Efavirenz for Healthy Subjects

Overseen By Toll Free Number

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Merck Sharp & Dohme LLC

Disqualifiers: Cancer, HIV, Hepatitis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 6 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to understand how the new drug, MK-7602, behaves in the body under various conditions. Researchers will evaluate the drug's effects when taken with or without efavirenz (an antiretroviral drug) and with different types of meals. As a Phase 1 trial, the focus is on assessing safety and the drug’s effects in healthy individuals. Those who are generally healthy, with no significant health issues and a body-mass index (BMI) between 18 and 32, may be suitable for this study. Participants will be among the first to receive this new treatment, contributing to essential research on its safety and effects.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that MK-7602 was tested for safety in healthy adults in earlier studies, focusing on its use as a treatment for malaria. The results indicated that participants generally tolerated MK-7602 well, with no serious side effects reported.

Efavirenz has FDA approval for treating HIV-1 infection. While it is usually safe for most patients, some have reported side effects like dizziness and trouble sleeping. These effects are typically mild and temporary but should be monitored.

Both MK-7602 and efavirenz have safety data from previous studies, suggesting they are tolerated by most people. However, since this is an early-phase trial, it remains important to assess safety when these two drugs are used together. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about MK-7602, especially when combined with efavirenz, because it offers a potentially new approach to managing conditions that are typically treated with standard antiretroviral therapies. Unlike other treatments that mainly focus on suppressing viral replication, MK-7602 could introduce an innovative mechanism that enhances the effects of existing medications like efavirenz. Its administration alongside different dietary conditions could also provide insights into optimizing treatment efficacy and patient adherence. This trial aims to explore how these factors might improve overall treatment outcomes, making it a promising area of study.

What evidence suggests that this trial's treatments could be effective?

Research has shown that MK-7602 is under investigation for its potential to combat malaria. In earlier studies, MK-7602 showed promise in targeting malaria parasites in healthy adults. However, more evidence is needed to confirm its effectiveness in treating malaria in humans.

Efavirenz is a well-known medication for treating HIV-1 infection. Studies have proven its effectiveness as a first-choice treatment, helping many patients control the virus.

This trial examines how MK-7602 functions in the body under different conditions. In Part 1, participants will receive a combination of MK-7602 and efavirenz to assess any interactions. In Part 2, participants will receive MK-7602 alone under various dietary conditions to evaluate its pharmacokinetics. The aim is to determine if using these drugs together affects their efficacy or safety. ^{6 7 8 9 10}

Who Is on the Research Team?

Medical Director

Principal Investigator

Merck Sharp & Dohme LLC

Are You a Good Fit for This Trial?

This trial is for healthy individuals with a BMI between 18 to 32 kg/m^2. Specific details about who can't join the trial are not provided, but typically participants must meet certain health standards and not be taking conflicting medications.

Inclusion Criteria

My BMI is between 18 and 32.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive MK-7602 with or without efavirenz to study pharmacokinetics

6 weeks

Multiple visits for blood sample collection

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Efavirenz
• MK-7602

Trial Overview The study investigates how MK-7602 levels change over time in the body of a healthy person when taken alone or combined with another drug called efavirenz. It's designed to understand the interaction between these two substances.

How Is the Trial Designed?

Group I: Part 2, Sequence 6: Low-Fat Meal→Moderate-Fat Meal→Fasted Experimental Treatment 1 Intervention

Participants will be administered MK-7602 with a low-fat meal, then with a moderate-fat meal, then in the fasted state.

Group II: Part 2, Sequence 5: Low-Fat Meal→Fasted→Moderate-Fat Meal Experimental Treatment 1 Intervention

Participants will be administered MK-7602 with a low-fat meal, then in the fasted state, then with a moderate-fat meal.

Group III: Part 2, Sequence 4: Moderate-Fat Meal→Fasted→Low-Fat Meal Experimental Treatment 1 Intervention

Participants will be administered MK-7602 with a moderate-fat meal, then in the fasted state, then with a low-fat meal.

Group IV: Part 2, Sequence 3: Moderate-Fat Meal→Low-Fat Meal→Fasted Experimental Treatment 1 Intervention

Participants will be administered MK-7602 with a moderate-fat meal, then with a low-fat meal, then in the fasted state.

Group V: Part 2, Sequence 2: Fasted→Low-Fat Meal→Moderate-Fat Meal Experimental Treatment 1 Intervention

Participants will be administered MK-7602 in the fasted state, then with a low-fat meal, then with a moderate-fat meal.

Group VI: Part 2, Sequence 1: Fasted→Moderate-Fat Meal→Low-Fat Meal Experimental Treatment 1 Intervention

Participants will be administered MK-7602 in the fasted state, then with a moderate-fat meal, then with a low-fat meal.

Group VII: Part 1: MK-7602 + Efavirenz Experimental Treatment 2 Interventions

Participants will be administered MK-7602 and efavirenz.

Who Is Running the Clinical Trial?

Merck Sharp & Dohme LLC

Lead Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Published Research Related to This Trial

A population pharmacokinetic model developed from 96 HIV-positive individuals revealed that genetic variations in the CYP2B6 gene significantly influence the clearance of efavirenz (EFV), with homozygous mutated individuals requiring dose adjustments due to lower clearance rates.

The study found that demographic factors and hepatitis C virus-HIV coinfection did not significantly affect EFV pharmacokinetics, emphasizing the importance of genetic testing for personalized dosing in HIV treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population Approach to Efavirenz Therapy. Duarte, H., Cruz, JP., Aniceto, N., et al.[2020]

Efavirenz has been a key medication in HIV treatment since 1996, showing strong efficacy in both treatment-naïve and treatment-experienced patients, supported by numerous clinical studies.

The introduction of a single 600 mg tablet formulation simplifies the treatment regimen, potentially improving patient adherence and outcomes, while its side effects are generally mild and manageable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efavirenz: enhancing the gold standard. Arribas, JR.[2020]

A new high-performance liquid chromatography method has been developed to accurately measure efavirenz levels in human plasma, which is crucial for monitoring HIV treatment in patients.

This method is highly reliable, with a low limit of quantitation of 10 ng/ml and a recovery rate of 106.4%, making it suitable for use in hospital laboratories to ensure effective dosing of efavirenz.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quantitative determination of efavirenz (DMP 266), a novel non-nucleoside reverse transcriptase inhibitor, in human plasma using isocratic reversed-phase high-performance liquid chromatography with ultraviolet detection. Veldkamp, AI., van Heeswijk, RP., Meenhorst, PL., et al.[2020]

A study involving 41 healthy subjects demonstrated that the generic efavirenz capsule formulation is bioequivalent to the innovator product, Sustiva, with similar pharmacokinetic profiles, indicating comparable effectiveness in treating HIV.

Both formulations showed similar safety profiles, with adverse events occurring at similar rates, supporting the use of the generic version as a viable alternative to the branded medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative bioavailability of a generic capsule formulation of the reverse transcriptase inhibitor efavirenz and the innovator product. Marier, JF., Morin, I., Al-Numani, D., et al.[2020]

In a study of 606 treatment-naïve patients, daily efavirenz 400 mg (EFV400) was found to be as effective as 600 mg (EFV600) in suppressing HIV viral load after 48 weeks, with 97% of patients on EFV400 achieving viral loads below 200 copies/mL.

Despite lower drug exposure with EFV400, the efficacy in terms of HIV suppression was comparable to EFV600, suggesting that the previously accepted threshold concentration for efavirenz may need reevaluation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic and Pharmacodynamic Comparison of Once-Daily Efavirenz (400 mg vs. 600 mg) in Treatment-Naïve HIV-Infected Patients: Results of the ENCORE1 Study. Dickinson, L., Amin, J., Else, L., et al.[2022]

In a study of 1,033 HIV-infected adults starting efavirenz treatment, 29.3% experienced adverse events (AEs), primarily CNS disturbances, but these were generally not severe and led to treatment interruption in only 8.23% of cases.

The safety profile of efavirenz is favorable even among a population with a high rate of intravenous drug use, with no significant associations found between prior psychiatric issues or drug use and increased AEs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerance of efavirenz in different antiretroviral regimens: results from a national multicenter prospective study in 1,033 HIV-infected patients. Pérez-Molina, JA.[2022]

Efavirenz has been a key treatment for HIV-1 since the late 1990s, demonstrating strong efficacy in numerous clinical trials compared to other antiretroviral therapies, making it a cornerstone of HIV treatment.

While efavirenz is generally well-tolerated and allows for convenient once-daily dosing, it can cause CNS-related side effects, and ongoing research into its pharmacokinetics may help manage these adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efavirenz for HIV-1 infection in adults: an overview. Fortin, C., Joly, V.[2020]

In a study of 606 treatment-naïve HIV-infected adults, daily efavirenz 400 mg (EFV400) was found to be effective in maintaining viral suppression, with no significant association between efavirenz pharmacokinetics and achieving a plasma HIV-RNA level of less than 200 copies/mL after 96 weeks.

The study identified genetic polymorphisms that influenced the risk of central nervous system-related adverse events, suggesting that the CYP2B6 983TC/CC genotype may lower the risk, while CYP2B6 15582CT/TT and ABCB1 3435TT genotypes may increase it, indicating the importance of genetic factors in efavirenz safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comprehensive Pharmacokinetic, Pharmacodynamic and Pharmacogenetic Evaluation of Once-Daily Efavirenz 400 and 600 mg in Treatment-Naïve HIV-Infected Patients at 96 Weeks: Results of the ENCORE1 Study. Dickinson, L., Amin, J., Else, L., et al.[2022]

A study involving 235 HIV-positive patients revealed significant interpatient variability in efavirenz levels, suggesting that individual plasma concentration monitoring could optimize dosing and improve treatment outcomes.

The research found a correlation between higher efavirenz exposure and lower viral loads, as well as a potential link to central nervous system toxicity, indicating that careful dosage adjustments could enhance efficacy while minimizing side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population pharmacokinetics and effects of efavirenz in patients with human immunodeficiency virus infection. Csajka, C., Marzolini, C., Fattinger, K., et al.[2020]

In a study of 34 healthy African American participants, higher plasma levels of efavirenz were linked to slower performance on neuropsychometric tests, indicating that increased drug exposure may lead to more pronounced central nervous system side effects.

The study suggests that genetic factors, specifically the CYP2B6 genotype, may influence how efavirenz is processed in the body, potentially affecting the severity of CNS side effects, and that strategies to reduce peak drug levels could help minimize these effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neuropsychometric correlates of efavirenz pharmacokinetics and pharmacogenetics following a single oral dose. Johnson, DH., Gebretsadik, T., Shintani, A., et al.[2021]

A new high-performance liquid chromatography method was developed to quickly and accurately measure efavirenz levels in human plasma, showing a linear detection range from 0.0625 to 10.0 microg/ml.

The method demonstrated high specificity and stability of efavirenz in plasma samples, with an average recovery rate of 101%, making it suitable for pharmacokinetic studies and monitoring therapeutic drug levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Simple and rapid liquid chromatography method for determination of efavirenz in plasma. Ramachandran, G., Kumar, AK., Swaminathan, S., et al.[2020]

Efavirenz, a common medication for HIV type-1, is mainly broken down by the CYP2B6 enzyme, and genetic variations in this enzyme can lead to higher risks of side effects, especially affecting the central nervous system.

Understanding a patient's CYP2B6 genotype can help healthcare providers make better prescribing decisions for efavirenz, potentially reducing the risk of adverse effects and treatment discontinuation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2B6 and Efavirenz-Containing Antiretroviral Therapy. Desta, Z., Gammal, RS., Gong, L., et al.[2021]

A population-based pharmacokinetic model for efavirenz was developed using data from 334 healthy volunteers across 16 phase I studies, confirming that efavirenz clearance varies based on dosage and frequency of administration, with specific differences noted among ethnic groups and genders.

The model demonstrated that while there are variations in efavirenz metabolism, these differences are small and do not necessitate dose adjustments for different populations, making it a reliable framework for evaluating efavirenz in HIV-infected patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population pharmacokinetic meta-analysis with efavirenz. Barrett, JS., Joshi, AS., Chai, M., et al.[2020]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC1884651/

Effect of efavirenz treatment on the pharmacokinetics ... The results obtained in 24 healthy subjects showed an increased nelfinavir AUC0−24 of 30%, Cmax of 29% and a C24 of 48% after addition of efavirenz. Exposure to ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3374961/

Comparative effectiveness of efavirenz-based antiretroviral ... The data derived from these studies show that both EFV and nevirapine are adequate first-line therapy options for HIV-1 infection in RLSs, even in patients with ...

3. journals.asm.org journals.asm.org/doi/10.1128/aac.01757-16

Evaluation of Doravirine Pharmacokinetics When Switching ... The results of a PK evaluation in healthy subjects were projected to be the same as those in subjects with HIV-1, as no major differences in the ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S1684118218301245

Effectiveness of half-a-tablet efavirenz plus 2 nucleos(t)ide ... The primary outcome of the study was PVL <50 copies/ml at week 48 using intention-to-treat (ITT) analysis. The secondary outcomes were PVL <50 copies/ml at week ...

5. thelancet.com thelancet.com/journals/lanwpc/article/PIIS2666-6065(23)00087-1/fulltext

Efficacy and safety of ainuovirine versus efavirenz ... To the best of our knowledge, this study is the first to investigate the efficacy and safety of ANV compared to EFV in a multicenter, randomized ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2772350/

Lack of Effect of Efavirenz on the Pharmacokinetics ... The combination of TPV/r with efavirenz (EFV) is an option in the treatment of HIV-infected individuals and should be assessed for possible drug interactions.

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/pepfar/202990PI.pdf

EFAVIRENZ - accessdata.fda.gov Use of efavirenz in patients younger than 3 months of age OR less than 3.5 kg body weight is not recommended because the safety, pharmacokinetics, and antiviral ...

8. clinicalinfo.hiv.gov clinicalinfo.hiv.gov/en/guidelines/perinatal/safety-toxicity-arv-agents-nnrtis-efavirenz-sustiva

Efavirenz (Sustiva) - Safety and Toxicity in Pregnancy | NIH A study that evaluated the genotoxicity of EFV in mice noted DNA damage in brain cells after daily dosing for 36 days; no damage was seen in ...

9. ema.europa.eu ema.europa.eu/en/documents/product-information/efavirenz-teva-epar-product-information_en.pdf

Efavirenz Teva, INN-efavirenz - European Medicines Agency The safety and efficacy of efavirenz has not been established in patients with significant underlying liver disorders. Patients with chronic hepatitis B or C ...

10. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK542316/

Efavirenz - StatPearls - NCBI Bookshelf Efavirenz is an FDA-approved medication used for the treatment and prevention of HIV-1 infection. The drug is a non-nucleoside reverse transcriptase inhibitor ...