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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.
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.
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Saliva sampling | Other | Stimulated saliva samples are taken using cotton rolls. | ||
| Plasma/serum sampling | Other | Simultaneously with saliva sampling. |
| 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 |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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Tuberculosis patients of University Medical Center Groningen Beatrixoord, Haren, The Netherlands.
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| Name | Affiliation | Role |
|---|---|---|
| Jan-Willem Alffenaar, PhD, PharmD | University Medical Center Groningen | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University Medical Center Groningen (UMCG) Beatrixoord | Haren | Provincie Groningen | 9751ND | Netherlands |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 32398308 | Derived | van den Elsen SHJ, Akkerman OW, Wessels M, Jongedijk EM, Ghimire S, van der Werf TS, Bolhuis MS, Touw DJ, Alffenaar JC. Dose optimisation of first-line tuberculosis drugs using therapeutic drug monitoring in saliva: feasible for rifampicin, not for isoniazid. Eur Respir J. 2020 Oct 22;56(4):2000803. doi: 10.1183/13993003.00803-2020. Print 2020 Oct. No abstract available. | |
| 31980497 |
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Encoded data can be shared for scientific use up to 15 years after study completion.
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| ID | Term |
|---|---|
| D014376 | Tuberculosis |
| ID | Term |
|---|---|
| D009164 | Mycobacterium Infections |
| D000193 | Actinomycetales Infections |
| D016908 | Gram-Positive Bacterial Infections |
| D001424 | Bacterial Infections |
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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 |
| Derived |
| van den Elsen SHJ, Akkerman OW, Jongedijk EM, Wessels M, Ghimire S, van der Werf TS, Touw DJ, Bolhuis MS, Alffenaar JC. Therapeutic drug monitoring using saliva as matrix: an opportunity for linezolid, but challenge for moxifloxacin. Eur Respir J. 2020 May 7;55(5):1901903. doi: 10.1183/13993003.01903-2019. Print 2020 May. No abstract available. |
| 29326320 | Derived | van den Elsen SHJ, Akkerman OW, Huisman JR, Touw DJ, van der Werf TS, Bolhuis MS, Alffenaar JC. Lack of penetration of amikacin into saliva of tuberculosis patients. Eur Respir J. 2018 Jan 11;51(1):1702024. doi: 10.1183/13993003.02024-2017. Print 2018 Jan. No abstract available. |
| D001423 | Bacterial Infections and Mycoses |
| D007239 | Infections |