Salivary Therapeutic Drug Monitoring of Anti-Tuberculosis Drugs

Completed

• Conditions: Tuberculosis

• Registration Number: NCT03080012
• Lead Sponsor: University Medical Center Groningen

Brief Summary

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

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.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2017-02-09
• Study Start: 2017-03-07
• Study First Submitted QC: 2017-03-08
• Study First Posted: 2017-03-15
• Primary Completion: 2018-05-02
• Study Completion: 2018-05-02
• Status Verified: 2018-11
• Last Update Submitted: 2018-11-20
• Last Update Posted: 2018-11-21

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 24

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

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Exclusion Criteria

• Patient with severe problems in the oral cavity, making saliva sampling painful

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Saliva-plasma ratio or saliva-serum ratio	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	Ratio of salivary versus blood concentration calculated with salivary and plasma/serum values of area under the time-concentration curve (AUC)

Secondary Outcome Measures

Name	Time	Method
Salivary drug concentration	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	Measured drug concentration in saliva
Plasma/serum drug concentration	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	Measured drug concentration in plasma or serum
Area under the time-concentration curve (AUC) in saliva and plasma/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	Calculated in both saliva and plasma/serum using the drug concentration at all time points.
Trough concentration (Cmin) in saliva and plasma/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	Calculated in both saliva and plasma/serum using the drug concentration at all time points.
Elimination constant (Kel) in saliva and plasma/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	Calculated in both saliva and plasma/serum using the drug concentration at all time points.
Peak concentration (Cmax) in saliva and plasma/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	Calculated in both saliva and plasma/serum using the drug concentration at all time points.
Half-life (t1/2) in saliva and plasma/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	Calculated in both saliva and plasma/serum using the drug concentration at all time points.
Time of peak concentration (Tmax) in saliva and plasma/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	Calculated in both saliva and plasma/serum using the drug concentration at all time points.
Clearance (Cl) in saliva and plasma/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	Calculated in both saliva and plasma/serum using the drug concentration at all time points.

Trial Locations

Locations (1)

University Medical Center Groningen (UMCG) Beatrixoord; 🇳🇱 Haren, Groningen, Netherlands