A descriptive systematic review of salivary therapeutic drug monitoring in neonates and infants

Abstract

AIMSSaliva, as a matrix, offers many benefits over blood in therapeutic drug monitoring (TDM), in particular for infantile TDM. However, the accuracy of salivary TDM in infants remains an area of debate. This review explored the accuracy, applicability and advantages of using saliva TDM in infants and neonates. METHODSDatabases were searched up to and including September 2016. Studies were included based on PICO as follows: P: infants and neonates being treated with any medication, I: salivary TDM vs. C: traditional methods and O: accuracy, advantages/disadvantages and applicability to practice. Compounds were assessed by their physicochemical and pharmacokinetic properties, as well as published quantitative saliva monitoring data. RESULTSTwenty-four studies and their respective 13 compounds were investigated. Four neutral and two acidic compounds, oxcarbazepine, primidone, fluconazole, busulfan, theophylline and phenytoin displayed excellent/very good correlation between blood plasma and saliva. Lamotrigine was the only basic compound to show excellent correlation with morphine exhibiting no correlation between saliva and blood plasma. Any compound with an acid dissociation constant (pKa) within physiological range (pH 6-8) gave a more varied response. CONCLUSIONThere is significant potential for infantile saliva testing and in particular for neutral and weakly acidic compounds. Of the properties investigated, pKa was the most influential with both logP and protein binding having little effect on this correlation. To conclude, any compound with a pKa within physiological range (pH 6-8) should be considered with extra care, with the extraction and analysis method examined and optimized on a case-by-case basis.

Therapeutic Drug Monitoring Is a Feasible Tool to Personalize Drug Administration in Neonates Using New Techniques: An Overview on the Pharmacokinetics and Pharmacodynamics in Neonatal Age

“…Phenobarbital administered to neonates under whole-body TH resulted in higher plasmatic concentrations and longer half-lives than expected in their normothermic peers [131], although no clinically relevant effect of TH on phenobarbital were identified with an observed responsiveness of 66% in a Dutch study [132]. According to the results of the Pharma-Cool study, TH did not influence clearance of PB or MID in (near-)term neonates with HIE but a PB dose of 30 mg/kg (instead of 20 mg/kg) was advised to reach therapeutic concentrations [46]. Furthermore, PB co-administration significantly increased MID clearance and a 50% lower MID maintenance dose might be more appropriate during the first days after birth.…”

“…However, dissociation constants of drug and salivary pH are primarily involved in this process. Indeed, neutral, and very weakly acidic drugs showed an excellent correlation between saliva and plasma [46]. Although collecting samples through spitting into tubes is the simpler method in adults and children, this is challenging in neonates.…”

Therapeutic Drug Monitoring Characteristics in a Tertiary University Hospital in 2019

“…For a better drug response, other biological fluids that can be obtained noninvasively, such as saliva, should be considered for TDM. Saliva samples may provide accurate levels for some drugs and might be chosen in the pediatric age group [10].…”

Membrane Transporters in Human Parotid Gland-Targeted Proteomics Approach

“…However, as evidenced in the present study, salivary expression of drug transporters may modulate the rate of salivary drug secretion (also variable due to altered activity of the drug transporters subjected to endo- and exogenous inhibitors/inducers). The engagement of the drug transporters in salivary glands may thus constitute one of the limitations (apart from, e.g., physico-chemical drug properties, blood pH and blood protein binding) for therapeutic drug monitoring [46,48,49].…”