Saliva vs. Plasma Bioequivalence of Metformin in Humans: Validation of Class II Drugs of the Salivary Excretion Classification System

Abstract

Aim:

To study saliva and plasma bioequivalence of metformin in humans, and to investigate the robustness of using saliva instead of plasma as surrogate for bioequivalence of class II drugs according to the salivary excretion classification system (SECS).

Methods:

Plasma and saliva samples were collected for 12 h after 500 mg oral dosing of metformin to 16 healthy humans. Plasma and saliva pharmacokinetic parameters, 90% confidence intervals and intra-subject variability values were calculated using Kinetica V5. Descriptive statistics and dimensional analysis were calculated by Excel. SimCYP program V13 was used for estimation of effective intestinal permeability.

Results and Discussion:

Metformin was subjected to salivary excretion since it falls into class II (Low permeability/High fraction unbound to plasma proteins), with correlation coefficients of 0.95–0.99 between plasma and saliva concentrations. Saliva/plasma concentration ratios were 0.29–0.39. The 90% confidence limits of all parameters failed in both saliva and plasma. Intra-subject variability values in saliva were higher than plasma leading to need for higher number of subjects to be used in saliva.

Conclusion:

Saliva instead of plasma can be used as surrogate for bioequivalence of class II drugs according to SECS when adequate sample size is used. Future work is planned to demonstrate SECS robustness in drugs that fall into class III.

Key words

SECS - metformin - bioequivalence - pharmacokinetics - SimCYP

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