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

Trial Summary

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.

What data supports the effectiveness of the drug Efavirenz for drug interactions?

Efavirenz is known to interact with various drugs by affecting enzymes in the liver that process medications, which can alter the effectiveness of other drugs taken alongside it. This interaction is important in managing HIV treatment, as it can influence the levels of other medications in the body, potentially enhancing or reducing their effects. ^{1 2 3 4 5}

Is Efavirenz generally safe for humans?

Efavirenz has been studied for safety in humans, and while it is generally well-tolerated, it can interact with other drugs, leading to increased side effects like neuropsychiatric symptoms when combined with tenofovir. It's important to monitor for interactions with other medications. ^{1 2 6 7 8}

What makes the drug Efavirenz unique compared to other treatments?

Efavirenz is unique because it is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that allows for once-daily dosing without regard to meals, making it convenient for patients. It is primarily used in combination with other drugs to treat HIV-1 infection and has shown significant efficacy in reducing viral loads and increasing CD4 cell counts. ^{2 9 10 11 12}

What is the purpose of this trial?

The main goal of this clinical study is to test how CYP2B6 genetic variations and efavirenz (cornerstone in HIV-1 therapy) dictate the disposition (PK) of CYP2B6 substrate (methadone) and PK and effect (PD) of CYP1A2 substrate (tizanidine). Specifically, the investigators will test whether efavirenz produces CYP2B6 genotype dependent unanticipated DDIs with CYP2B6 (methadone) and CYP1A2 (tizanidine), leading to lack of efficacy or increased toxicity. Healthy volunteers genotyped for CYP2B6\*6 and \*18 alleles will be grouped in to three genotype predicted phenotype groups: 20 normal metabolizer (NM) (CYP2B6\*1/\*1); 20 intermediate metabolizer (IM) (\*1/\*6, or \*1/\*18); and 20 poor metabolizer (PM) (\*6/\*6, \*6/\*18 or \*18/\*18). Each phenotype group will receive methadone and tizanidine (separated by a washout period) on two occasions: at baseline (control) and after treatment with efavirenz (600 mg/day for 17 days).

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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 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 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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

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

2. England pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and safety of GW433908 and ritonavir, with and without efavirenz, in healthy volunteers. [2020]

3. United States pubmed.ncbi.nlm.nih.gov

Efavirenz Pharmacokinetics and Pharmacodynamics in HIV-Infected Persons Receiving Rifapentine and Isoniazid for Tuberculosis Prevention. [2020]

4. England 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. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Pharmacokinetic interaction between voriconazole and efavirenz at steady state in healthy male subjects. [2020]

6. England pubmed.ncbi.nlm.nih.gov

Does tenofovir influence efavirenz pharmacokinetics? [2020]

7. United States 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. [2017]

8. United States pubmed.ncbi.nlm.nih.gov

Lack of clinically important PK interaction between coformulated ledipasvir/sofosbuvir and rilpivirine/emtricitabine/tenofovir alafenamide. [2021]

9. England pubmed.ncbi.nlm.nih.gov

Efavirenz for HIV-1 infection in adults: an overview. [2020]

10. United States pubmed.ncbi.nlm.nih.gov

Potential Hepatotoxicity of Efavirenz and Saquinavir/Ritonavir Coadministration in Healthy Volunteers. [2021]

11. England pubmed.ncbi.nlm.nih.gov

Efavirenz DuPont Pharmaceuticals Co. [2008]

12. England pubmed.ncbi.nlm.nih.gov

Clinical history of efavirenz. [2020]