Efavirenz for Drug Interaction

Recruiting at 1 trial location

Overseen By Abi Colwell

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Indiana University

Must not be taking: CYP2B6 inhibitors, CYP1A2 inducers

Disqualifiers: Heart, liver, kidney disease, others

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

Compensation: Varies

Number of Visits: 4

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to understand how the drug efavirenz, a key medication in HIV treatment, interacts with methadone and tizanidine. Researchers seek to determine if genetic differences influence these drug interactions, potentially leading to unexpected effects or changes in effectiveness. Healthy volunteers who don't smoke and can avoid certain medications during the study period are ideal candidates. Participants should not have significant health issues or a history of mental health conditions. As an Early Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the chance to contribute to groundbreaking insights in drug interactions.

Will I have to stop taking my current medications?

Yes, you will need to stop taking any prescription medications, over-the-counter medications, and herbal, dietary, and alternative supplements that might interact with the study drugs at least two weeks before the study starts and throughout the entire study period.

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

Studies have shown that efavirenz, a drug commonly used to treat HIV, is generally well-tolerated. However, it interacts with many other drugs—about 894, to be exact—potentially causing unexpected effects when combined with certain medications.

While efavirenz has been used safely for HIV treatment, this trial examines its interactions with methadone and tizanidine in people with different genetic backgrounds. Previous research suggests efavirenz is safe, but understanding its interactions with other drugs remains important. This trial aims to provide more insight into these interactions, especially for those with unique genetic profiles. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about the Efavirenz treatment because it offers a new perspective on drug interactions, particularly for individuals with different genetic profiles affecting drug metabolism. Unlike current treatments, which may not consider genetic variations in metabolizing enzymes, Efavirenz is being investigated for its ability to interact with methadone and tizanidine based on different CYP2B6 metabolizer statuses (normal, intermediate, and poor). This approach could lead to more personalized treatment plans, ensuring medications are more effective and safer for patients with varying genetic backgrounds.

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

Research shows that efavirenz can change how the body processes certain drugs by affecting enzymes like CYP3A and CYP2B6. This means it can alter how other drugs, such as methadone and tizanidine, work when taken together. In this trial, one group of participants will receive efavirenz to assess its impact on these interactions. Studies have found that efavirenz strongly blocks CYP2B6, which might change how effective these drugs are or what side effects they cause. Because of these interactions, researchers are testing efavirenz to see how it affects drug effectiveness and side effects in people with different genetic versions of the CYP2B6 enzyme. This research might help predict who could experience more side effects or less benefit from certain drugs when used with efavirenz. ^{2 6 7 8 9}

Are You a Good Fit for This Trial?

Healthy adults aged 18-65, who are non-smokers or willing to abstain from tobacco and marijuana, can join this trial. They must not take any interfering substances for two weeks before and during the study. Participants should have specific CYP2B6 genotypes (NM, IM, PM) without significant health issues as confirmed by screening tests.

Inclusion Criteria

Judged healthy without any significant medical condition as determined by a pre-enrollment screening session including medical history, laboratory tests, vital signs, and an electrocardiogram (EKG) done no more than six weeks before the study

Able and willing to adhere to study medication restrictions two weeks before and during the entire study, refraining from certain medications and supplements

I am a nonsmoker or willing to quit smoking and using tobacco or marijuana for the study duration.

Exclusion Criteria

Inability to follow study rules

Employees or students under supervision of study investigators

I am willing to commit the required time for the study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Control Phase

Tizanidine and methadone pharmacokinetics and pharmacodynamics determined at baseline

4 days

2 inpatient visits, 2 outpatient visits

Efavirenz Treatment Phase

Participants take efavirenz 600 mg/day for 16 days at home

16 days

Home-based with diary entries

Steady State Phase

Tizanidine and methadone pharmacokinetics and pharmacodynamics determined after efavirenz treatment

4 days

2 inpatient visits, 2 outpatient visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

1-2 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Efavirenz
• Methadone
• Tizanidine

Trial Overview The study examines how genetic differences in CYP2B6 affect the body's handling of methadone and tizanidine when taken with efavirenz. It involves healthy volunteers grouped by their metabolism rate (normal, intermediate, poor), testing drug interactions at baseline and after taking efavirenz for 17 days.

How Is the Trial Designed?

Group I: Efavirenz (treatment) Experimental Treatment 1 Intervention

Each CYP2B6 normal metabolizer (NM) (\*1/\*1), intermediate metabolizer (IM) (\*1/\*6), and poor metabolizer (PM) (\*6/\*6, \*6/\*18, or \*18/\*18) group will be administered a single dose of methadone (10 mg) and a single dose of tizanidine (4 mg) orally simultaneously after 16-day oral treatment with 600 mg/day efavirenz

Group II: Baseline (control) Experimental Treatment 1 Intervention

Each CYP2B6 normal metabolizer (NM) (\*1/\*1), intermediate metabolizer (IM) (\*1/\*6), and poor metabolizer (PM) (\*6/\*6, \*6/\*18, or \*18/\*18) group will receive a single dose of methadone (10 mg) and a single dose of tizanidine (4 mg) orally simultaneously at baseline (control).

Efavirenz is already approved in United States, European Union, Canada, Japan, Switzerland for the following indications:

Approved in United States as Sustiva for:

• HIV-1 infection

Approved in European Union as Stocrin for:

• HIV-1 infection

Approved in Canada as Atripla for:

• HIV-1 infection

Approved in Japan as Sustiva for:

• HIV-1 infection

Approved in Switzerland as Stocrin for:

• HIV-1 infection

Who Is Running the Clinical Trial?

Indiana University

Lead Sponsor

Trials

1,063

Recruited

1,182,000+

National Institute of General Medical Sciences (NIGMS)

Collaborator

Trials

315

Recruited

251,000+

Published Research Related to This Trial

Coadministration of lopinavir/ritonavir with itraconazole significantly increased itraconazole levels while decreasing its active metabolite, hydroxyitraconazole, in a patient with HIV and disseminated histoplasmosis.

Due to this drug-drug interaction, the dosage of itraconazole had to be reduced when used alongside lopinavir/ritonavir to avoid potential toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug-drug interaction between itraconazole and the antiretroviral drug lopinavir/ritonavir in an HIV-1-infected patient with disseminated histoplasmosis. Crommentuyn, KM., Mulder, JW., Sparidans, RW., et al.[2017]

In a Phase 1 study involving 42 healthy subjects, the combination of ledipasvir/sofosbuvir for hepatitis C and emtricitabine/rilpivirine/TAF for HIV showed no significant drug-drug interactions affecting the pharmacokinetics of ledipasvir and sofosbuvir, indicating they can be safely coadministered without dosage adjustments.

While tenofovir levels increased when combined with ledipasvir/sofosbuvir, the overall exposure was still much lower than that seen with tenofovir disoproxil fumarate (TDF), suggesting that the combination is well tolerated and clinically relevant for HIV/hepatitis C co-infected patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lack of clinically important PK interaction between coformulated ledipasvir/sofosbuvir and rilpivirine/emtricitabine/tenofovir alafenamide. Custodio, JM., Chuck, SK., Chu, H., et al.[2021]

Efavirenz is an effective once-daily treatment for HIV-1, showing strong inhibitory activity and good durability when used in combination with other antiretroviral medications.

It is important to note that efavirenz can interact with other drugs metabolized by the cytochrome P450 enzymes, which may affect the efficacy of treatments like indinavir and saquinavir.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical history of efavirenz. Ruiz, N.[2020]

In a study of 169 individuals on an efavirenz (EFV) regimen, no overall pharmacokinetic interaction between tenofovir (TFV) and EFV was found, as EFV plasma levels were similar regardless of TFV use.

However, in individuals with genetic variations that slow EFV metabolism (CYP2B6 loss/diminished-function alleles), those taking TFV had significantly higher EFV plasma levels, suggesting a potential interaction in this specific group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Does tenofovir influence efavirenz pharmacokinetics? Rotger, M., Colombo, S., Furrer, H., et al.[2020]

Efavirenz, a non-nucleoside reverse transcriptase inhibitor (NNRTI), has shown significant efficacy in reducing HIV viral load to undetectable levels in patients when used in combination with other antiretroviral drugs, as demonstrated in multiple studies involving hundreds of participants.

In a phase III study, efavirenz combined with zidovudine and lamivudine resulted in a significant increase in CD4 cell counts, indicating its effectiveness in improving immune function in HIV-infected individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efavirenz DuPont Pharmaceuticals Co. Dong, BJ.[2008]

Co-administration of certain medications, like omeprazole or rifampin, can significantly reduce the effectiveness of HIV drugs such as atazanavir and saquinavir, highlighting the importance of monitoring drug-drug interactions in HIV treatment.

Some combinations, like the double-boosted regimen of atazanavir/saquinavir/ritonavir, can increase drug exposure, suggesting that specific combinations can enhance therapeutic effects while others may lead to reduced efficacy or increased toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug-drug interactions and the pharmacotherapy of HIV infection. Kashuba, AD.[2006]

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]

The study evaluated the safety and pharmacokinetic interactions of GW433908, ritonavir (RTV), and efavirenz (EFV) in a controlled setting with subjects receiving different dosing regimens over 14 days.

It was found that coadministering EFV with GW433908 700 mg + RTV 100 mg did not require dosage adjustments, while the higher dose of GW433908 1395 mg + RTV 200 mg necessitated an increase in RTV to 300 mg to maintain effective plasma levels of the drug.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and safety of GW433908 and ritonavir, with and without efavirenz, in healthy volunteers. Wire, MB., Ballow, C., Preston, SL., et al.[2020]

The study aimed to investigate the effects of combining saquinavir/ritonavir with efavirenz in healthy volunteers, but it was terminated early due to nonserious adverse events experienced by two participants.

Only limited pharmacokinetic data were collected, and the early termination prevented any definitive conclusions about the safety or efficacy of the drug combination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Potential Hepatotoxicity of Efavirenz and Saquinavir/Ritonavir Coadministration in Healthy Volunteers. Jamois, C., Riek, M., Schmitt, C.[2021]

In a study involving 87 HIV-infected participants, the combination of daily rifapentine and isoniazid with efavirenz did not significantly reduce efavirenz levels, maintaining concentrations above the therapeutic threshold throughout the 4-week treatment period.

Virologic suppression was effectively maintained, with 95% of participants having undetectable HIV-1 RNA at week 8, indicating that this combination therapy is safe and effective for preventing tuberculosis without compromising HIV treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efavirenz Pharmacokinetics and Pharmacodynamics in HIV-Infected Persons Receiving Rifapentine and Isoniazid for Tuberculosis Prevention. Podany, AT., Bao, Y., Swindells, S., et al.[2020]

Efavirenz is a strong competitive inhibitor of the CYP2B6 and CYP2C8 enzymes, which can significantly affect the metabolism of other drugs processed by these enzymes, potentially slowing their elimination.

Chronic use of efavirenz may lead to increased plasma concentrations of drugs metabolized by CYP2C8 and CYP2C9, with predicted increases in drug exposure ranging from 1.7 to 4.4 times, highlighting the importance of monitoring drug interactions in patients on efavirenz-based therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro analysis and quantitative prediction of efavirenz inhibition of eight cytochrome P450 (CYP) enzymes: major effects on CYPs 2B6, 2C8, 2C9 and 2C19. Xu, C., Desta, Z.[2021]

In a study involving 34 healthy male subjects, the antifungal voriconazole's effectiveness was significantly reduced when coadministered with the HIV medication efavirenz, with voriconazole's exposure dropping by 80% in terms of area under the curve (AUC) and 66% in peak concentration (Cmax).

Conversely, voriconazole increased the exposure of efavirenz by 43% in AUC and 37% in Cmax, indicating that voriconazole inhibits the metabolism of efavirenz. Due to these interactions, coadministration of voriconazole and efavirenz is contraindicated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic interaction between voriconazole and efavirenz at steady state in healthy male subjects. Liu, P., Foster, G., LaBadie, RR., et al.[2020]

Citations

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

Efavirenz - StatPearls - NCBI Bookshelf The recommended adult dose is 600 mg/d, but some data show that 400 mg/d yields equivalent outcomes with fewer adverse effects. [6] Patients should not cut, ...

2. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2016/020972s049-021360s038lbl.pdf

SUSTIVA (efavirenz) Label - accessdata.fda.gov The most prominent effect of efavirenz at steady-state is induction of CYP3A and. CYP2B6. [See Dosage and Administration (2.1) and Drug Interactions (7.1).] 5.2.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11268839/

Effect of Efavirenz on the Pharmacokinetics of SHR6390 in ... The data show that the combination of SHR6390 and rifampicin reduces AUC0-t, AUC0–∞, and Cmax by approximately 80.5%, 80.7%, and 64.0%, ...

4. hiv-druginteractions.org hiv-druginteractions.org/interactions/2093/all

Efavirenz (EFV) Efavirenz induces CYP3A4 and may significantly decrease abiraterone concentrations and consequently reduce its efficacy. It is recommended to use an alternative ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1347436715304262

In Vitro Analysis and Quantitative Prediction of Efavirenz ... The present study showed that efavirenz was a potent competitive inhibitor of CYP2B6 (average Ki = 1.68 μΜ in HLMs and Ki = 1.38μΜ in expressed CYP2B6) and ...

6. drugs.com drugs.com/drug-interactions/efavirenz.html

Efavirenz Interactions Checker Efavirenz Interactions. There are 893 drugs known to interact with efavirenz, along with 4 disease interactions, and 1 alcohol/food interaction.

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

EFAVIRENZ - accessdata.fda.gov Concomitant Antiretroviral Therapy Efavirenz tablets must be given in combination with other antiretroviral medications [see Indications and Usage (1), ...

8. drugs.com drugs.com/drug-interactions/efavirenz,sustiva.html

Sustiva Interactions Checker Sustiva Interactions. There are 894 drugs known to interact with Sustiva (efavirenz), along with 4 disease interactions, and 1 alcohol/food interaction.

9. webmd.com webmd.com/drugs/2/drug-16569/efavirenz-oral/details

Efavirenz (Sustiva) - Uses, Side Effects, and More Drug Interactions. Efavirenz should not be taken while you are using certain other medicines.