Clinical trial NCT03080012: Salivary Therapeutic Drug Monitoring of Anti-Tuberculosis Drugs
Official title: An Observational Study of Salivary Versus Blood Concentrations of Various Anti-Tuberculosis Drugs in Tuberculosis Patients
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Tuberculosis
Lead sponsor: University Medical Center Groningen
Sponsor class: OTHER
First posted: 2017-03-15
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Tuberculosis patients of University Medical Center Groningen Beatrixoord, Haren, The Netherlands.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Saliva-plasma ratio or saliva-serum ratio
timeFrame: 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 outcomes:
measure: Salivary drug concentration
timeFrame: 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: Plasma/serum drug concentration
timeFrame: 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: Area under the time-concentration curve (AUC) in saliva and plasma/serum
timeFrame: 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: Peak concentration (Cmax) in saliva and plasma/serum
timeFrame: 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: Time of peak concentration (Tmax) in saliva and plasma/serum
timeFrame: 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: Trough concentration (Cmin) in saliva and plasma/serum
timeFrame: 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: Clearance (Cl) in saliva and plasma/serum
timeFrame: 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: Half-life (t1/2) in saliva and plasma/serum
timeFrame: 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: Elimination constant (Kel) in saliva and plasma/serum
timeFrame: 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
Other outcomes:
Locations:
city: Haren
country: Netherlands
facility: University Medical Center Groningen (UMCG) Beatrixoord
state: Groningen
Study officials:
affiliation: University Medical Center Groningen
name: Jan-Willem Alffenaar, PhD, PharmD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.