The purpose of this study is to assess pharmacokinetic parameters of atorvastatin at different doses when combined with the standard first line tuberculosis (TB) treatment regimen in adults with drug sensitive pulmonary TB. The pharmacokinetics parameters will be correlated with Pharmcodynamic measures and a PK/PD model that will identify an optimal dosing regimen of atorvastatin that is appropriate for the treatment of pulmonary tuberculosis will be developed.
Sputum specimen positive for tubercle bacilli on Gene Xpert or direct smear microscopy
Either no previous anti-TB chemotherapy, or less than 2 weeks of previous chemotherapy
Aged 12years and above
A firm home address that is readily accessible for visiting
Participants known or suspected of having any form of drug resistance TB.
Patients co infected with HIV
Those with poor general condition where no delay in treatment can be tolerated
Evidence of clinically significant metabolic or co morbid medical conditions ; malignancy; or other diseases like history of or current cardiovascular disorder such as heart failure, coronary heart disease, arrhythmia.
Parallel
Atorvastatin 20 mg
DrugParticipants will receive 16weeks of daily oral treatment with 20mg atorvastatin 4AT(20)\]
Atorvastatin 40 mg
DrugParticipants will receive 16 weeks of daily oral treatment with 40mg atorvastatin 4AT(40)\]
Atorvastatin 60 mg
DrugParticipants will receive 16weeks of daily oral treatment with 60mg atorvastatin 4AT(60)
Fixed dose combination of Rifampicin (R) Isoniazid (H) Pyrazinamid (Z) Ethambutol (E)
DrugParticipants will receive 8 weeks of daily oral treatment with rifampin, isoniazid, pyrazinamide, ethambutol, followed by 16 weeks of daily treatment with rifampin, isoniazid \[2RHZE/4RH\]
Area under the plasma concentration versus time curve (AUC 0-24) for atorvastatin acid, rifampicin, isoniazid and their metabolites at steady state
Sparse pharmacokinetic sampling will be employed during participants treatment follow up visits for the determination of plasma concentrations of atorvastatin acid, rifampicin, isoniazid. and their active metabolites (2-hydroxyl atorvastatin 4- hydroxyl atorvastatin, acetyl - isoniazid, desacetyl - rifampicin). AUC will be estimated using Population Pharmacokinetics analysis
Peak Plasma Concentration (Cmax) for atorvastatin acid, rifampicin, isoniazid and their metabolites at steady state
Sparse pharmacokinetic sampling will be employed during participants treatment follow up visits for the determination of plasma concentrations of atorvastatin acid, rifampicin, isoniazid. and their active metabolites (2-hydroxyl atorvastatin 4- hydroxyl atorvastatin, acetyl - isoniazid, desacetyl - rifampicin). Cmax will be estimated using Population Pharmacokinetics analysis
Plasma Clearance (Cl/F) in mL/min of atorvastatin acid, rifampicin, isoniazid and their metabolites at steady state
Sparse pharmacokinetic sampling will be employed during participants treatment follow up visits for the determination of plasma concentrations of atorvastatin acid, rifampicin, isoniazid. and their active metabolites (2-hydroxyl atorvastatin 4- hydroxyl atorvastatin, acetyl - isoniazid, desacetyl - rifampicin). Plasma clearance of aforementioned drugs and metabolites will be estimated using Population Pharmacokinetics analysis
Correlation between AUC 0-24 of atorvastatin acid, 2-hydroxyl atorvastatin and 4- hydroxyl atorvastatin at steady state and days 0-14 early bactericidal activity in participants on atorvastatin-based regimens
steady state AUC 0-24 of atorvastatin acid, 2-hydroxyl atorvastatin and 4- hydroxyl atorvastatin will be correlated with early bactericidal activity on day 14. Early bactericidal activity will be measured as the daily rate of change in log10 Colony Forming Units of M. Tuberculosis in Sputum on Solid Media
Correlation between Cmax of atorvastatin acid, 2-hydroxyl atorvastatin and 4- hydroxyl atorvastatin at steady state and days 0-14 early bactericidal activity in participants on atorvastatin-based regimens
Cmax of atorvastatin acid, 2-hydroxyl atorvastatin and 4- hydroxyl atorvastatin will be correlated with early bactericidal activity on day 14. Early bactericidal activity will be measured as the daily rate of change in log10 Colony Forming Units of M. Tuberculosis in Sputum on Solid Media
Correlation between Cmax of atorvastatin acid, 2-hydroxyl atorvastatin and 4- hydroxyl atorvastatin at steady state and time to stable sputum culture conversion
Time to achieve culture negative sputum result as measured by growth on solid mycobacteria culture medium
Correlation between AUC 0-24 of atorvastatin, atorvastatin acid, 2-hydroxyl atorvastatin and 4- hydroxyl atorvastatin) at steady state and change in baseline chest Xray severity score at 4, 6 and 12 months
Change in baseline chest Xray severity score as measured by Timika Chest X ray scoring system. At least 30% reduction in Chest x-ray severity score is desirable
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Obafemi Awolowo University Teaching Hospital
Lead sponsor
Open Philanthropy
Collaborator
Obafemi Awolowo University
Collaborator
