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Background and Objectives Saliva is a patient-friendly matrix for therapeutic drug monitoring (TDM) but is infrequently used in routine care. This is due to the uncertainty of saliva-based TDM results to inform dosing. This study aimed to retrieve data on saliva-plasma concentration and subsequently determine the physicochemical properties that influence the excretion of drugs into saliva to increase the foundational knowledge underpinning saliva-based TDM. Methods Medline, Web of Science and Embase (1974-2023) were searched for human clinical studies, which determined drug pharmacokinetics in both saliva and plasma. Studies with at least ten subjects and five paired saliva-plasma concentrations per subject were included. For each study, the ratio of the area under the concentration-time curve between saliva and plasma was determined to assess excretion into saliva. Physicochemical properties of each drug (e.g. pKa, lipophilicity, molecular weight, polar surface area, rotatable bonds and fraction of drug unbound to plasma proteins) were obtained from PubChem and Drugbank. Drugs were categorised by their ionisability, after which saliva-to-plasma ratios were predicted with adjustment for protein binding and physiological pH via the Henderson-Hasselbalch equation. Spearman correlation analyses were performed for each drug category to identify factors predicting saliva excretion (α = 5%). Study quality was assessed by the risk of bias in non-randomised studies of interventions tool. Results Overall, 42 studies including 40 drugs (anti-psychotics, anti-microbials, immunosuppressants, anti-thrombotic, anti-cancer and cardiac drugs) were included. The median saliva-to-plasma ratios were similar for drugs in the amphoteric (0.59), basic (0.43) and acidic (0.41) groups and lowest for drugs in the neutral group (0.21). Higher excretion of acidic drugs (n = 5) into saliva was associated with lower ionisation and protein binding (correlation between predicted versus observed saliva-to-plasma ratios: R 2 = 0.85, p = 0.02). For basic drugs (n = 21), pKa predicted saliva excretion (Spearman correlation coefficient: R = 0.53, p = 0.02). For amphoteric drugs (n = 10), hydrogen bond donor (R = − 0.76, p = 0.01) and polar surface area (R = − 0.69, p = 0.02) were predictors. For neutral drugs (n = 10), protein binding (R = 0.84, p = 0.004), lipophilicity (R = − 0.65, p = 0.04) and hydrogen bond donor count (R = − 0.68, p = 0.03) were predictors. Drugs considered potentially suitable for saliva-based TDM are phenytoin, tacrolimus, voriconazole and lamotrigine. The studies had a low-to-moderate risk of bias. Conclusions Many commonly used drugs are excreted into saliva, which can be partly predicted by a drug's ionisation state, protein binding, lipophilicity, hydrogen bond donor count and polar surface area. The contribution of drug transporters and physiological factors to the excretion needs to be evaluated. Continued research on drugs potentially suitable for saliva-based TDM will aid in adopting this person-centred TDM approach...
Background and Objectives Saliva is a patient-friendly matrix for therapeutic drug monitoring (TDM) but is infrequently used in routine care. This is due to the uncertainty of saliva-based TDM results to inform dosing. This study aimed to retrieve data on saliva-plasma concentration and subsequently determine the physicochemical properties that influence the excretion of drugs into saliva to increase the foundational knowledge underpinning saliva-based TDM. Methods Medline, Web of Science and Embase (1974-2023) were searched for human clinical studies, which determined drug pharmacokinetics in both saliva and plasma. Studies with at least ten subjects and five paired saliva-plasma concentrations per subject were included. For each study, the ratio of the area under the concentration-time curve between saliva and plasma was determined to assess excretion into saliva. Physicochemical properties of each drug (e.g. pKa, lipophilicity, molecular weight, polar surface area, rotatable bonds and fraction of drug unbound to plasma proteins) were obtained from PubChem and Drugbank. Drugs were categorised by their ionisability, after which saliva-to-plasma ratios were predicted with adjustment for protein binding and physiological pH via the Henderson-Hasselbalch equation. Spearman correlation analyses were performed for each drug category to identify factors predicting saliva excretion (α = 5%). Study quality was assessed by the risk of bias in non-randomised studies of interventions tool. Results Overall, 42 studies including 40 drugs (anti-psychotics, anti-microbials, immunosuppressants, anti-thrombotic, anti-cancer and cardiac drugs) were included. The median saliva-to-plasma ratios were similar for drugs in the amphoteric (0.59), basic (0.43) and acidic (0.41) groups and lowest for drugs in the neutral group (0.21). Higher excretion of acidic drugs (n = 5) into saliva was associated with lower ionisation and protein binding (correlation between predicted versus observed saliva-to-plasma ratios: R 2 = 0.85, p = 0.02). For basic drugs (n = 21), pKa predicted saliva excretion (Spearman correlation coefficient: R = 0.53, p = 0.02). For amphoteric drugs (n = 10), hydrogen bond donor (R = − 0.76, p = 0.01) and polar surface area (R = − 0.69, p = 0.02) were predictors. For neutral drugs (n = 10), protein binding (R = 0.84, p = 0.004), lipophilicity (R = − 0.65, p = 0.04) and hydrogen bond donor count (R = − 0.68, p = 0.03) were predictors. Drugs considered potentially suitable for saliva-based TDM are phenytoin, tacrolimus, voriconazole and lamotrigine. The studies had a low-to-moderate risk of bias. Conclusions Many commonly used drugs are excreted into saliva, which can be partly predicted by a drug's ionisation state, protein binding, lipophilicity, hydrogen bond donor count and polar surface area. The contribution of drug transporters and physiological factors to the excretion needs to be evaluated. Continued research on drugs potentially suitable for saliva-based TDM will aid in adopting this person-centred TDM approach...
BackgroundSalivary therapeutic drug monitoring (TDM) offers the potential to reduce the risks, burden, time, and costs of blood-based TDM, but its feasibility in oxazolidinone antibiotics and the influence of food intake remain unknown.MethodsA total of 12 healthy volunteers participated in this study. Linezolid and tedizolid were intravenously administered to 6 participants each. Saliva samples were taken at 15 time points and peripheral venous blood samples were also taken at 12 time points simultaneously with saliva. Total and unbound serum and saliva concentrations of linezolid and tedizolid were measured using high-performance liquid chromatography.ResultsIndividual concentration–time curves in saliva versus serum (total and unbound) were similar in linezolid, but different in tedizolid. Saliva concentrations were significantly correlated with total and unbound serum concentrations in both agents. However, concentrations in each case and area under the concentration–time curve from 0 to 10 h (AUC0–10) in saliva were correlated with those in total or unbound serum for linezolid, but not for tedizolid. The mean saliva-to-serum (total and unbound) concentration and AUC0–10ratios were 0.90 and 0.90 in total and 1.09 and 0.99 in unbound. Food intake did not influence these correlations in linezolid.ConclusionsThe analysis of linezolid in saliva is applicable for TDM as a promising alternative to conventional serum sampling without correlation factors, but application of tedizolid is less feasible. Easy sampling using a noninvasive technique may facilitate TDM even in underdeveloped countries with limited resources and specific patient categories.
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