How Feasible is the Use of Saliva for Antiviral Therapeutic Drug Monitoring? A Systematic Review and Analysis

Abstract

Immunosuppressed patients are susceptible to serious viral infections, often necessitating antiviral prophylaxis and/or treatment. Therapeutic drug monitoring (TDM) has been proposed to optimise drug exposure and clinical outcomes and is typically performed on full blood/plasma samples. Saliva offers a less invasive, patient-friendly approach, and this systematic review aims to assess the feasibility of saliva-based assays for antiviral TDM. We conducted a search on MEDLINE, EMBASE and ClinicalTrials.gov databases, governmental regulatory websites and conference abstracts. Primary studies reporting both saliva and plasma concentrations of antivirals used forprophylaxis or treatment of opportunistic viral infections were included. Physicochemical properties of eachantiviral were compiled from PubChem and DrugBank to predict salivary excretion. Feasibility classifications were defined as follows: (1) likely, (2) possible, (3) unlikely, (4) unclear but possible, (5) unclear but unlikely . We included nine studies in our review. (Val)acyclovir and favipiravir were considered possibly feasible for saliva-based TDM, whereas molnupiravir and oseltamivir were unclear but possible. Nirmatrelvir was deemed unclear but unlikely. For other included antivirals, no primary studies were available, however, physicochemical profiles suggest that salivary penetration may be feasible for some agents but limited for others. Studies documenting both saliva and plasma concentrations were scarce, and data was inconsistent. Findings from clinical studies sometimes contradicted predictions of penetration based on drug properties, suggesting that other factors, such as drug transporters, may significantly influence the salivary excretion of antivirals. Future robust, standardised investigations are required to confirm the clinical utility of saliva-based TDM. Feasibility is therefore currently inconclusive, but preliminary evidence is promising.