Salivary Therapeutic Drug Monitoring of Anti-Tuberculosis Drugs

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

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.

Study Overview

• Status: Completed
• Conditions: Tuberculosis
• Intervention / Treatment: Other: Saliva sampling; Other: Plasma/serum sampling

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.

• Study Type: Observational
• Enrollment (Actual): 24

Contacts and Locations

Study Locations

• Netherlands
  • Groningen
    • Haren, Groningen, Netherlands, 9751ND
      • University Medical Center Groningen (UMCG) Beatrixoord

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Tuberculosis patients of University Medical Center Groningen Beatrixoord, Haren, The Netherlands.

Description

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

Study Plan

How is the study designed?

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University Medical Center Groningen
• Investigators: Principal Investigator: Jan-Willem Alffenaar, PhD, PharmD, University Medical Center Groningen

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 7, 2017
• Primary Completion (ACTUAL): May 2, 2018
• Study Completion (ACTUAL): May 2, 2018

Study Registration Dates

• First Submitted: February 9, 2017
• First Submitted That Met QC Criteria: March 8, 2017
• First Posted (ACTUAL): March 15, 2017

Study Record Updates

• Last Update Posted (ACTUAL): November 21, 2018
• Last Update Submitted That Met QC Criteria: November 20, 2018
• Last Verified: November 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis
• Other Study ID Numbers: SALIV-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Encoded data can be shared for scientific use up to 15 years after study completion.