Effect of Rifabutin on the Pharmacokinetics of Oral Cabotegravir in Healthy Subjects
- Conditions
- Infection, Human Immunodeficiency VirusHIV Infections
- Interventions
- Registration Number
- NCT03149848
- Lead Sponsor
- ViiV Healthcare
- Brief Summary
This is a Phase I, single-center, open-label, fixed-sequence, 2-period crossover study in healthy adults to evaluate the effect of oral rifabutin (RBT) 300 milligram (mg) on the pharmacokinetics of oral cabotegravir (CAB) 30 milligram ( mg). This study will evaluate the drug-drug interaction (DDI) potential between CAB and RBT to inform dosing strategies for tuberculosis in subjects receiving CAB for human immunodeficiency virus (HIV) treatment or prevention. In Treatment Period 1 (Treatment A) participants will receive CAB 30 mg once daily for 14 days, followed by Treatment Period 2 (Treatment B) where participants will receive RBT 300 mg once daily with CAB 30 mg once daily for 14 days. The total study duration will be approximately for 10 weeks. Approximately 15 healthy subjects will be enrolled to ensure that 12 subjects complete dosing and critical assessments.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 15
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description Treatment A Cabotegravir Participants will be administered a single oral dose of CAB 30 mg after an overnight fast of at least 6 hours for 14 days in Period 1. Dosing of study medication on non-PK days may be with or without food. Treatment B Cabotegravir Participants will be administered a single dose of RBT 300 mg and a single dose of CAB 30 mg after an overnight fast of at least 6 hours once daily for 14 days in Period 2. Dosing of study medication on non-PK days may be with or without food. Treatment B Rifabutin Participants will be administered a single dose of RBT 300 mg and a single dose of CAB 30 mg after an overnight fast of at least 6 hours once daily for 14 days in Period 2. Dosing of study medication on non-PK days may be with or without food.
- Primary Outcome Measures
Name Time Method Assessment of Plasma CAB Pharmacokinetic (PK) Parameter: Area Under the Concentration-time Curve Over One Dosing Interval (AUC [0 to Tau]) Pre-dose (within 15 minutes prior to dose) on Days 13 and 14; and 1, 2, 3, 4, 8, 12, and 24 hours post-dose on Day 14, pre-dose (within 15 minutes prior to dose) on Days 26, 27 and 28; and 1, 2, 3, 4, 8, 12 and 24 hours post-dose on Day 28 Blood samples for PK analysis of CAB were collected at pre-dose (within 15 minutes prior to dose) on Days 13 and 14; and 1, 2, 3, 4, 8, 12, and 24 hours post-dose on Day 14, pre-dose (within 15 minutes prior to dose) on Days 26, 27 and 28; and 1, 2, 3, 4, 8, 12 and 24 hours post-dose on Day 28. AUC (0 to tau) was calculated using the linear trapezoidal rule for each incremental trapezoid and the log trapezoidal rule for each decremental trapezoid. PK Summary Population included participants who had CAB PK parameter estimates from both serial PK sampling time periods 1 and 2. Comparisons were made for the repeated dose PK parameters of CAB when given alone in Period 1 and when co-administered with steady-state RBT in Period 2.
Assessment of Plasma CAB PK Parameter: Maximum Observed Concentration (Cmax) Pre-dose (within 15 minutes prior to dose) on Days 13 and 14; and 1, 2, 3, 4, 8, 12, and 24 hours post-dose on Day 14, pre-dose (within 15 minutes prior to dose) on Days 26, 27 and 28; and 1, 2, 3, 4, 8, 12 and 24 hours post-dose on Day 28 Blood samples for PK analysis of CAB were collected at pre-dose (within 15 minutes prior to dose) on Days 13 and 14; and 1, 2, 3, 4, 8, 12, and 24 hours post-dose on Day 14, pre-dose (within 15 minutes prior to dose) on Days 26, 27 and 28; and 1, 2, 3, 4, 8, 12 and 24 hours post-dose on Day 28. Cmax was determined directly from the concentration-time data. Comparisons were made for the repeated dose PK parameters of CAB when given alone in Period 1 and when co-administered with steady-state RBT in Period 2.
- Secondary Outcome Measures
Name Time Method Assessment of Hematology Parameters: Erythrocytes Distribution Width (EDW) Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose) Blood samples for hematology assessment was collected for EDW. NA indicated data not available since only one participant was analyzed, therefore standard deviation was not derived. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Assessment of Plasma CAB PK Parameter: Concentration at the End of the Dosing Interval (Ctau) Pre-dose (within 15 minutes prior to dose) on Days 13 and 14; and 1, 2, 3, 4, 8, 12, and 24 hours post-dose on Day 14, pre-dose (within 15 minutes prior to dose) on Days 26, 27 and 28; and 1, 2, 3, 4, 8, 12 and 24 hours post-dose on Day 28 Blood samples for PK analysis of CAB were collected at pre-dose (within 15 minutes prior to dose) on Days 13 and 14; and 1, 2, 3, 4, 8, 12, and 24 hours post-dose on Day 14, pre-dose (within 15 minutes prior to dose) on Days 26, 27 and 28; and 1, 2, 3, 4, 8, 12 and 24 hours post-dose on Day 28. Comparisons were made for the repeated dose PK parameters of CAB when given alone in Period 1 and when co-administered with steady-state RBT in Period 2.
Assessment of Plasma CAB PK Parameter: Time of Occurrence of Cmax (Tmax) Pre-dose (within 15 minutes prior to dose) on Days 13 and 14; and 1, 2, 3, 4, 8, 12, and 24 hours post-dose on Day 14, pre-dose (within 15 minutes prior to dose) on Days 26, 27 and 28; and 1, 2, 3, 4, 8, 12 and 24 hours post-dose on Day 28 Blood samples for PK analysis of CAB were collected at pre-dose (within 15 minutes prior to dose) on Days 13 and 14; and 1, 2, 3, 4, 8, 12, and 24 hours post-dose on Day 14, pre-dose (within 15 minutes prior to dose) on Days 26, 27 and 28; and 1, 2, 3, 4, 8, 12 and 24 hours post-dose on Day 28. Tmax was determined directly from the concentration-time data.
Assessment of Plasma CAB PK Parameter: Terminal Phase Half-life (t1/2) Pre-dose (within 15 minutes prior to dose) on Days 13 and 14; and 1, 2, 3, 4, 8, 12, and 24 hours post-dose on Day 14, pre-dose (within 15 minutes prior to dose) on Days 26, 27 and 28; and 1, 2, 3, 4, 8, 12 and 24 hours post-dose on Day 28 Blood samples for PK analysis of CAB were collected at pre-dose (within 15 minutes prior to dose) on Days 13 and 14; and 1, 2, 3, 4, 8, 12, and 24 hours post-dose on Day 14, pre-dose (within 15 minutes prior to dose) on Days 26, 27 and 28; and 1, 2, 3, 4, 8, 12 and 24 hours post-dose on Day 28. Apparent terminal half-life was calculated as: t1/2 = ln2 / Lambda_z, where Lambda_z is the terminal phase rate constant. Plasma t1/2 was not estimated for either period due to limited PK sampling in the terminal phase.
Concurrent Medication Assessment in Treatment Period 1 and 2 Up to 10 weeks Concurrent medications included paracetamol and ibuprofen. Number of participants who took concurrent medications during the study are presented.
Assessment of Plasma CAB PK Parameter: The Apparent Oral Clearance (CL/F) Pre-dose (within 15 minutes prior to dose) on Days 13 and 14; and 1, 2, 3, 4, 8, 12, and 24 hours post-dose on Day 14, pre-dose (within 15 minutes prior to dose) on Days 26, 27 and 28; and 1, 2, 3, 4, 8, 12 and 24 hours post-dose on Day 28 Blood samples for PK analysis of CAB were collected at pre-dose (within 15 minutes prior to dose) on Days 13 and 14; and 1, 2, 3, 4, 8, 12, and 24 hours post-dose on Day 14, pre-dose (within 15 minutes prior to dose) on Days 26, 27 and 28; and 1, 2, 3, 4, 8, 12 and 24 hours post-dose on Day 28. CL/F was calculated as CL/F =Dose/AUC(0 to tau).
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) Up to 10 weeks An AE is any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect and associated with liver injury and impaired liver function. Safety Population comprised of all participants who enrolled in the study and received at least one dose of study drug.
Assessment of Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets and Leukocytes Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose) Blood samples for hematology assessment were collected for basophils, eosinophils, lymphocytes, monocytes, neutrophils, platelets and leukocytes. NA indicate data not available since only one participant was analyzed, therefore standard deviation was not derived. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Assessment of Hematology Parameters: Hematocrit and Reticulocytes/Erythrocytes (R/E) Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose) Blood samples for hematology assessment were collected for Hematocrit and R/E. NA indicate data not available since only one participant was analyzed, therefore standard deviation was not derived. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Assessment of Hematology Parameter: Hemoglobin Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose) Blood samples for hematology assessment was collected for Hemoglobin. NA indicate data not available since only one participant was analyzed, therefore standard deviation was not derived. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Assessment of Hematology Parameter: Eryrocyte Mean Corpuscular Hemoglobin Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose) Blood samples for hematology assessment was collected for Eryrocyte Mean Corpuscular Hemoglobin. NA indicated data not available since only one participant was analyzed, therefore standard deviation was not derived. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Assessment of Hematology Parameter: Erythrocye Mean Corpuscular Volume Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose) Blood samples for hematology assessment was collected for Erythrocyte Mean Corpuscular Volume. NA indicated data not available since only one participant was analyzed, therefore standard deviation was not derived. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Assessment of Hematology Parameters: Erythrocytes and Reticulocytes Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose) Blood samples for hematology assessment were collected for Erythrocytes and reticulocytes. NA indicated data not available since only one participant was analyzed, therefore standard deviation was not derived. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Assessment of Clinical Chemistry Parameters: Albumin and Protein Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose) Samples for clinical chemistry assessment were collected for Albumin and Protein. NA indicated data not available since only one participant was analyzed, therefore standard deviation was not derived. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Assessment of Clinical Chemistry Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Kinase (CK) and Gamma Glutamyl Transferase (GGT) Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose) Samples for clinical chemistry assessment were collected for ALP, AST, ALT, CK and GGT. NA indicated data not available since only one participant was analyzed, therefore standard deviation was not derived. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Assessment of Clinical Chemistry Parameters: Direct Bilirubin (DB), Bilirubin and Creatinine Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose) Samples for clinical chemistry assessment were collected for DB, bilirubin and creatinine. NA indicated data not available since only one participant was analyzed, therefore standard deviation was not derived. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Assessment of Clinical Chemistry Parameters: Calcium, Chloride, Carbon Dioxide, Glucose, Potassium, Sodium and Urea Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose) Samples for clinical chemistry assessment were collected for Calcium, Chloride, Carbon Dioxide, Glucose, Potassium, Sodium and Urea. NA indicated data not available since only one participant was analyzed, therefore standard deviation was not derived. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Number of Participants With Abnormal Urinalysis Result Day -1, Day 13, Day 21, Day 27 and follow-up (10 to 14 days after last dose) Samples for urinalysis assessment was collected at Day -1, Day 13, Day 21, Day 27 and during follow-up period (10 to 14 daya after last dose). Data for participants with abnormal urinalysis results has been presented.
Number of Participants With Abnormal Electrocardiogram (ECG) Findings Day 1, 14, 21, 28 and follow-up (10 to 14 days after last dose) ECG measurements was performed with the participant in a semi-supine position having rested in this position for at least 10 minutes beforehand. Data has been presented for Period 1, Day 14 pre-dose which showed abnormal- not clinically significant ECG finding. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Baseline to follow-up (10 to 14 days after last dose) Vital signs measurement was done in semi-supine position after 10 minutes rest and included SBP and DBP. Two blood pressure measurement were taken at pre-dose on Day 1, at least 1 minute apart. The mean value recorded at pre-dose was classified as Baseline. Single blood pressure was obtained at all other time points during the study. Change from Baseline was calculated by subtracting the post-dose value from the Baseline value. NA indicated data not available since only one participant was analyzed, therefore standard deviation was not derived. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Change From Baseline in Pulse Rate Baseline to follow-up (10 to 14 days after last dose) Vital signs measurement was done in semi-supine position after 10 minutes rest and included pulse rate. Two pulse rate measurement were taken at pre-dose on Day 1, at least 1 minute apart. The mean value recorded at pre-dose was classified as Baseline. Single pulse rate was obtained at all other time points during the study. Change from Baseline was calculated by subtracting the post-dose value from the Baseline value. NA indicated data not available since only one participant was analyzed, therefore standard deviation was not derived. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
Trial Locations
- Locations (1)
GSK Investigational Site
🇬🇧Cambridge, United Kingdom