Saliva versus Plasma Relative Bioavailability of Tolterodine in Humans: Validation of Class III Drugs of the Salivary Excretion Classification System

Abstract

Relative bioavailability study of tolterodine in healthy human volunteers was done using saliva and plasma matrices in order to investigate the robustness of using saliva instead of plasma as a surrogate for bioavailability and bioequivalence of class III drugs according to the salivary excretion classification system (SECS). Saliva and plasma samples were collected up to 16 h after 2 mg oral dose. Saliva and plasma pharmacokinetic parameters were calculated by non compartmental analysis using Kinetica program V5. Human effective intestinal permeability was optimized by SimCYP program V13. Tolterodine falls into class III (High permeability/Low fraction unbound to plasma proteins) and hence was subjected to salivary excretion. A high pearsons correlation coefficient of 0.97 between mean saliva and plasma concentrations, and saliva/plasma concentrations ratio of 0.33 were observed. In addition, correlation coefficients and saliva/plasma ratios of area under curve and maximum concentration were 0.98, 0.95 and 0.42, 0.34 respectively. On the other hand, time to reach maximum concentration was higher in saliva by 2.37 fold. In addition, inter subject variability values in saliva were slightly higher than plasma leading to need for slightly higher number of subjects to be used in saliva studies (55 vs. 48 subjects). Non-invasive saliva sampling instead of invasive plasma sampling method can be used as a surrogate for bioavailability and bioequivalence of SECS class I drugs when adequate sample size is used.

Key words

SECS - tolterodine - bioequivalence - pharmacokinetics - simCYP

• References

• 1 Gorodischer R, Koren G. Salivary excretion of drugs in children: theoretical and practical issues in therapeutic drug monitoring. Dev Pharmacol Ther 1992; 19: 161-177
• 2 Ruiz ME, Conforti P, Fagiolino P et al. The use of saliva as a biological fluid in relative bioavailability studies: comparison and correlation with plasma results. Biopharm Drug Dispos 2010; 31: 476-485
• 3 Idkaidek N, Arafat T. Saliva versus Plasma Pharmacokinetics: Theory and Application of a Salivary Excretion Classification System. Mol Pharmaceutics 2012; 9: 2358-2363
• 4 Amidon GL, Lennernäs H, Shah VP et al. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res 1995; 12: 413-420
• 5 Jambhekar SS, Breen PJ. Basic Pharmacokinetics. First Edition London: Pharmaceutical Press; 2009
• 6 Idkaidek N, Arafat T. Saliva vs. plasma bioequivalence of paracetamol in humans: validation of class I drugs of the salivary excretion classification system. Drug Res (Stuttg) 2014; 64: 559-562 DOI: 10.1055/s-0033-1363995. Epub 2014 Jan 22
• 7 Idkaidek N, Arafat T. Saliva vs. plasma bioequivalence of metformin in humans: validation of class II drugs of the salivary excretion classification system. Drug Res (Stuttg) 2014; 64: 559-562 DOI: 10.1055/s-0033-1363995. Epub 2014 Jan 22
• 8 Idkaidek N, Arafat T. Saliva vs. plasma bioequivalence of rosuvastatin in humans: validation of class III drugs of the salivary excretion classification system. Drugs R D 2015; 15: 79-83 DOI: 10.1007/s40268-015-0080-1.
• 9 Jamei M, Turner D, Yang J et al. Population-based mechanistic prediction of oral drug absorption. AAPS J 2009; 11: 225-237
• 10 Takamatsu N, Kim ON, Welage LS et al. Human jejunal permeability of two polar drugs: cimetidine and ranitidine. Pharm Res 2001; 18: 742-744
• 11 Påhlman I, Gozzi P. Serum protein binding of tolterodine and its major metabolites in humans and several animal species. Biopharm Drug Dispos 1999; 20: 91-99
• 12 Guidance for Industry. Bioavailability and Bioequivalence Studies for Orally Administered Drug Products — General Considerations. March 2003. Division of Drug Information, Center for Drug Evaluation and Research, Food and Drug Administration 5600 Fishers Lane Rockville, MD 20857, USA