Salivary Therapeutic Drug Monitoring of Anti-Tuberculosis Drugs

Study Overview
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Brief Summary
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In tuberculosis patients, salivary concentrations will be compared to plasma/serum concentrations of several anti-tuberculosis drugs. If salivary concentrations correctly represent blood concentrations, this non-invasive sampling of saliva could be used for TDM of the tested drugs.

Detailed Description
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TDM (Therapeutic Drug Monitoring) with blood samples is already part of the treatment of some tuberculosis (TB) patients to reduce development of drug resistance and toxic drug concentrations. Performing TDM with saliva instead of plasma or serum could reduce the burden of blood sampling. This study examines if this non-invasive sampling of saliva could be used for TDM of several anti-TB drugs. The study is an observational cohort study with adult tuberculosis patients as subjects. The drugs that are studied are isoniazid, rifampicin, ethambutol, pyrazinamide, moxifloxacin, amikacin, kanamycin, capreomycin, ethionamide, prothionamide, cycloserine, terizidone, linezolid, clofazimine, bedaquiline, delamanid, p-aminosalicylic acid (PAS), imipenem-cilastatin, meropenem, ertapenem, amoxicillin-clavulanate and thioacetazone. Saliva samples will be taken simultaneously with blood samples for standard TDM. Serum/plasma and saliva drug concentrations will be determined with a validated LC-MS/MS (liquid chromatography-tandem mass spectrometry) method. The correlation and linearity between saliva and plasma/serum concentrations will be tested. The saliva-plasma or serum ratio based on area under the time-concentration curve (AUC) is calculated for the investigated anti-TB drugs. Also pharmacokinetic parameters in serum/plasma and saliva will be calculated and compared to provide a complete image of pharmacokinetics of the anti-TB drugs in saliva.

Official Title
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An Observational Study of Salivary Versus Blood Concentrations of Various Anti-Tuberculosis Drugs in Tuberculosis Patients

Conditions
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Tuberculosis

Intervention / Treatment
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* Other: Saliva sampling
* Other: Plasma/serum sampling


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Tuberculosis is confirmed by culture or molecular test Patient is treated with anti-tuberculosis drugs included in study Patient receives Therapeutic Drug Monitoring (TDM) in routine care Patient signed informed consent Exclusion Criteria: Patient with severe problems in the oral cavity, making saliva sampling painful

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Intervention/Treatment |
| --- |
|Other: Saliva sampling|Stimulated saliva samples are taken using cotton rolls.|
|Other: Plasma/serum sampling|Simultaneously with saliva sampling.|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Saliva-plasma ratio or saliva-serum ratio | Ratio of salivary versus blood concentration calculated with salivary and plasma/serum values of area under the time-concentration curve (AUC) | 0, 0.5, 1, 2, 3, 4, 7 hours post-dose for isoniazid, rifampicin, ethambutol and pyrazinamide or 0, 1, 2, 3, 4, 8 hours post-dose for all other drugs | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Salivary drug concentration | Measured drug concentration in saliva | 0, 0.5, 1, 2, 3, 4, 7 hours post-dose for isoniazid, rifampicin, ethambutol and pyrazinamide or 0, 1, 2, 3, 4, 8 hours post-dose for all other drugs | 
| Plasma/serum drug concentration | Measured drug concentration in plasma or serum | 0, 0.5, 1, 2, 3, 4, 7 hours post-dose for isoniazid, rifampicin, ethambutol and pyrazinamide or 0, 1, 2, 3, 4, 8 hours post-dose for all other drugs | 
| Area under the time-concentration curve (AUC) in saliva and plasma/serum | Calculated in both saliva and plasma/serum using the drug concentration at all time points. | 0, 0.5, 1, 2, 3, 4, 7 hours post-dose for isoniazid, rifampicin, ethambutol and pyrazinamide or 0, 1, 2, 3, 4, 8 hours post-dose for all other drugs | 
| Peak concentration (Cmax) in saliva and plasma/serum | Calculated in both saliva and plasma/serum using the drug concentration at all time points. | 0, 0.5, 1, 2, 3, 4, 7 hours post-dose for isoniazid, rifampicin, ethambutol and pyrazinamide or 0, 1, 2, 3, 4, 8 hours post-dose for all other drugs | 
| Time of peak concentration (Tmax) in saliva and plasma/serum | Calculated in both saliva and plasma/serum using the drug concentration at all time points. | 0, 0.5, 1, 2, 3, 4, 7 hours post-dose for isoniazid, rifampicin, ethambutol and pyrazinamide or 0, 1, 2, 3, 4, 8 hours post-dose for all other drugs | 
| Trough concentration (Cmin) in saliva and plasma/serum | Calculated in both saliva and plasma/serum using the drug concentration at all time points. | 0, 0.5, 1, 2, 3, 4, 7 hours post-dose for isoniazid, rifampicin, ethambutol and pyrazinamide or 0, 1, 2, 3, 4, 8 hours post-dose for all other drugs | 
| Clearance (Cl) in saliva and plasma/serum | Calculated in both saliva and plasma/serum using the drug concentration at all time points. | 0, 0.5, 1, 2, 3, 4, 7 hours post-dose for isoniazid, rifampicin, ethambutol and pyrazinamide or 0, 1, 2, 3, 4, 8 hours post-dose for all other drugs | 
| Half-life (t1/2) in saliva and plasma/serum | Calculated in both saliva and plasma/serum using the drug concentration at all time points. | 0, 0.5, 1, 2, 3, 4, 7 hours post-dose for isoniazid, rifampicin, ethambutol and pyrazinamide or 0, 1, 2, 3, 4, 8 hours post-dose for all other drugs | 
| Elimination constant (Kel) in saliva and plasma/serum | Calculated in both saliva and plasma/serum using the drug concentration at all time points. | 0, 0.5, 1, 2, 3, 4, 7 hours post-dose for isoniazid, rifampicin, ethambutol and pyrazinamide or 0, 1, 2, 3, 4, 8 hours post-dose for all other drugs |