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

Malaria Clinical Trial

Official title: 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

Status Completed

Clinical Trial 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.

Clinical Trial 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. ;

Related Conditions & MeSH terms

• Malaria

• NCT number: NCT05236530
• Study type: Interventional
• Source: Novartis
• Status: Completed
• Phase: Phase 1
• Start date: March 9, 2022
• Completion date: October 17, 2022