Saliva as a sampling matrix for therapeutic drug monitoring of gentamicin in neonates: A prospective population pharmacokinetic and simulation study

Abstract

Therapeutic drug monitoring (TDM) of gentamicin in neonates is recommended for safe and effective dosing and is currently performed by plasma sampling, which is an invasive and painful procedure. In this study, feasibility of a non-invasive gentamicin TDM strategy using saliva was investigated.Methods: This was a multicentre, prospective, observational cohort study including 54 neonates. Any neonate treated with intravenous gentamicin was eligible for the study. Up to eight saliva samples were collected per patient at different time-points.Gentamicin levels in saliva were determined with liquid chromatography tandem mass-spectrometry (LC-MS/MS). A population pharmacokinetic (PK) model was developed using nonlinear mixed-effects modelling (NONMEM) to describe the relation between gentamicin concentrations in saliva and plasma. Monte Carlo simulations with a representative virtual cohort (n = 3000) were performed to evaluate the probability of target attainment with saliva versus plasma TDM.Results: Plasma PK was adequately described with an earlier published model. An additional saliva compartment describing the salivary gentamicin concentrations was appended to the model with first-order input (k 13 0.023 h À1 ) and first-order elimination (k 30 0.169 h À1 ). Inter-individual variability of k 30 was 38%. Postmenstrual age Amadou Samb and Matthijs Kruizinga contributed equally to this study.The authors confirm that the Principal Investigator for this paper is Timo R. de Haan and that he had direct clinical responsibility for patients.

Therapeutic drug monitoring of amikacin in preterm and term neonates with late‐onset sepsis. Can saliva samples replace plasma samples?

“…Thus, it seems that low detection limits of the quantification method is essential for the development of a saliva TDM method of aminoglycosides. We have previously investigated and reported that gentamicin is distributed in the saliva of NICU admitted neonates with (suspected) early‐onset sepsis 7 . Moreover, gentamicin PK in plasma and saliva was described and TDM using 4 saliva samples was shown to be feasible, with a pTA of 81%, similar to our findings for amikacin as reported in the present study.…”

“…This finding is evident when comparing the salivary amikacin PK profile of premature and term neonates, as depicted in Figure 2. The aforementioned findings demonstrate high similarities to our previous study with gentamicin, as the final model structure is near identical 7 . Moreover, results from that study also suggested that higher salivary gentamicin levels are present in premature neonates, when compared to term neonates, possibly reflecting differences in blood/saliva barrier development.…”

“…Moreover, saliva sampling is safe, fast, low‐cost and requires little training 6 . We recently found that saliva could potentially serve as a sampling matrix for the TDM of gentamicin, another aminoglycoside 7 . Although a number of studies investigating salivary TDM of aminoglycosides in different populations have been conducted with varying results, no studies specifically investigating salivary amikacin TDM in the NICU setting have been performed 8–11 …”

Electrochemical Aptamer-Based Biosensors for Measurements in Undiluted Human Saliva

“…8 Thus, measuring concentrations of molecules directly in undiluted saliva can prove transformative in the early detection and diagnostic of diseases to support decision-making in treatments. 1,4,9,10 Current techniques for salivary molecular measurements rely on high-performance liquid chromatography 11−14 and immuno or lateral flow assays. 15−21 Despite their high accuracy and sensitivity, chromatographic methods and immunoassays require cumbersome, laboratory-bound, and expensive instru-ments operated by trained personnel to only provide a single snapshot of one's health hours to days after sample collection, 22,23 which ultimately causes delayed diagnostics and higher analysis costs.…”

“…Saliva, in contrast, through natural drooling, can be collected with minimal effort and discomfort from patients, − thus offering an alternative biological matrix. − In a clinical setting, saliva has been reported to be informative as it contains biomarkers with highly correlated concentrations to ones measured in blood . Thus, measuring concentrations of molecules directly in undiluted saliva can prove transformative in the early detection and diagnostic of diseases to support decision-making in treatments. ,,, …”