title: Saliva Versus Plasma Bioequivalence of Azithromycin in Humans: Validation of Class I Drugs of the Salivary Excretion Classification System.
abstract: OBJECTIVE
  The aim of this study was to compare human pharmacokinetics and bioequivalence metrics in saliva versus plasma for azithromycin as a model class I drug of the Salivary Excretion Classification System (SECS).
  
  
  METHODS
  A pilot, open-label, two-way crossover bioequivalence study was done, and involved a single 500-mg oral dose of azithromycin given to eight healthy subjects under fasting conditions, followed by a 3-week washout period. Blood and unstimulated saliva samples were collected over 72 h and deep frozen until analysis by a validated liquid chromatography with mass spectroscopy method. The pharmacokinetic parameters and bioequivalence metrics of azithromycin were calculated by non-compartment analysis using WinNonlin V5.2. Descriptive statistics and dimensional analysis of the pharmacokinetic parameters of azithromycin were performed using Microsoft Excel. PK-Sim V5.6 was used to estimate the effective intestinal permeability of azithromycin.
  
  
  CONCLUSIONS
  No statistical differences were shown in area under the concentration curves to 72 h (AUC0-72), maximum measured concentration (Cmax) and time to maximum concentration (Tmax) between test and reference azithromycin products (P > 0.05) in the saliva matrix and in the plasma matrix. Due to the high intra-subject variability and low sample size of this pilot study, the 90% confidence intervals of AUC0-72and Cmaxdid not fall within the acceptance range (80-125%). However, saliva levels were higher than that of plasma, with a longer salivary Tmax. The mean saliva/plasma concentration of test and reference were 2.29 and 2.33, respectively. The mean ± standard deviation ratios of saliva/plasma of AUC0-72, Cmaxand Tmaxfor test were 2.65 ± 1.59, 1.51 ± 0.49 and 1.85 ± 1.4, while for the reference product they were 3.37 ± 2.20, 1.57 ± 0.77 and 2.6 ± 1.27, respectively. A good correlation of R = 0.87 between plasma and saliva concentrations for both test and reference products was also observed. Azithromycin is considered a class I drug based on the SECS, since it has a high permeability and high fraction unbound, and saliva sampling could be used as an alternative to plasma sampling to characterize its pharmacokinetics and bioequivalence in humans when adequate sample size is used.
authors.affiliation: Faculty of Pharmacy, Petra University, Amman, Jordan. nidkaidek@uop.edu.jo.
authors.forename: Nasir
authors.initials: N
authors.lastname: Idkaidek
authors.affiliation: Faculty of Pharmacy, Petra University, Amman, Jordan.
authors.forename: Tawfiq
authors.initials: T
authors.lastname: Arafat
authors.affiliation: Faculty of Pharmacy, Petra University, Amman, Jordan.
authors.forename: Hazim
authors.initials: H
authors.lastname: Hamadi
authors.affiliation: Faculty of Pharmacy, Petra University, Amman, Jordan.
authors.forename: Salim
authors.initials: S
authors.lastname: Hamadi
authors.affiliation: Faculty of Pharmacy, Petra University, Amman, Jordan.
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Al-Adham
mesh_terms: D000284:Administration, Oral; D017963:Azithromycin / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics*; D002853:Chromatography, Liquid; D018592:Cross-Over Studies; D064368:Healthy Volunteers; D006801:Humans; D013058:Mass Spectrometry; D010865:Pilot Projects; D012463:Saliva / Q000378:metabolism*; D065787:Salivary Elimination
chemical_list: D017963:Azithromycin