REFERENCE-SCALED AVERAGE BIOEQUIVALENCE STUDY OF PAROXETINE UNDER FED CONDITIONS: VALIDATION OF SAMPLE SIZE ESTIMATION BY BOOTSTRAPPING TECHNIQUE

Chandrakala V Chandrakala V,Utpal Kumar Sanki Utpal Kumar Sanki

doi:10.22159/ajpcr.2019.v12i5.32319

Chandrakala V Chandrakala V, Utpal Kumar Sanki Utpal Kumar Sanki

Open Access

https://doi.org/10.22159/ajpcr.2019.v12i5.32319

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Abstract

Objective: New technique was adopted and validated to estimate pivotal sample size from the pilot study data and to establish bioequivalence (BE) of highly variable drugs (HVD), paroxetine, a novel controlled release (CR) matrix tablets utilized ghatti Gum as a rate controlling membrane, in human subject under fed conditions by reference scale design. Methods: Bootstrapping technique was adopted to calculate the pivotal sample size from pilot study data for HVD paroxetine. The reliability and validation of the method were tested in a semi replicate three sequence (RRT, RTR, and TRR where T stand for test drug and R stand for reference drug) cross-over BE study in 24 healthy subjects under fed conditions. Results: The ratio of the pharmacokinetic (PK) metric obtained from the bootstrapping technique after log transformation was 1.04 for Cmax, 1.23 for AUCT, and 1.21 for AUCI with corresponding power of the study which was greater than 80% from pilot study data simulation. The ratio of the PK metric obtained from the reference scaling design in the present study was 1.00 for Cmax, 1.21 for AUCT, and 1.17 for AUCI. The upper limit of the Cmax, AUCT, and AUCI at 95% confidence limit was −0.143, −0.136, and −0.17, respectively. Conclusion: The test paroxetine CR formulation was bioequivalent with reference drug under fed conditions. The technique used for estimation of the sample size in the pivotal study was found reliable, and bootstrapping technique plays an important role in calculating sample size where intrasubject variability was immaterial.

Highlights

Paroxetine hydrogen chloride is an antidepressant and belongs to the class of selective serotonin reuptake inhibitors (SSRIs) [1,2]
Polyethylene glycol and polymethyl methacrylate of the innovator formulation were replaced by ghatti gum
The study results revealed that the two formulations of paroxetine were similar in PK characteristics among these healthy Indian subjects under fed conditions

Summary

Introduction

Paroxetine hydrogen chloride (paroxetine [HCl]) is an antidepressant and belongs to the class of selective serotonin reuptake inhibitors (SSRIs) [1,2]. Paroxetine has the highest known affinity for the serotonin transporter (0.13 nanomoles) of any currently used antidepressant [3]. Paroxetine was previously reviewed as an antidepressant drug in 1991 and reported some amount of hepatic toxicity following the chronic use of the drug [4,5]. Paroxetine (HCl) is used to treat obsessivecompulsive disorders and panic disorders [6,7]. Paroxetine (HCl) is not available in any combination preparations. The reason was to reduce acute toxicity and improved tolerability of SSRI compared to previously frequently used tri- and tetracyclic antidepressants [10,11]. Controlled release (CR) formulation of paroxetine is highly safe and tolerable compared to immediate release formulation [12]

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Discussion

Conclusion