Drug-drug Interaction Study of Ganaplacide and Lumefantrine With Midazolam, Repaglinide, Dextromethorphan, Metformin, Rosuvastatin and Dolutegravir
Condition: Malaria
MeSH terms: Malaria
Study type: Interventional
Phase: Phase 1

Summary: 
      The purpose of this study is to assess the effect of multiple doses of ganaplacide and
      lumefantrine combination on the substrates of cytochrome P450 (CYP) 3A4 (midazolam), CYP2C8
      (repaglinide), CYP2D6 (dextromethorphan), organic cation transporter (OCT) 1, multidrug and
      toxin extrusion (MATE) 1 (metformin) in Cohort 1 and a substrate of the organic anion
      transporting polypeptide (OATP) 1B1, OATP1B3 and Breast Cancer Resistance Protein (BCRP)
      transporter (rosuvastatin) and an antiretroviral drug (dolutegravir) in Cohort 2.

      Results from this study will provide guidance on prescribing ganaplacide and lumefantrine
      combination when co-administered with substrates of the CYP enzymes (CYP3A4, CYP2C8 and
      CYP2D6) and transporters (OCT1, MATE1, OATP1B1, OATP1B3, and BCRP), and dolutegravir.
    

Detailed description: 
      This is an open-label, 2-cohort, fixed-sequence, 2-period, crossover, drug-drug interaction
      (DDI) study to evaluate the effect of multiple doses of ganaplacide and lumefantrine
      combination on the single-dose PK of CYP substrates (midazolam [CYP3A4 substrate],
      repaglinide [CYP2C8 substrate], dextromethorphan [CYP2D6 substrate]), transporter substrates
      (metformin [OCT1 and MATE1 substrate] and rosuvastatin [OATP1B1, OATP1B3 and BCRP substrate])
      and a human immunodeficiency virus (HIV) integrase inhibitor (dolutegravir) in healthy
      participants.

      For each cohort, the study will consist of a screening period of up to 28 days, Baseline
      evaluations (on Day -1 of Period 1) and 2 treatment periods which are separated by a washout
      period. Participants who meet the eligibility criteria at Screening will be admitted to the
      study site for Baseline evaluations on Day -1 of Period 1. Baseline safety assessments will
      be performed prior to first dosing of study treatment in Period 1.

      Participants will be enrolled in 1 of 2 cohorts only. Cohort 1 Participants enrolled will
      receive a single oral dose of the 4-probe substrate cocktail consisting of midazolam,
      repaglinide, dextromethorphan and metformin on Day 1 of Period 1. There will be a washout
      period of at least 2 days, beginning from the last PK sample collection in Period 1 and
      continuing until the first dose of study treatment in Period 2. In Period 2, participants
      will receive ganaplacide and lumefantrine combination orally once daily (q.d.) on Days 1
      through 3, with a single oral dose of the 4-probe substrate cocktail co-administered on Day
      3. There will be 72 hours of sequential blood sampling for PK assessment of substrates
      starting after the 4-probe cocktail dosing in each treatment period. Blood samples for
      ganaplacide, its metabolites and lumefantrine PK will also be collected on Days 1 through 6
      of Period 2.

      All study treatments will be administered after at least 10 hours of overnight fasting and
      will be followed by at least 4 hours of post dose fasting.

      Cohort 2 Participants enrolled will receive a single oral dose of the 2-probe substrate
      cocktail consisting of rosuvastatin and dolutegravir on Day 1 of Period 1. There will be a
      washout period of at least 2 days, beginning from the last PK sample collection in Period 1
      and continuing until the first dose of study treatment in Period 2. In Period 2, participants
      will receive ganaplacide and lumefantrine combination orally q.d. on Days 1 through 3, with a
      single oral dose of the 2-probe substrate cocktail co-administered on Day 3. There will be
      168 hours of sequential blood sampling for PK assessment of substrates starting after the
      2-probe cocktail dosing in each treatment period. Blood samples for ganaplacide, its
      metabolites and lumefantrine PK will also be collected on Days 1 through 10 of Period 2.

      All study treatments will be administered after at least 10 hours of overnight fasting and
      will be followed by at least 4 hours of post dose fasting.

      Both Cohorts Safety assessments (including physical examinations, electrocardiograms (ECGs),
      vital signs, clinical laboratory evaluations [hematology, chemistry, coagulation and
      urinalysis], pulse oximetry [Cohort 1 only], blood glucose monitoring [Cohort 1 only] and
      adverse event [AE] and serious adverse event [SAE] monitoring) will be performed during the
      study.

      The Study Completion evaluations will occur on Day 6 of Period 2 for Cohort 1 and on Day 10
      of Period 2 for Cohort 2, followed by a post-study safety contact (e.g. follow-up telephone
      call, email) approximately 30 days after the last dose of study treatment. In the case of
      early termination, Study Completion evaluations will be conducted prior to discharge from the
      study.
    

Intervention name(s): Midazolam; Repaglinide; Dextromethorphan; Metformin; Ganaplacide; Lumefantrine; Rosuvastatin; Dolutegravir; Ganaplacide; Lumefantrine
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Combination Product; Drug; Drug; Drug; Combination Product
Intervention description(s): Midazolam 2 mg (1 mL of 2 mg/mL oral solution) administered as a single dose in a 4-probe cocktail in the morning in Period 1 on Day 1 and in Period 2 on Day 3.; Repaglinide 0.5 mg (1 x 0.5 mg tablet) administered as a single dose in a 4-probe cocktail in the morning in Period 1 on Day 1 and in Period 2 on Day 3.; Dextromethorphan 15 mg (10 mL of 7.5 mg/5 mL syrup) administered as a single dose in a 4-probe cocktail in the morning in Period 1 on Day 1 and in Period 2 on Day 3.; Metformin 500 mg (1 x 500 mg tablet) administered as a single dose in a 4-probe cocktail in the morning in Period 1 on Day 1 and in Period 2 on Day 3.; Ganaplacide 400 mg (4 x 100 mg tablets) administered q.d. in Period 2 on Days 1 - 3, with the 4-probe cocktail co administered on the morning of Day 3.; Lumefantrine 960 mg (4 x 240 mg sachets) administered q.d. on Days 1 - 3, with the 4-probe cocktail (as a single dose) co administered on the morning of Day 3.; Rosuvastatin 5 mg (1 x 5 mg tablet) administered as a single dose in a 2-probe cocktail in the morning in Period 1 on Day 1 and in Period 2 on Day 3.; Dolutegravir 50 mg (1 x 50 mg tablet) administered as a single dose in a 2-probe cocktail in the morning in Period 1 on Day 1 and in Period 2 on Day 3.; Ganaplacide 400 mg (4 x 100 mg tablets) administered q.d. in Period 2 on Days 1 - 3, with the 2-probe cocktail co administered on the morning of Day 3.; Lumefantrine 960 mg (4 x 240 mg sachets) administered q.d. on Days 1 - 3, with the 4-probe cocktail (as a single dose) co administered on the morning of Day 3.
Other intervention name(s): KAF156; LUM566; KAF156; LUM566
Intervention MeSH terms: Metformin; Repaglinide; Dolutegravir; Lumefantrine; Midazolam; Dextromethorphan; Rosuvastatin Calcium
Allocation: Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Drug-drug interaction; DDI; probe; cocktail; ganaplacide; lumefantrine; midazolam; repaglinide; dextromethorphan; rosuvastatin; metformin; dolutegravir; CYP2C8; CYP2D6; CYP3A4; OATP1B1; MATE1; Pharmacokinetic; PK; safety and tolerability; healthy participants