# Saliva as an Alternative Matrix for Pharmacokinetic Research and Therapeutic Drug Monitoring of the Antituberculosis Drug Pyrazinamide

## TL;DR

This study explores using saliva instead of blood to monitor pyrazinamide levels in tuberculosis patients, finding saliva can predict blood drug levels with some accuracy.

## Contribution

The study introduces saliva as a potential alternative matrix for pyrazinamide pharmacokinetic monitoring with a proposed conversion factor.

## Key findings

- Saliva pyrazinamide concentrations were lower than plasma but showed similar peak timing.
- A saliva/plasma ratio of 0.59 was observed, allowing for plasma concentration prediction from saliva.
- Using a conversion factor of 1.49 improved prediction accuracy during the 2–6 hour post-dose interval.

## Abstract

Introduction: Plasma is the standard biological fluid used in pharmacokinetic (PK) studies and therapeutic drug monitoring (TDM) of pyrazinamide, a key antituberculosis (TB) drug. This study described the PK of pyrazinamide in saliva and investigated whether saliva could serve as an alternative matrix for pyrazinamide PK evaluations. Methods: Fifteen adult Tanzanian TB patients in the intensive treatment phase participated in a descriptive PK study. Time-matched saliva (stimulated using a Salivette® with citric acid) and plasma samples were collected at multiple intervals up to 24 h after drug intake. Pyrazinamide concentrations were measured using validated HPLC methods, exposure measures were assessed, and predictive performance for salivary concentrations was determined. Results: Salivary exposure to pyrazinamide (AUC0–24h: 230 h·mg/L; Cmax: 28.6 mg/L) was lower than plasma exposure (AUC0–24h: 377 h·mg/L; Cmax: 36.4 mg/L, p < 0.001), but Tmax was similar (median 2.0 h, p = 0.893). A saliva/plasma ratio of 0.59 was assessed, and a reciprocal conversion factor of 1.68 allowed for reasonably accurate (bias 5.8%) but imprecise (imprecision 24.3%) plasma concentration predictions from saliva. Use of a conversion factor of 1.49, based on more stable saliva/plasma concentration ratios for samples between 2 and 6 h post-dose, resulted in a bias of 0.74% and imprecision of 17.7% for predicting plasma concentrations from salivary concentrations in the 2–6 h interval. Conclusions: The exposure to pyrazinamide in saliva is relatively high. Salivary measurement of pyrazinamide can be used as a semi-quantitative predictor of pyrazinamide plasma concentrations.