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

Abstract

Aims:

To study saliva and plasma bioequivalence of paracetamol in healthy human volunteers, and to investigate the robustness of using saliva instead of plasma as surrogate for bioequivalence of class I drugs according to the salivary excretion classification system (SECS).

Methods:

Saliva and plasma pharmacokinetic parameters were calculated by non compartmental analysis. Analysis of variance, 90% confidence intervals, intra-subject and inter-subject variability values of pharmacokinetic parameters were calculated after logarithmic transformation. Calculations were done using Kinetica program V5. Descriptive and comparative statistics were also calculated by Excel.

Results and Discussion:

Paracetamol falls into class I (High permeability/High fraction unbound to plasma proteins) and was subjected to salivary excretion, with correlation coefficient of 0.99 between saliva and plasma concentrations and saliva/plasma concentrations ratios of 1.45–1.50. The 90% confidence limits of areas under curve (AUC_last and AUC_∞) showed similar trend and passed the 80–125% acceptance criteria in both saliva and plasma. On the other hand for maximum concentration (C_max), the 90% confidence limits passed the acceptance criteria in plasma and failed in saliva. Inter and intra subject variability values in saliva were higher than plasma leading to need for higher number of subjects to be used in saliva. Saliva and plasma parameter ratios were not significantly different (P>0.05).

Conclusions:

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

Key words

salivary excretion classification system - paracetamol - 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 vs. 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 Jamei M, Turner D, Yang J et al. Population-based mechanistic prediction of oral drug absorption. AAPS J 2009; 11: 225-237
• 7 Gandia P, Bareille MP, Saivin S et al. Influence of simulated weightlessness on the Oral pharmacokinetics of acetaminophen as a gastric emptying Probe in man: a plasma and a saliva study. J Clin Pharmacol 2003; 43: 1235-1243
• 8 Kamali F, Edwards C, Rawlins M. The effect of pirenzepine on gastric emptying and salivary flow rate: constraints on the use of saliva paracetamol concentrations for the determination of paracetamol pharmacokinetics. Br J clin Pharmac 1992; 33: 309-312
• 9 Rhie J. The pellet gastric emptying (PGE) test: Development of a non-invasive method to assess gastric emptying. PhD Diss. University of Michigan 1996
• 10 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