Effect of Dexamethasone on CYP Enzyme Activity in Healthy Male Subjects

Официальное название

A Clinical Study Evaluating the Effects of Dexamethasone on the Activities of CYP2C9, CYP2C19, and CYP3A4 Substrates in Healthy Male Subjects

Обзор

Purpose: The purpose of this study is to understand how dexamethasone affects the activity of drug-metabolizing enzymes in the body and how this may influence interactions with other medicines, such as voriconazole. Background: Many medicines are broken down in the body by enzymes called cytochrome P450 (CYP) enzymes. Differences in CYP enzyme activity between individuals can lead to variability in drug response and drug-drug interactions. Dexamethasone is known to affect CYP enzyme activity, and voriconazole is a medication that is metabolized by these enzymes. Participants: This study will include a total of 12 healthy adult male volunteers. Participants will be grouped based on their metabolic status, including 6 normal metabolizers (NM) and 6 poor metabolizers (PM). Interventions: Participants will receive a combination of probe drugs known as a CYP probe cocktail to assess baseline CYP enzyme activity. Dexamethasone will be administered, and the CYP probe cocktail will be given again to evaluate changes in enzyme activity. Voriconazole will be used to assess the potential for drug-drug interactions related to changes in CYP enzyme activity. Blood samples will be collected during the study. Outcome Measures: The main outcomes of this study are changes in blood concentrations of the probe drugs, which reflect changes in CYP enzyme activity, and comparisons of these changes between normal metabolizers and poor metabolizers. Hypothesis: The study hypothesizes that dexamethasone alters CYP enzyme activity and that the magnitude of this effect differs between normal metabolizers and poor metabolizers, potentially affecting the metabolism of drugs such as voriconazole.

Подробное описание

This study is designed as an open-label, single-sequence clinical pharmacology study to evaluate the effects of dexamethasone on cytochrome P450 (CYP) enzyme activity in healthy adult male volunteers.

CYP enzyme activity will be assessed using a validated CYP probe cocktail consisting of multiple probe substrates administered concurrently to evaluate the functional activity of selected CYP isoforms. The probe cocktail will be administered at baseline to characterize individual CYP enzyme activity prior to dexamethasone exposure.

Following baseline assessment, dexamethasone will be administered for a predefined period. After completion of dexamethasone administration, the CYP probe cocktail will be administered again to evaluate changes in CYP enzyme activity induced by dexamethasone. Voriconazole, a CYP-metabolized drug, will be included to assess the potential impact of dexamethasone-induced enzyme modulation on clinically relevant drug-drug interactions.

Serial blood samples will be collected after administration of the probe cocktail and voriconazole to determine pharmacokinetic parameters, including maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC). Changes in these parameters before and after dexamethasone administration will be used as indicators of alterations in CYP enzyme activity.

Participants will be stratified based on CYP2C19 genotype into normal metabolizers (NM) and poor metabolizers (PM). Comparative analyses will be conducted between these groups to explore the influence of genetic polymorphism on dexamethasone-induced changes in CYP enzyme activity.

The results of this study are expected to provide mechanistic insight into dexamethasone-mediated modulation of CYP enzymes and its potential implications for drug-drug interactions involving CYP-metabolized medications.

Вмешательства

• Препарат Dexamethasone
  Dexamethasone will be administered orally to evaluate its effect on cytochrome P450 enzyme activity.
• Препарат CYP Probe Cocktail
  A CYP probe cocktail composed of approved, commercially available drugs (caffeine, flurbiprofen, omeprazole, and midazolam) will be administered concomitantly as a single-dose cocktail to phenotypically assess cytochrome P450 enzyme activities before and after dexamethasone administration.
• Препарат voriconazole
  Voriconazole will be administered to assess drug-drug interactions associated with changes in cytochrome P450 enzyme activity.

Первичные конечные точки

• Cmax of CYP Probe Substrates(Voriconazole, Midazolam, Omeprazole, Flurbiprofen) [Срок оценки: Up to the last PK sampling time (Period 2 Day 9 for voriconazole; Period 2 Day 8 for midazolam, omeprazole, and flurbiprofen)]
• AUClast of CYP Probe Substrates(Voriconazole, Midazolam, Omeprazole, Flurbiprofen) [Срок оценки: Up to the last PK sampling time (Period 2 Day 9 for voriconazole; Period 2 Day 8 for midazolam, omeprazole, and flurbiprofen)]
• AUCinf of CYP Probe Substrates(Voriconazole, Midazolam, Omeprazole, Flurbiprofen) [Срок оценки: Up to the last PK sampling time (Period 2 Day 9 for voriconazole; Period 2 Day 8 for midazolam, omeprazole, and flurbiprofen)]

Вторичные конечные точки (12)

• Tmax of Perpetrator(Dexamethasone) [Срок оценки: Up to the last PK sampling time (Period 2 Day 9 )]
• Cmax of Perpetrator(Dexamethasone) [Срок оценки: Up to the last PK sampling time (Period 2 Day 9 )]
• AUCtau of Perpetrator(Dexamethasone) [Срок оценки: Up to the last PK sampling time (Period 2 Day 9 )]
• t1/2 of Perpetrator(Dexamethasone) [Срок оценки: Up to the last PK sampling time (Period 2 Day 9 )]
• CL/F of Perpetrator(Dexamethasone) [Срок оценки: Up to the last PK sampling time (Period 2 Day 9 )]
• Vz/F of Perpetrator(Dexamethasone) [Срок оценки: Up to the last PK sampling time (Period 2 Day 9 )]
• Tmax,ss of Perpetrator(Dexamethasone) [Срок оценки: Up to the last PK sampling time (Period 2 Day 9 )]
• Cmax,ss of Perpetrator(Dexamethasone) [Срок оценки: Up to the last PK sampling time (Period 2 Day 9 )]
• Cmin,ss of Perpetrator(Dexamethasone) [Срок оценки: Up to the last PK sampling time (Period 2 Day 9 )]
• Cavg,ss of Perpetrator(Dexamethasone) [Срок оценки: Up to the last PK sampling time (Period 2 Day 9 )]
• AUCtau,ss of Perpetrator(Dexamethasone) [Срок оценки: Up to the last PK sampling time (Period 2 Day 9 )]
• t1/2,ss of Perpetrator(Dexamethasone) [Срок оценки: Up to the last PK sampling time (Period 2 Day 9 )]

Критерии участия

\[Inclusion Criteria\]

• Healthy male volunteers aged 19 to 50 years, inclusive, at the time of screening.
• Body weight between 50.0 kg and 90.0 kg, and body mass index (BMI) between 18.5 kg/m² and 29.9 kg/m² at the time of screening.

\- BMI (kg/m²) = body weight (kg) / \[height (m)\]²

• Subjects with a CYP2C19 genotype classified as either normal metabolizers (\*1/\*1) or poor metabolizers (\*2/\*2, \*2/\*3, 3/3) based on genotyping results.
• Subjects who have received sufficient explanation of the study, fully understood the study procedures, voluntarily agreed to participate, and provided written informed consent prior to any study-related procedures.

\[Exclusion Criteria\]

• Subjects with any clinically significant disease or medical history involving the hepatobiliary, renal, neurological, immunological, respiratory, gastrointestinal, endocrine, hematologic/oncologic, cardiovascular (including heart failure and Torsades de pointes), urogenital, psychiatric (including mood disorders and obsessive-compulsive disorder), or sexual dysfunction systems.
• Subjects with a history of gastrointestinal diseases (e.g., Crohn's disease, ulcer, gastritis, gastric spasm, gastroesophageal reflux disease) or gastrointestinal surgery that may affect the safety or pharmacokinetics of the investigational products, except for uncomplicated appendectomy or hernia repair.
• Subjects with known hypersensitivity or clinically significant allergic reactions to any components of the investigational products or to other drugs (e.g., aspirin, antibiotics).
• Subjects with hereditary disorders, including sucrase-isomaltase deficiency, galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.
• Subjects who have received any live vaccine within 6 months prior to screening.
• Subjects with a history of active infection (including herpes simplex, herpes zoster, varicella, or systemic fungal infection) within 4 weeks prior to screening, or with evidence of ongoing infection at screening.
• Subjects without a history of varicella or measles infection and who have not been vaccinated against these diseases.
• Subjects with active or latent tuberculosis.
• Subjects with positive serologic test results for hepatitis B, hepatitis C, human immunodeficiency virus (HIV), or syphilis.
• Subjects with a history of drug abuse or a positive urine drug screening test for drugs of abuse at screening.
• Subjects with the following vital sign abnormalities measured in the seated position after at least 3 minutes of rest at screening:

• Systolic blood pressure ≤ 90 mmHg or ≥ 150 mmHg
• Diastolic blood pressure ≤ 60 mmHg or ≥ 100 mmHg
• Subjects with a QTc interval > 450 msec or any clinically significant abnormal cardiac rhythm on a 12-lead electrocardiogram (ECG) at screening.
• Subjects with any of the following clinically significant laboratory abnormalities at screening (including additional confirmatory tests):

• AST or ALT > 60 IU/L
• Estimated glomerular filtration rate (eGFR, CKD-EPI equation) < 90 mL/min/1.73 m²
• Fasting plasma glucose ≥ 126 mg/dL
• Subjects who have taken any prescription medications or herbal medicines within 2 weeks, or any over-the-counter medications (OTC), dietary supplements, functional foods, or vitamin products (including liver function supplements) within 1 week prior to the first planned dose of the investigational product, or who are expected to require such products during the study period (except when deemed acceptable by the investigator).
• Subjects who have taken enzyme-inducing drugs (e.g., barbiturates) or enzyme-inhibiting drugs (e.g., clarithromycin) within 1 month prior to the first planned dose of the investigational product.
• Subjects who have participated in another clinical trial (including bioequivalence studies) and received any investigational product within 6 months prior to the first planned dose.
• Subjects who have donated whole blood within 2 months, donated blood components within 1 month, or received a blood transfusion within 6 months prior to the first planned dose.
• Current smokers, unless smoking cessation occurred at least 3 months prior to the first planned dose of the investigational product.
• Subjects with chronic alcohol consumption exceeding 21 units per week (1 unit = 10 g of pure alcohol), or who are unable to abstain from alcohol from 3 days prior to the first dose until the end of the study.
• Subjects with excessive habitual caffeine intake (> 5 units per day; 1 unit = 80 mg caffeine), or who are unable to refrain from consuming caffeine-containing foods and beverages (e.g., coffee, tea, carbonated beverages, coffee milk, tonic drinks, energy drinks) from 3 days prior to the first dose until the end of the study.
• Subjects who have consumed grapefruit, grapefruit juice, or grapefruit-containing products from 3 days prior to the first dose until the end of the study, or who are unable to refrain from consuming such products during this period.
• Subjects with unusual dietary habits (e.g., consumption of more than 1 L of grapefruit juice per day) or who are unable to consume the standardized meals provided by the study site during the confinement period.
• Subjects who do not agree to use condoms, and whose female partners of childbearing potential do not agree to use a highly effective method of contraception from 3 days prior to the first dose until the end of the study.

<Highly effective methods of contraception include>

• Combined hormonal contraception associated with inhibition of ovulation (oral, vaginal, transdermal)
• Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable)
• Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)
• Bilateral tubal occlusion or a vasectomized partner
• Sexual abstinence, defined as refraining from heterosexual intercourse throughout the entire period of risk
• Subjects who do not agree to refrain from sperm donation from 3 days prior to the first dose until the end of the study.
• Subjects who are deemed unsuitable for participation in the study at the investigator's discretion for any reason not otherwise specified above.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Да

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Список центров уточняется — проверьте первичный протокол.

Идентификаторы

NCT: NCT07426042 · Dexamethasone_cocktail

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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