title: Bioequivalence of venlafaxine modified-release capsule revisited with an innovative approach using experimental and predictive models.
abstract: BACKGROUND
  To evaluate the venlafaxine:O-desmethyl venlafaxine (active metabolite) in vivo formation ratio (MR) in three independent bioequivalence (BE) studies consisting of single-dosed (under fasted and fed conditions) and multiple-dosed clinical trials on healthy subjects. The pooled data pharmacokinetic (PK) analysis demonstrates a model to conduct enantiomer/racemate/active metabolite bioanalysis for regulatory submission of bioavailability/bioequivalence (BA/BE) studies using an interesting MR concept.
  
  
  RESULTS
  BE was established for all three studies. Moreover, the venlafaxine:O-desmethyl venlafaxine MR for C(max) and AUC(last) differed by more than 50% for fasted and fed single-dosed studies, while pooled data analysis found the MR for C(max) to be approximately 0.63 and the AUC to be approximately 0.36 for both test and reference drugs. However, negligible variation was observed for both rate and extent of drug and active metabolite absorption into the systemic circulation at steady state, as the MR for both C(max) and AUC was approximately 0.62.
  
  
  CONCLUSIONS
  The applications/consequences of the above results are immense. First, an achiral assay for venlafaxine and O-desmethyl venlafaxine estimation in human plasma has been justified for the regulatory acceptance of BA/BE studies, supported with both single- and multiple-dosed PK data showing negligible variation in terms of MR at C(max). Second, the current investigation shows the MR to be within ±10% when compared with the single-dosed reported study on a western population. Third, the racial effect would not lead to any significant clinical outcome using an interchangeable venlafaxine 150-mg capsule manufactured by Ranbaxy with an Efexor 150-mg capsule manufactured by Wyeth. Furthermore, a decision tree is proposed to evaluate if a racemate or an enantiomer drug and active metabolite bioanalysis should be executed for BA/BE regulatory submission using respective achiral or chiral assays when the drug moiety is a racemate or an enantiomer, formulated in modified-release dosage forms.
authors.affiliation: Department of Clinical Pharmacology & PKs, Ranbaxy Research Laboratories, HSIDC, GP-5, Old Delhi Gurgaon Road, Udyog Vihar Industrial Area, Gurgaon - 122 015, Haryana, India. dipanjan.goswami@ranbaxy.com
authors.forename: Dipanjan
authors.initials: D
authors.lastname: Goswami
authors.forename: Arshad H
authors.initials: AH
authors.lastname: Khuroo
authors.forename: Sanjay
authors.initials: S
authors.lastname: Gurule
authors.forename: Ajay
authors.initials: A
authors.lastname: Kumar
authors.forename: Tausif
authors.initials: T
authors.lastname: Monif
mesh_terms: D000293:Adolescent; D000328:Adult; D000465:Algorithms; D019540:Area Under Curve; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D003511:Cyclohexanols / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics*; D003627:Data Interpretation, Statistical; D003663:Decision Trees; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D057230:Limit of Detection; D008962:Models, Theoretical; D013237:Stereoisomerism; D053719:Tandem Mass Spectrometry; D013810:Therapeutic Equivalency; D000069470:Venlafaxine Hydrochloride
chemical_list: D003511:Cyclohexanols; D003692:Delayed-Action Preparations; D000069470:Venlafaxine Hydrochloride