Clinical trial
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
Name
CKAF156A2104
Description
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.
Trial arms
Trial start
2022-03-09
Estimated PCD
2022-10-17
Trial end
2022-10-17
Status
Completed
Phase
Early phase I
Treatment
Midazolam
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.
Arms:
Cohort 1
Repaglinide
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.
Arms:
Cohort 1
Dextromethorphan
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.
Arms:
Cohort 1
Metformin
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.
Arms:
Cohort 1
Ganaplacide
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.
Arms:
Cohort 1
Other names:
KAF156
Lumefantrine
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.
Arms:
Cohort 1
Other names:
LUM566
Rosuvastatin
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.
Arms:
Cohort 2
Dolutegravir
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.
Arms:
Cohort 2
Ganaplacide
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.
Arms:
Cohort 2
Other names:
KAF156
Lumefantrine
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.
Arms:
Cohort 2
Other names:
LUM566
Size
48
Primary endpoint
Observed maximum plasma concentration (Cmax) for midazolam, repaglinide, dextromethorphan and metformin
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
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
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
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
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
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
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
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
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
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
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
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
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
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.
Eligibility criteria
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.
Protocol
{'studyType': 'INTERVENTIONAL', 'phases': ['PHASE1'], 'designInfo': {'allocation': 'RANDOMIZED', 'interventionModel': 'SEQUENTIAL', 'primaryPurpose': 'TREATMENT', 'maskingInfo': {'masking': 'NONE'}}, 'enrollmentInfo': {'count': 48, 'type': 'ACTUAL'}}
Updated at
2022-11-04
1 organization
8 products
1 indication
Organization
Novartis PharmaceuticalsProduct
MidazolamIndication
MalariaProduct
DextromethorphanProduct
RosuvastatinProduct
RepaglinideProduct
MetforminProduct
GanaplacideProduct
LumefantrineProduct
Dolutegravir