Clinical Pharmacology: Advances and Applications (Nov 2016)
A prospective, observational study comparing the PK/PD relationships of generic Meropenem (Mercide®) to the innovator brand in critically ill patients
Abstract
Mervyn Mer,1 Jacques Rene Snyman,2 Constance Elizabeth Jansen van Rensburg,2 Jacob John van Tonder,3 Ilze Laurens2 1Department of Medicine, Divisions of Critical Care and Pulmonology, University of the Witwatersrand, Johannesburg, South Africa; 2Office of the Dean, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa; 3Scientific Affairs Department, Triclinium Clinical Development (Pty) Ltd, Centurion, South Africa Introduction: Clinicians’ skepticism, fueled by evidence of inferiority of some multisource generic antimicrobial products, results in the underutilization of more cost-effective generics, especially in critically ill patients. The aim of this observational study was to demonstrate equivalence between the generic or comparator brand of meropenem (Mercide®) and the leading innovator brand (Meronem®) by means of an ex vivo technique whereby antimicrobial activity is used to estimate plasma concentration of the active moiety. Methods: Patients from different high care and intensive care units were recruited for observation when prescribed either of the meropenem brands under investigation. Blood samples were collected over 6 hours after a 30 minute infusion of the different brands. Meropenem concentration curves were established against United States Pharmacopeia standard meropenem (Sigma-Aldrich) by using standard laboratory techniques for culture of Klebsiella pneumoniae. Patients’ plasma samples were tested ex vivo, using a disc diffusion assay, to confirm antimicrobial activity and estimate plasma concentrations of the two brands. Results: Both brands of meropenem demonstrated similar curves in donor plasma when concentrations in vials were confirmed. Patient-specific serum concentrations were determined from zones of inhibition against a standard laboratory Klebsiella strain ex vivo, confirming at least similar in vivo concentrations as the concentration curves (90% confidence interval) overlapped; however, the upper limit of the area under the curve for the ratio comparator/innovator exceeded the 1.25-point estimate, i.e., 4% higher for comparator meropenem. Conclusion: This observational, in-practice study demonstrates similar ex vivo activity and in vivo plasma concentration time curves for the products under observation. Assay sensitivity is also confirmed. Current registration status of generic small molecules is in place. The products are therefore clinically interchangeable based on registration status as well as bioassay results, demonstrating sufficient overlap for clinical comfort. The slightly higher observed comparator meropenem concentration (4%) is still clinically acceptable due to the large therapeutic index and should ally fears of inferiority. Keywords: bioequivalence, antimicrobial, multisource products, Meropenem, pharmacokinetics, pharmacodynamics
