonly use multiple drug treatments, with the potential for DDIs. Each study was an open-label, single-arm, single-sequence, crossover study. Rimegepant was tested as a victim drug by separate co-administration of itraconazole (a strong CYP3A4 inhibitor and P-glycoprotein inhibitor) in Study 1, rifampin (a strong CYP3A4 inducer and moderate CYP2C9 inducer) in Study 2, and fluconazole (a strong CYP2C9 inhibitor and moderate CYP3A4 inhibitor) in Study 3, and as a perpetrator drug by co-administration with midazolam (a CYP3A4 substrate) in Study 4. Mean values of single-dose rimegepant maximum concentration (Cmax) and area under the curve from time 0 to infinity (AUC0-inf) increased with itraconazole co-administration (n = 22) by 1.42-fold (90% confidence interval [CI] 1.25-1.61) and by 4.14-fold (90% CI 3.87-4.44), respectively, and decreased with rifampin co-administration (n = 21) to 36% (90% CI 31.2-41.4%) and to 19% (90% CI 16.3-21.4%), respectively. Co-administration with fluconazole (n = 23) increased rimegepant mean AUC0-inf by 1.80-fold (90% CI 1.68-1.93), with no impact on Cmax (1.04-fold; 90% CI 0.94-1.15). Co-administration of rimegepant single dose (300 mg; n = 14) or multiple doses (150 mg/day; n = 14) increased the mean Cmax of midazolam by 1.38-fold (90% CI 1.13-1.67) and 1.53-fold (90% CI 1.32-1.78), respectively, and the AUC0-inf of midazolam by 1.86-fold (90% CI 1.58-2.19) and 1.91-fold (90% CI 1.63-2.25), respectively. Based on the magnitude of DDIs, these studies indicate the following: co-administration of rimegepant with a strong CYP3A4 inhibitor should be avoided; during co-administration with a moderate CYP3A4 inhibitor, another dose of rimegepant within 48 h should be avoided; co-administration of rimegepant with a strong or moderate CYP3A4 inducer should be avoided; CYP2C9 does not play a meaningful role in rimegepant metabolism; and there is no clinically meaningful CYP3A4 inhibition by rimegepant.

Induction of drug metabolizing enzyme and drug transporter expression by antifungal triazole pesticides in human HepaSH hepatocytes

Triazole pesticides are widely used fungicides, to which humans are rather highly exposed. They are known to activate drug-sensing receptors regulating expression of hepatic drug metabolizing enzymes and drug transporters, thus suggesting that the hepatic drug detoxification system is modified by these agrochemicals. To investigate this hypothesis, the effects of 9 triazole fungicides towards expression of drug metabolizing enzymes and transporters were characterized in cultured human HepaSH cells, that are human hepatocytes deriving from chimeric humanized liver TK-NOG mice. Most of triazoles used at 10 μM were found to act as inducers of cytochrome P-450 (CYP) 1A1, CYP1A2, CYP2B6, CYP3A4 and UDP-glucuronosyltransferase 1A1 mRNA levels and of CYP3A4 protein; some triazoles also enhanced mRNA expression of the canalicular transporters P-glycoprotein/MDR1, multidrug resistance-associated protein 2 and breast cancer resistance protein. Triazoles however concomitantly inhibited CYP2B6 and CYP3A4 activities and thus appeared as dual regulators of these CYPs, being both inducers of their expression and inhibitors of their activity. The inducing effect however predominated, at least for bromuconazole, propiconazole and tebuconazole. Bromuconazole was moreover predicted to enhance CYP2B6 and CYP3A4 expression in humans exposed to this fungicide in a chronic, acute or occupational context. These data demonstrate that key-actors of the human hepatic detoxification system are impacted by triazole pesticides, which may have to be considered for the risk assessment of these agrochemicals. They additionally highlight that the use of human HepaSH cells as surrogates to primary human hepatocytes represents an attractive and promising way for studying hepatic effects of environmental chemicals.

Prediction of Pharmacokinetic Drug-Drug Interactions Involving Anlotinib as a Victim by Using Physiologically Based Pharmacokinetic Modeling.

Anlotinib was approved as a third line therapy for advanced non-small cell lung cancer in China. However, the impact of concurrent administration of various clinical drugs on the drug-drug interaction (DDI) potential of anlotinib remains undetermined. As such, this study aims to evaluate the DDI of anlotinib as a victim by establishing a physiologically based pharmacokinetic (PBPK) model. The PBPK model of anlotinib as a victim drug was constructed and validated in the Simcyp® incorporating parameters derived from in vitro studies, pre-clinical investigations, and clinical research encompassing patients with cancer. Subsequently, plasma exposure of anlotinib in cancer patients was predicted for single- and multi-dose co-administration with typical perpetrators mentioned in Food and Drug Administration (FDA) industrial guidance. Based on predictions, the CYP3A potent inhibitor ketoconazole demonstrated the most significant DDI with anlotinib, regardless of whether anlotinib is administered as a single dose or multiple doses. Ketoconazole increased the area under the concentration-time curve (AUC) and maximum concentration (Cmax) of single-dose anlotinib to 1.41-fold and 1.08-fold, respectively. In contrast, rifampicin, a potent inducer of CYP3A enzymes, exhibited a relatively higher level of DDI, with AUCR and CmaxR values of 0.44 and 0.79, respectively. Based on the PBPK modeling, there is a low risk of DDI between anlotinib and potent CYP3A/1A2 inhibitors, but caution and enhanced monitoring for adverse reactions are advised. To mitigate the risk of anti-tumor treatment failure, it is recommended to avoid concurrent use of strong CYP3A inducers. In conclusion, our study enhances understanding of anlotinib's interaction with medications, aiding scientists, prescribers, and drug labels in gauging the expected impact of CYP3A/1A2 modulators on anlotinib's pharmacokinetics.

Applications of the Cholesterol Metabolite, 4β-Hydroxycholesterol, as a Sensitive Endogenous Biomarker for Hepatic CYP3A Activity Evaluated within a PBPK Framework

Background/Objectives: Plasma levels of 4β-hydroxycholesterol (4β-OHC), a CYP3A-specific metabolite of cholesterol, are elevated after administration of CYP3A inducers like rifampicin and carbamazepine. To simulate such plasma 4β-OHC increase, we developed a physiologically based pharmacokinetic (PBPK) model of cholesterol and 4β-OHC in the Simcyp PBPK Simulator (Version 23, Certara UK Ltd.) using a middle-out approach. Methods: Relevant physicochemical properties and metabolic pathway data for CYP3A and CYP27A1 was incorporated in the model. Results: The PBPK model recovered the observed baseline plasma 4β-OHC levels in Caucasian, Japanese, and Korean populations. The model also captured the higher baseline 4β-OHC levels in females compared to males, indicative of sex-specific differences in CYP3A abundance. More importantly, the model recapitulated the increased 4β-OHC plasma levels after multiple-dose rifampicin treatment in six independent studies, indicative of hepatic CYP3A induction. The verified model also captured the altered 4β-OHC levels in CYP3A4/5 polymorphic populations and with other CYP3A inducers. The model is limited by scant data on relative contributions of CYP3A and CYP27A1 pathways and does not account for regulatory mechanisms that control plasma cholesterol and 4β-OHC levels. Conclusion: This study provides a quantitative fit-for-purpose and framed-for-future modelling framework for an endogenous biomarker to evaluate the DDI risk with hepatic CYP3A induction.

The effects of photochemical aging and interactions with secondary organic aerosols on cellular toxicity of combustion particles

Fine particulate matter (PM2.5) is associated with numerous adverse health effects, including pulmonary and cardiovascular diseases and premature death. Significant contributors to ambient PM2.5 include combustion particles and secondary organic aerosols (SOA). Combustion particles enter the atmosphere and undergo an aging process that changes their shape and composition, but there is limited study on the health effects of combustion particle aging and interactions with SOA. This study aimed to understand how biological responses to combustion particles would be affected by atmospheric aging and interaction with anthropogenic SOA. Fresh combustion particles underwent photochemical aging in a potential aerosol mass (PAM) oxidation flow reactor and interacted with SOA produced by the oxidation of toluene vapor in the PAM reactor. Photochemical aging and SOA interactions lead to significant changes in the PAH content and oxidative potential of the particle. Photochemical aging and SOA interactions also affected the biological responses, such as the inflammatory response and CYP1A1 induction of the particles in monoculture and coculture cells. These findings highlight the significance of photochemical aging and SOA interactions on the composition and cellular responses of combustion particles.

Targeting Calcitriol Metabolism in Acute Vitamin D Toxicity-A Comprehensive Review and Clinical Insight.

High-dose vitamin D supplementation is common in the general population, but unsupervised high-dose supplementation in vitamin D-replete individuals poses a risk of severe toxicity. Susceptibility to vitamin D toxicity shows a significant inter-individual variability that may in part be explained by genetic predispositions (i.e., CYP24A1 polymorphism). The classic manifestation of vitamin D toxicity is hypercalcemia, which may be refractory to conventional therapy. Its causes include the endogenous overaction of 1α-hydroxylase, monogenic alterations affecting vitamin D metabolizing enzymes and exogenous vitamin D intoxication. In this manuscript, we include a literature review of potential pharmacological interventions targeting calcitriol metabolism to treat vitamin D intoxication and present a case of severe, exogenous vitamin D intoxication responding to systemic corticosteroids after the failure of conventional therapy. Systemic glucocorticoids alleviate acute hypercalcemia by inhibiting enteric calcium absorption and increasing the degradation of vitamin D metabolites but may cause adverse effects. Inhibitors of 1α-hydroxylase (keto/fluconazole) and inducers of CYP3A4 (rifampicin) may be considered steroid-sparing alternatives for the treatment of vitamin D intoxication.

Mammalian Target of Rapamycin Inhibitor Levels Decrease Under Cenobamate Treatment

BackgroundEverolimus therapy has been approved in Tuberous Sclerosis Complex (TSC), for drug-resistant epilepsy as adjunctive therapy. A novel anti-seizure medication is cenobamate, which was approved for adults as adjunctive treatment for focal-onset seizures in drug-resistant epilepsy and is now commonly used in patients with TSC. Drug-drug interactions between cenobamate and mammalian target of rapamycin (mTORi) have not been prospectively evaluated, even though these agents are frequently administered together. MethodsWe performed a retrospective analysis of patients with TSC and compared mTORi drug levels before and after treatment initiation with cenobamate. ResultsWe evaluated 20 patients with clinically diagnosed TSC (male: 55%, female: 45%) with a median current age at last visit of 17.0 years (range: 4-41 years, interquartile range [IQR]: 12.5 years). All patients received mTORi treatment of either everolimus (N = 12, 60%) or sirolimus (N = 8, 40%). Cenobamate treatment led to seizure freedom in 2 patients (10%), reduction of seizures in 9 patients (45%) and no change in seizure frequency in 9 patients (45%). Median maximal cenobamate dose was 200 mg (range: 100-500 mg, IQR: 262.5 mg), for example, 3.2 mg/kg/day (range: 0.8-9.5 mg/kg/day, IQR: 3.2 mg/kg/day). Median everolimus levels decreased significantly after cenobamate initiation from 5.1 ng/ml (range: 1.9-11.6 ng/ml, IQR: 3.8 ng/ml) to 3.4 ng/ml (range: 1-7.9 ng/ml, IQR: 1.7 ng/ml, P = 0.01221). The median sirolimus level did not decrease significantly (P = 0.3828). ConclusionEverolimus levels decreased following cenobamate initiation. This is likely due to CYP3A4 induction of cenobamate. We recommend monitoring of serum plasma levels of mTORi co-administered with cenobamate and adjustment of mTORi doses accordingly.

Safety, tolerability and pharmacokinetics of the phosphodiesterase 2 inhibitor BI 474121: An overview of phase I randomized trials in healthy volunteers.

Cognitive impairment associated with schizophrenia predicts poor functional outcomes, but currently no efficacious pharmacotherapies are available. Four phase I trials examined the safety, tolerability and pharmacokinetics of the phosphodiesterase 2 inhibitor BI 474121, along with potential drug-drug interactions. Trial 1 evaluated single rising doses (SRDs) of BI 474121 versus placebo in healthy males. The influence of drug formulation and food on drug bioavailability was also examined. Trial 2 evaluated SRD of BI 474121 versus placebo in healthy Japanese males. Trial 3 evaluated multiple rising doses of BI 474121 in healthy young (with/without midazolam) and elderly (without midazolam) participants versus placebo. Trial 4 investigated interactions between itraconazole and single-dose BI 474121 in healthy males. No deaths, serious adverse events (AEs), severe AEs or protocol-specified AEs of special interest were observed. BI 474121 absorbed rapidly during fasting, achieved maximum concentration of analyte in plasma and dose proportionality via tablet formulation, and decreased in a multiphasic manner. BI 474121 steady state occurred within 11 days of multiple oral administration. Multiple doses increased BI 474121 plasma concentrations, but did not alter the time course of plasma concentrations. Urinary excretion of unchanged BI 474121 was negligible. No clinically relevant inhibition or induction of CYP3A4 by BI 474121 was observed. Itraconazole co-administration produced higher exposures of BI 474121 versus BI 474121 alone. BI 474121 demonstrated favourable safety and pharmacokinetic profiles in healthy Caucasian and Japanese individuals, supporting further clinical development.

Concomitant Administration of Psychotropic and Prostate Cancer Drugs: A Pharmacoepidemiologic Study Using Drug-Drug Interaction Databases.

Prostate cancer (PC) represents the second most common diagnosed cancer in men. The burden of diagnosis and long-term treatment may frequently cause psychiatric disorders in patients, particularly depression. The most common PC treatment option is androgen deprivation therapy (ADT), which may be associated with taxane chemotherapy. In patients with both PC and psychiatric disorders, polypharmacy is frequently present, which increases the risk of drug-drug interactions (DDIs) and drug-related adverse effects. Therefore, this study aimed to conduct a pharmacoepidemiologic study of the concomitant administration of PC drugs and psychotropics using three drug interaction databases (Lexicomp®, drugs.com®, and Medscape®). This study assayed 4320 drug-drug combinations (DDCs) and identified 814 DDIs, out of which 405 (49.63%) were pharmacokinetic (PK) interactions and 411 (50.37%) were pharmacodynamic (PD) interactions. The most common PK interactions were based on CYP3A4 induction (n = 275, 67.90%), while the most common PD interactions were based on additive torsadogenicity (n = 391, 95.13%). Proposed measures for managing the identified DDIs included dose adjustments, drug substitutions, supplementary agents, parameters monitoring, or simply the avoidance of a given DDC. A significant heterogenicity was observed between the selected drug interaction databases, which can be mitigated by cross-referencing multiple databases in clinical practice.

Pharmacokinetics of olverembatinib (HQP1351) in the presence of a strong CYP3A4 inhibitor (itraconazole) or inducer (rifampin) in healthy volunteers.

Olverembatinib (HQP1351) is a BCR-ABL1 tyrosine kinase inhibitor with promising clinical activity. It is approved in China for the treatment of patients with chronic myeloid leukemia harboring drug-resistant mutations, such as T315I. Invitro studies suggested that metabolism of olverembatinib is primarily mediated by cytochrome P450 (CYP3A4). The effects of CYP3A4 inhibition and induction on the pharmacokinetics of olverembatinib were evaluated in an open-label, 2-part, fixed-sequence study in healthy volunteers. In Part 1 of this study, 16 participants received a single oral dose of olverembatinib (20 mg) and the oral CYP3A4 inhibitor itraconazole (200 mg). In Part 2, 16 participants received a single oral dose of olverembatinib (40 mg) and the oral CYP3A4 inducer rifampin (600 mg). To measure pharmacokinetic parameters, serial blood samples were collected after administration of olverembatinib alone and combined with itraconazole or rifampin. Coadministration of olverembatinib with itraconazole increased the peak plasma concentration of olverembatinib, its area under the time-concentration curve (AUC)0-last, and AUC0-inf by 75.63%, 147.06%, and 158.66%, respectively. Coadministration with rifampin decreased these same variables by 61.27%, 74.21%, and 75.19%, respectively. These results confirm that olverembatinib is primarily metabolized by CYP3A4 in humans, suggesting that caution should be exercised with concurrent use of olverembatinib and strong CYP3A4 inhibitors or inducers.

Determination of anamorelin concentration in human plasma using a simple high-performance liquid chromatography-ultraviolet detection method.

Anamorelin, a non-peptide ghrelin analog and growth hormone secretagogue, is a novel oral drug used to treat cancer cachexia. Patients with cancer cachexia frequently use several drugs and anamorelin is a substrate of cytochrome P450 (CYP) 3A4; therefore, drug-drug interactions with CYP3A4 inhibitors and inducers pose a clinical problem. In this study, we aimed to determine the concentration of anamorelin in human plasma using a simple high-performance liquid chromatography-ultraviolet (HPLC-UV)-based method. The analysis involved extracting a 200-μL plasma sample and protein precipitation using solid-phase extraction. Anamorelin was isocratically separated using a mobile phase consisting of 0.5% potassium dihydrogen phosphate (pH 4.5) and acetonitrile (61:39, v/v) on a Capcell Pack C18 MG II column (250 mm × 4.6 mm) at a flow rate of 1.0 mL/min and monitored at a detection wavelength of 220 nm. The calibration curve was linear within a plasma concentration range of 12.5-1,500 ng/mL, with a coefficient of determination of 0.9999. The intra- and inter-day coefficients of variation were 0.37-6.71% and 2.05-4.77%, respectively. The accuracy of the assay and recovery were 85.25-112.94% and > 86.58%, respectively. This proposed HPLC-UV method is simple and can be applied in clinical settings.