Interaction Between Etravirine or Darunavir/Ritonavir and Artemether / Lumefantrine (DDI Coartem)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Janssen Pharmaceutica N.V., Belgium
ClinicalTrials.gov Identifier:
NCT01876966
First received: November 19, 2012
Last updated: June 11, 2013
Last verified: June 2013
  Purpose

The purpose of this study is to investigate the pharmacokinetic interaction between etravirine and artemether/lumefantrine and darunavir/ritonavir and artemether/lumefantrine in healthy Human Immunodeficiency Virus- (HIV-)negative patients. 'Pharmacokinetic interaction' means that one medication can influence the absorption and elimination from the body of the other medication.


Condition Intervention Phase
HIV
Drug: Etravirine
Drug: Darunavir/ritonavir
Drug: artemether/lumefantrine
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Health Services Research
Official Title: A Phase I, Partially Randomized, Open Label, Two-way, Two Period Cross-over Study to Investigate the Pharmacokinetic Interaction Between Etravirine or Darunavir/Rtv and Artemether/Lumefantrine at Steady-state in Healthy HIV-negative Subjects

Resource links provided by NLM:


Further study details as provided by Janssen Pharmaceutica N.V., Belgium:

Primary Outcome Measures:
  • effect of ETR or DRV/rtv on the plasma concentrations of artemether, lumefantrine and dihydroartemisinin [ Time Frame: Treatment A: Day 1-2 & Day 4-15; Treatment B: Day 8-9 & Day 11-22 ] [ Designated as safety issue: No ]
    the effect of ETR or DRV/rtv on the pharmacokinetics of artemether, lumefantrine and the artemether metabolite dihydroartemisinin (DHA) after single and multiple dose(s) in healthy subjects. plasma concentrations: minimum (Cmin) and maximum (Cmax): artemether and DHA (Day 11 of Treatment B versus Day 4 of Treatment A, Days 11-14 of Treatment B versus Days 4-7 of Treatment A ), lumefantrine (Days 11-22 of Treatment B versus Days 4-15 of Treatment A ); Cmax artemether and DHA (Day 8-9 of Treatment B versus Day 1-2 of Treatment A )

  • effect of ETR or DRV/rtv on the Area under the concentration-time curve (AUC) in plasma for artemether, lumefantrine and dihydroartemisinin [ Time Frame: Treatment A: Day 1-2 & Day 4-15; Treatment B: Day 8-9 & 11-22 ] [ Designated as safety issue: No ]
    effect of ETR or DRV/rtv on the AUC from time of administration (0 hours) to 8 hours after dosing (AUC8h): artemether and DHA (Day 8-9 of Treatment B versus Day 1-2 of Treatment A); AUC from 0 to 12 hours (AUC 12h) artemether and DHA (Day 11 of Treatment B versus Day 4 of Treatment A ); AUC from 0 to 264 hours (AUC264h) lumefantrine (Days 11-22 of Treatment B versus Days 4-15 of Treatment A ; AUC from 0 to the last time point with a measurable concentration post dosing (AUClast) artemether and DHA (Days 11-14 of Treatment B versus Days 4-7 of Treatment A )

  • Plasma concentrations of ETR, DRV and rtv [ Time Frame: Treatment B: Day 8 & Day 11 ] [ Designated as safety issue: No ]
    Cmin and Cmax for ETR, DRV and ritonavir (Day 11 of Treatment B versus Day 8 of Treatment B )

  • Area under the concentration-time curve (AUC) in plasma for ETR, DRV and rtv [ Time Frame: Treatment B: Day 8 & Day 11 ] [ Designated as safety issue: No ]
    AUC from time of administration to 12 hours after dosing (AUC12h) for ETR, DRV and ritonavir (Day 11 of Treatment B versus Day 8 of Treatment B)


Secondary Outcome Measures:
  • Number of Participants with Adverse Events as a Measure of Safety and Tolerability [ Time Frame: at screening, during treatment and at day 7 and 30, 31 or 32 after last study medication intake ] [ Designated as safety issue: No ]
    short-term safety and tolerability of coadministration of ETR or DRV/rtv and artemether/lumefantrine in healthy subjects.

  • Profile of pharmacokinetics of ETR by cytochrome P450 (CYP)2C9 and CYP2C19 genotype [ Time Frame: Treatment B: Day 8 ] [ Designated as safety issue: No ]
    the effect of CYP2C9 and CYP2C19 genotypes will be evaluated by comparison of these genotypes with the Cmax and AUC12 for ETR

  • Profile of pharmacokinetics of artemether and DHA after single and multiple dose(s) [ Time Frame: Treatment A: Day 1-2 & Day 4-7 ] [ Designated as safety issue: No ]
    Cmax (both periods), AUC8h (Day 1-2) and AUClast (Day 4-7) for artemether and DHA


Enrollment: 33
Study Start Date: March 2011
Study Completion Date: July 2011
Primary Completion Date: July 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: ETR, artemether/lumefantrine
treatment with artemether/lumefantrine 80/480 mg during 3 days (treatment A) and treatment during 22 days with etravirine for 22 days and artemether/lumefantrine 80/480 mg from day 8 to day 11 (treatment B) with a washout of at least 4 weeks between the 2 treatment periods
Drug: Etravirine
200 mg ETR b.i.d. from Day 1 to Day 21 with a single 200 mg dose of ETR in the morning on Day 22
Drug: artemether/lumefantrine
3 days of treatment with artemether/lumefantrine 80/480 mg (6 doses of 4 tablets [20/120 mg] at 0, 8, 24, 36, 48, and 60 hours)
Experimental: DRV/rtv, artemether/lumefantrine
treatment with artemether/lumefantrine 80/480 mg during 3 days (treatment A) and treatment during 22 days with darunavir/ritonavir and artemether/lumefantrine 80/480 mg from day 8 to day 11 (treatment B) with a washout of at least 4 weeks between the 2 treatment periods
Drug: Darunavir/ritonavir
DRV/rtv 600/100 mg b.i.d. from Day 1 to Day 21 with a single dose of DRV/rtv in the morning on Day 22
Drug: artemether/lumefantrine
3 days of treatment with artemether/lumefantrine 80/480 mg (6 doses of 4 tablets [20/120 mg] at 0, 8, 24, 36, 48, and 60 hours)

Detailed Description:

This is a Phase I, partially randomized, open-label, single-center, two-way, two-period cross-over study to investigate the pharmacokinetic interaction between etravirine (ETR) or darunavir/ritonavir (DRV/rtv) and the antimalarial drugs artemether/lumefantrine at steady-state in healthy human immunodeficiency virus (HIV)-negative patients. The study population will consist of 32 healthy patients, equally divided over 2 panels. Patients in Panel 1 will be treated with ETR and artemether/lumefantrine; patients in Panel 2 will be treated with DRV/rtv and artemether/lumefantrine. Treatment A will consist of 3 days of treatment with artemether/lumefantrine. Treatment B will consist of 200 mg ETR twice daily (b.i.d.) (Panel 1) or 600/100 mg DRV/rtv b.i.d. (Panel 2) from Day 1 to Day 21 with a single dose of ETR (Panel 1) or DRV/rtv (Panel 2) in the morning on Day 22. From Day 8, 3 days of treatment with artemether/lumefantrine. In a first stage of treatment in Panel 2, only 4 patients will be allowed to start Treatment B. Based on the ECG results of the first 4 patients with evaluable ECG data after assessments on Day 11 (66 hours after the combined intake of DRV/rtv and artemether/lumefantrine), the Sponsor will decide whether additional patients can be allowed to start Treatment B. There will be a washout period of at least 4 weeks between Treatments A and B. Half of the patients of Panel 1 (8 patients) and Panel 2 (8 patients) will be randomized to sequence AB and half will be randomized to sequence BA. Randomization in Panel 2 will occur in two steps. In Step 1, 4 patients will be allocated to sequence BA and evaluated for QTc prolongation. Based on the outcome of their ECG results, the Sponsor will decide whether the remainder of patients will be randomized in Step 2, i.e. 4 patients to BA and 8 patients to AB (1:2 randomization). Serial pharmacokinetic assessments will be determined for Panels 1 and 2 in Treatments A and B for artemether and its metabolite dihydroartemisinin (DHA) after the first intake of artemether/lumefantrine over 8 hours and after the last intake of artemether/lumefantrine over 72 hours (3 days), and for lumefantrine after the last intake of artemether/lumefantrine over 264 hours (11 days). Serial pharmacokinetic assessments will be determined for ETR (Panel 1) or DRV and rtv (Panel 2) over the 12-hour dosing interval on Day 8 (after the morning intake) and Day 11 (after the last dose of artemether/lumefantrine) of Treatment B. All ETR, DRV/rtv and artemether/lumefantrine treatments will be administered under fed conditions and will be taken within 10 minutes after completion of a meal. Safety and tolerability evaluations will be recorded on an ongoing basis.

  Eligibility

Ages Eligible for Study:   18 Years to 55 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • if of childbearing potential or if male, use a highly effective method of birth control.
  • Able to comply with protocol requirements.
  • A BMI (weight in kg divided by the square of height in meters) of 18.5 to 30.0 kg/m2, extremes included.
  • healthy on the basis of a medical evaluation
  • Non-smoking for at least 3 months prior to selection.

Exclusion Criteria:

  • previously demonstrated clinically significant allergy, hypersensitivity or intolerance to any of the investigational medications or its excipients
  • Use of concomitant medication, including over-the-counter products and dietary supplements.
  • Having participated in more than 1 study (single or multiple dose) with ETR (TMC125), DRV (TMC114), dapivirine (TMC120) and/or rilpivirine (TMC278, formerly known as R278474), or having developed a rash, erythema or urticaria while participating in a study with the aforementioned compounds.
  • A positive pregnancy test or breast feeding at screening or on Day 1.
  • Any condition that, in the opinion of the investigator, would compromise the study or the well-being of the patient or prevent the patient from meeting or performing study requirements
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

No Contacts or Locations Provided
  More Information

Publications:
Responsible Party: Janssen Pharmaceutica N.V., Belgium
ClinicalTrials.gov Identifier: NCT01876966     History of Changes
Other Study ID Numbers: CR018409, 2010-023289-31, TMC125VIR1001
Study First Received: November 19, 2012
Last Updated: June 11, 2013
Health Authority: Poland: Ministry of Health

Keywords provided by Janssen Pharmaceutica N.V., Belgium:
HIV
pharmacokinetic interaction
healthy HIV-negative person

Additional relevant MeSH terms:
Artemether
Artemisinins
Lumefantrine
Artemether-lumefantrine combination
Etravirine
Darunavir
Ritonavir
Antifungal Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Coccidiostats
Schistosomicides
Antiplatyhelmintic Agents
Anthelmintics
HIV Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors

ClinicalTrials.gov processed this record on August 01, 2014