Drug-drug Interaction Study of Ganaplacide and Lumefantrine With Midazolam, Repaglinide, Dextromethorphan, Metformin, Rosuvastatin and Dolutegravir

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase I, Open-label, Fixed-sequence, Two-period, Crossover, Drug-drug Interaction Study to Evaluate the Effect of Multiple Doses of Ganaplacide and Lumefantrine Combination on the Pharmacokinetics of Midazolam, Repaglinide, Dextromethorphan, Metformin, Rosuvastatin and Dolutegravir in Healthy Participants

Conditions
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Malaria

Intervention / Treatment
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* Drug: Midazolam
* Drug: Repaglinide
* Drug: Dextromethorphan
* Drug: Metformin
* Drug: Ganaplacide
* Combination Product: Lumefantrine
* Drug: Rosuvastatin
* Drug: Dolutegravir
* Drug: Ganaplacide
* Combination Product: Lumefantrine


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Signed informed consent must be obtained prior to participation in the study. Healthy male and non-childbearing potential female participants 18 to 55 years of age inclusive, at Screening. In good health as determined by medical history, physical examination, vital signs, ECG and clinical laboratory tests at Screening. Must weigh at least 50 kg with a body mass index (BMI) within the range of 18.0 to 29.9 kg/m2 inclusive, at Screening. Key Exclusion Criteria: Use of other investigational drugs within 5 half-lives or 30 days prior to first dosing of study treatment, whichever is longer. Known family history or presence of long QT syndrome. Known history or current clinically significant arrhythmias. History or presence of malignancy of any organ system (other than treated localized basal cell or squamous cell carcinoma of the skin or in-situ cervical cancer), treated or untreated, within 5 years of Screening, regardless of whether there is evidence of local recurrence or metastases. History or presence of duodenal ulcer, ulcerative colitis or Crohn's disease. Presence of active or uncontrolled thyroid disease. Has had cholecystectomy (gallbladder removed). Other protocol-defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Each participant will receive a single oral dose of the 4-probe substrate cocktail consisting of midazolam, repaglinide, dextromethorphan and metformin in the morning of Day 1 of Period 1. In Period 2, participants will receive ganaplacide and lumefantrine combination orally once daily (q.d.) in the morning on Days 1 through 3, with a single oral dose of the 4-probe substrate cocktail co-administered on Day 3. | Drug: Midazolam<br>* 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.<br>Drug: Repaglinide<br>* 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.<br>Drug: Dextromethorphan<br>* 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.<br>Drug: Metformin<br>* 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.<br>Drug: Ganaplacide<br>* 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.<br>* Other names: KAF156;Combination Product: Lumefantrine<br>* 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.<br>* Other names: LUM566;|
| Experimental: Cohort 2<br>Each participant will receive a single oral dose of the 2 probe substrate cocktail consisting of rosuvastatin and dolutegravir in the morning on Day 1 of Period 1. In Period 2, participants will receive ganaplacide and lumefantrine combination orally q.d. in the morning on Days 1 through 3, with a single oral dose of the 2 probe substrate cocktail co-administered on Day 3. | Drug: Rosuvastatin<br>* 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.<br>Drug: Dolutegravir<br>* 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.<br>Drug: Ganaplacide<br>* 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.<br>* Other names: KAF156;Combination Product: Lumefantrine<br>* 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.<br>* Other names: LUM566;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Observed maximum plasma concentration (Cmax) for midazolam, repaglinide, dextromethorphan and metformin | Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Cmax will be listed and summarized using descriptive statistics. | 0 (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post dose. | 
| Area under the serum concentration-time curve from time zero to the time of last quantifiable concentration (AUClast) for midazolam, repaglinide, dextromethorphan and metformin | Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. AUClast will be listed and summarized using descriptive statistics. | 0 (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post dose. | 
| Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUCinf) for midazolam, repaglinide, dextromethorphan and metformin | Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. AUCinf will be listed and summarized using descriptive statistics. | 0 (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post dose. | 
| Time of maximum observed drug concentration occurrence (Tmax) for midazolam, repaglinide, dextromethorphan and metformin | Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Tmax will be listed and summarized using descriptive statistics. | 0 (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post dose. | 
| Apparent total body clearance of drug from plasma following extravascular administration (CL/F) for midazolam, repaglinide, dextromethorphan and metformin | Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. CL/F will be listed and summarized using descriptive statistics. | 0 (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post dose. | 
| Apparent volume of distribution during terminal elimination phase following extravascular administration (Vz/F) for midazolam, repaglinide, dextromethorphan and metformin | Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Vz/F will be listed and summarized using descriptive statistics. | 0 (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post dose. | 
| Terminal elimination half-life (T^1/2) for midazolam, repaglinide, dextromethorphan and metformin | Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. T^1/2 will be listed and summarized using descriptive statistics. | 0 (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post dose. | 
| Observed maximum plasma concentration (Cmax) for rosuvastatin and dolutegravir | Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Cmax will be listed and summarized using descriptive statistics. | 0 (pre dose) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours post dose. | 
| Area under the serum concentration-time curve from time zero to the time of last quantifiable concentration (AUClast) for rosuvastatin and dolutegravir | Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. AUClast will be listed and summarized using descriptive statistics. | 0 (pre dose) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours post dose. | 
| Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUCinf) for rosuvastatin and dolutegravir | Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. AUCinf will be listed and summarized using descriptive statistics. | 0 (pre dose) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours post dose. | 
| Time of maximum observed drug concentration occurrence (Tmax) for rosuvastatin and dolutegravir | Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Tmax will be listed and summarized using descriptive statistics. | 0 (pre dose) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours post dose. | 
| Apparent total body clearance of drug from plasma following extravascular administration (CL/F) for rosuvastatin and dolutegravir | Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. CL/F will be listed and summarized using descriptive statistics. | 0 (pre dose) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours post dose. | 
| Apparent volume of distribution during terminal elimination phase following extravascular administration (Vz/F) for rosuvastatin and dolutegravir | Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Vz/F will be listed and summarized using descriptive statistics. | 0 (pre dose) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours post dose. | 
| Terminal elimination half-life (T^1/2) for rosuvastatin and dolutegravir | Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. T^1/2 will be listed and summarized using descriptive statistics. | 0 (pre dose) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours post dose. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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OATP1B1, MATE1, Drug-drug interaction, DDI, probe, cocktail, ganaplacide, lumefantrine, midazolam, repaglinide, dextromethorphan, rosuvastatin, metformin, dolutegravir, CYP2C8, CYP2D6, CYP3A4, Pharmacokinetic, PK, safety and tolerability, healthy participants