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

NCT05236530 | Completed Phase 1

• 1 other identifier: CKAF156A2104
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Malaria

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

Outcome Measures

Primary Outcomes (14)

• 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.

Study Arms (2)

Cohort 1

EXPERIMENTAL

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; Drug: Repaglinide; Drug: Dextromethorphan; Drug: Metformin; Drug: Ganaplacide; Combination Product: Lumefantrine

Cohort 2

EXPERIMENTAL

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; Drug: Dolutegravir; Drug: Ganaplacide; Combination Product: Lumefantrine

Interventions

Midazolam DRUG

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.

Cohort 1

Repaglinide DRUG

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.

Cohort 1

Dextromethorphan DRUG

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.

Cohort 1

Metformin DRUG

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.

Cohort 1

Ganaplacide DRUG

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.

Also known as: KAF156

Cohort 1

Lumefantrine COMBINATION_PRODUCT

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.

Also known as: LUM566

Cohort 1

Rosuvastatin DRUG

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.

Cohort 2

Dolutegravir DRUG

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.

Cohort 2

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead
• Medicines for Malaria Venture: collaborator

Study Sites (1)

Novartis Investigative Site

Belfast, Northern Ireland, BT9 6AD, United Kingdom

Location

MeSH Terms

Conditions

Malaria

Interventions

Midazolam; repaglinide; Dextromethorphan; Metformin; ganaplacide; Lumefantrine; Rosuvastatin Calcium; dolutegravir

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Intervention Hierarchy (Ancestors)

Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; Biguanides; Guanidines; Amidines; Organic Chemicals; Fluorenes; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sulfonamides; Amides; Fluorobenzenes; Hydrocarbons, Fluorinated; Hydrocarbons, Halogenated; Sulfones; Sulfur Compounds; Pyrimidines; Heterocyclic Compounds, 1-Ring

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 4, 2022
• First Posted: February 11, 2022
• Study Start: March 9, 2022
• Primary Completion: October 17, 2022
• Study Completion: October 17, 2022
• Last Updated: November 4, 2022

Record last verified: 2022-11

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)