Efavirenz for Healthy Subjects
Recruiting in Palo Alto (17 mi)
Age: 18 - 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Merck Sharp & Dohme LLC
Disqualifiers: Cancer, HIV, Hepatitis, others
No Placebo Group
Trial Summary
What is the purpose of this trial?The goal of the study is to learn what happens to levels of MK-7602 in a healthy person's body over time. Researchers will compare what happens to MK-7602 in the body when it is given with or without another medicine called efavirenz.
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.
What data supports the effectiveness of the drug Efavirenz for healthy subjects?
Efavirenz has been effectively used as a key part of HIV treatment since 1996, showing success in both new and experienced patients, and is known for its once-daily dosing that helps with treatment adherence.
12345Is efavirenz generally safe for humans?
Efavirenz has been used safely in many people with HIV, but it can cause side effects related to the brain, like dizziness or trouble sleeping. These effects are not fully understood, but the drug is generally well-tolerated.
46789What makes the drug Efavirenz unique compared to other treatments?
Efavirenz is unique because it is a potent, once-daily non-nucleoside reverse transcriptase inhibitor (NNRTI) used for HIV treatment, available as a single 600 mg tablet, which simplifies therapy and reduces the number of pills a patient needs to take, potentially improving adherence and treatment outcomes.
210111213Eligibility Criteria
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.
Trial Timeline
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
Participant Groups
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.
1Treatment groups
Experimental Treatment
Group I: MK-7602 + EfavirenzExperimental Treatment2 Interventions
Participants will be administered MK-7602 and efavirenz.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Fortrea Clinical Research Unit Inc ( Site 0001)Daytona Beach, FL
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Who Is Running the Clinical Trial?
Merck Sharp & Dohme LLCLead Sponsor
References
Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2B6 and Efavirenz-Containing Antiretroviral Therapy. [2021]The HIV type-1 nonnucleoside reverse transcriptase inhibitor, efavirenz, is widely used to treat HIV type-1 infection. Efavirenz is predominantly metabolized into inactive metabolites by cytochrome P450 (CYP)2B6, and patients with certain CYP2B6 genetic variants may be at increased risk for adverse effects, particularly central nervous system toxicity and treatment discontinuation. We summarize the evidence from the literature and provide therapeutic recommendations for efavirenz prescribing based on CYP2B6 genotypes.
Efavirenz: enhancing the gold standard. [2020]Efavirenz, the potent, once-daily non-nucleoside reverse transcriptase inhibitor, has been successfully used since 1996 and is still a cornerstone of antiretroviral therapy for use in treatment-naïve, treatment-experienced and difficult-to-treat patients. The efficacy of efavirenz in these patient groups has been established in many clinical and cohort studies. Furthermore, efavirenz is now available as a single 600 mg tablet, providing a simplified therapy and decreased pill burden, which may lead to improved adherence and treatment outcomes. Efavirenz has a well-characterized tolerability profile, the more notable side effects being mainly short-term and non-life-threatening, such as central nervous system disturbances and rash.
Population pharmacokinetics and effects of efavirenz in patients with human immunodeficiency virus infection. [2020]The reverse transcriptase inhibitor efavirenz is currently used at a fixed dose of 600 mg/d. However, dosage individualization based on plasma concentration monitoring might be indicated. This study aimed to assess the efavirenz pharmacokinetic profile and interpatient versus intrapatient variability in patients who are positive for human immunodeficiency virus, to explore the relationship between drug exposure, efficacy, and central nervous system toxicity and to build up a Bayesian approach for dosage adaptation.
Neuropsychometric correlates of efavirenz pharmacokinetics and pharmacogenetics following a single oral dose. [2021]To determine pharmacokinetic and pharmacogenomic correlates of efavirenz central nervous system (CNS) side effects following a single dose.
Population pharmacokinetic meta-analysis with efavirenz. [2020]A population-based pharmacokinetic (PK) model has been developed for efavirenz based on 16 phase I studies. The combined data set consisted of 334 healthy volunteers, 2,907 efavirenz dose administrations and 9,342 measured plasma concentrations across a range of doses from 100-600 mg. The pharmacokinetic structural model was a 2-compartment model with first-order absorption with differentiation between single- and multiple-dose exposure to account for known hepatic cytochrome P450 induction of efavirenz metabolism. Model-building was performed on the index data set (66% of the total database), as a data-splitting technique was used to validate the final model using NONMEM. The final model confirmed the appropriateness of separate clearance terms for single and multiple dose administration (2.65 versus 10.2 l/h, respectively). Clearance increased with dose and frequency of administration. A lower clearance was predicted in Asians and Blacks relative to Caucasians. A slightly lower clearance was observed in females relative to males (9.08 compared to 10.2 l/h in males) and interactions on clearance due to co-administration of fluconazole, ritonavir, rifampin, indinavir and azithromycin were identified. The magnitudes of these effects were small and did not suggest dose adjustment in the various subpopulations. With little exception, these results agree with the findings from the non-compartmental analyses. The residual variability was 21% CV and the intersubject variation in CL/F and V/F was 48 and 85%, respectively. The phase I meta-analysis was able to substantiate the pharmacokinetic characteristics of efavirenz derived from the composite of individual well-defined studies. The model was deemed adequate for subsequent evaluation in HIV-infected patients. Covariates and outlier classes identified in this phase I meta-analysis were similarly identified in subsequent analyses of patient data.
Safety and tolerance of efavirenz in different antiretroviral regimens: results from a national multicenter prospective study in 1,033 HIV-infected patients. [2022]To evaluate the incidence and severity of adverse events (AEs) and treatment interruption (TI) with efavirenz in a population with a high rate of intravenous drug use (IVDU).
Efavirenz for HIV-1 infection in adults: an overview. [2020]Efavirenz (Sustiva), Bristol-Myers Squibb) is a non-nucleoside reverse transcriptase inhibitor that has been used successfully since the late 1990s to treat HIV-1 infection, and has since become a cornerstone of antiretroviral therapy. The efficacy and potency of efavirenz has been established in many clinical trials and cohort studies, where it has been compared with unboosted or ritonavir (Norvir, Abbott Laboratories Ltd)-boosted protease inhibitors, nevirapine (Viramune, Boehringer Ingelheim Ltd); and three nucleoside analog-based regimens. Pharmacokinetics allowing for a convenient once-daily administration make efavirenz one of the first agents to be included in once-daily regimens. Tolerability of efavirenz is satisfactory, although CNS-related toxicity can occur, and is still poorly understood. New insights into the pharmacokinetics of efavirenz could help to manage this unwanted toxicity. This drug profile will examine the principal data concerning the efficacy, pharmacokinetics and safety that have made efavirenz a standard of care in HIV-1 therapy, and will comment on new data that could change the way efavirenz is used in the near future.
Pharmacokinetic and Pharmacodynamic Comparison of Once-Daily Efavirenz (400 mg vs. 600 mg) in Treatment-Naïve HIV-Infected Patients: Results of the ENCORE1 Study. [2022]Daily efavirenz 400 mg (EFV400) was virologically noninferior to 600 mg (EFV600) at 48 weeks in treatment-naïve patients. We evaluated EFV400 and EFV600 pharmacokinetics (NONMEM v. 7.2), assessing patient demographics and genetic polymorphisms (CYP2B6, CYP2A6, CYP3A4, NR1I3) as covariates and explored relationships with efficacy (plasma HIV-RNA (pVL) T/983T>C/CYP2A6*9B/*17 and weight were associated with efavirenz CL/F. Exposure was significantly lower for EFV400 (geometric mean ratio, GMR; 90% confidence interval, CI: 0.73 (0.68-0.78)) but 97% (EFV400) and 98% (EFV600) of evaluable pVL was
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. [2022]ENCORE1 demonstrated non-inferiority of daily efavirenz 400 mg (EFV400) versus 600 mg (EFV600) to 96 weeks in treatment-naïve, HIV-infected adults but concerns regarding lower EFV400 concentrations remained. Therefore, relationships between EFV pharmacokinetics (PK) and key genetic polymorphisms with 96-week efficacy and safety were investigated.
Comparative bioavailability of a generic capsule formulation of the reverse transcriptase inhibitor efavirenz and the innovator product. [2020]Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that has been used successfully for more than a decade to treat human immunodeficiency virus (HIV) infection. The objective of the current study was to determine the bioequivalence between a generic capsule formulation of efavirenz and the innovator product.
Simple and rapid liquid chromatography method for determination of efavirenz in plasma. [2020]A simple and rapid high performance liquid chromatographic method for determination of efavirenz in human plasma was developed. The method involved extraction of sample with ethyl acetate and analysis using a reversed-phase C(18) column (150 mm) with UV detection. The assay was linear from 0.0625 to 10.0 microg/ml. The method was specific for efavirenz estimation and the drug was stable in plasma up to one month at -20 degrees C. The average recovery of efavirenz from plasma was 101%. Due to its simplicity, the assay can be used for pharmacokinetic studies and therapeutic drug monitoring of efavirenz.
Population Approach to Efavirenz Therapy. [2020]Efavirenz (EFV) is a nonnucleoside reverse transcriptase inhibitor commonly used as first-line therapy in the treatment of human immunodeficiency virus (HIV), with a narrow therapeutic range and a high between-subject variability which can lead to central nervous system toxicity or therapeutic failure. To characterize the sources of variability and better predict EFV steady-state plasma concentrations, a population pharmacokinetic model was developed from 96 HIV-positive individuals, using a nonlinear mixed-effect method with Monolix® software. A one-compartment with first-order absorption and elimination model adequately described the data. To explain between-subject variability, demographic characteristics, biochemical parameters, hepatitis C virus-HIV coinfection, and genetic polymorphisms were tested. A combination of the single-nucleotide polymorphisms rs2279343 and rs3745274, both in the CYP2B6 gene, were the only covariates influencing clearance, included in the final model. Oral clearance was estimated to be 19.6 L/h, 14.15 L/h, and 6.08 L/h for wild-type, heterozygous mutated and homozygous mutated individuals, respectively. These results are in accordance with the current knowledge of EFV metabolism and also suggest that in homozygous mutated individuals, a dose adjustment is necessary. Hepatitis C virus-HIV coinfection does not seem to be a predictive indicator of EFV pharmacokinetic disposition.
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. [2020]Efavirenz is a novel non-nucleoside reverse transcriptase inhibitor for the treatment of HIV-1-infected individuals. A simple and rapid high-performance liquid chromatographic method for the quantification of efavirenz in human plasma suitable for therapeutic drug monitoring in plasma is described. Sample pretreatment consists of protein precipitation with acetonitrile and subsequent evaporation of the extract to concentrate the analyte. The drug is separated from endogenous compounds by isocratic reversed-phase high-performance liquid chromatography with ultraviolet detection at 246 nm. The method has been validated over the range of 10 to 10,000 ng/ml using a volume of 250 microl of plasma. The assay is linear over this concentration range as indicated by the F-test for lack of fit. Within- and between-day precisions are less than 4.3% for all quality control samples. The lower limit of quantitation is 10 ng/ml and the recovery of efavirenz from human plasma is 106.4% (+/- 1.8%). Frequently co-administered drugs did not interfere with the described methodology. Efavirenz is stable under various relevant storage conditions, for example when stored for 24 h at room temperature. This validated assay is suited for use in pharmacokinetic studies with efavirenz and can readily be implemented in the setting of a hospital laboratory for the monitoring of efavirenz concentrations.