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1.
Ann N Y Acad Sci ; 1407(1): 75-89, 2017 11.
Article in English | MEDLINE | ID: mdl-29168242

ABSTRACT

Copaxone (glatiramer acetate, GA), a structurally and compositionally complex polypeptide nonbiological drug, is an effective treatment for multiple sclerosis, with a well-established favorable safety profile. The short antigenic polypeptide sequences comprising therapeutically active epitopes in GA cannot be deciphered with state-of-the-art methods; and GA has no measurable pharmacokinetic profile and no validated pharmacodynamic markers. The study reported herein describes the use of orthogonal standard and high-resolution physicochemical and biological tests to characterize GA and a U.S. Food and Drug Administration-approved generic version of GA, Glatopa (USA-FoGA). While similarities were observed with low-resolution or destructive tests, differences between GA and USA-FoGA were measured with high-resolution methods applied to an intact mixture, including variations in surface charge and a unique, high-molecular-weight, hydrophobic polypeptide population observed only in some USA-FoGA lots. Consistent with published reports that modifications in physicochemical attributes alter immune-related processes, genome-wide expression profiles of ex vivo activated splenocytes from mice immunized with either GA or USA-FoGA showed that 7-11% of modulated genes were differentially expressed and enriched for immune-related pathways. Thus, differences between USA-FoGA and GA may include variations in antigenic epitopes that differentially activate immune responses. We propose that the assays reported herein should be considered during the regulatory assessment process for nonbiological complex drugs such as GA.


Subject(s)
Drugs, Generic/pharmacology , Gene Expression/drug effects , Glatiramer Acetate/pharmacology , Immune System Phenomena/drug effects , Animals , Cells, Cultured , Chemical Phenomena , Drugs, Generic/chemistry , Drugs, Generic/pharmacokinetics , Female , Gene Expression Profiling/methods , Glatiramer Acetate/chemistry , Glatiramer Acetate/pharmacokinetics , Humans , Immune System Phenomena/genetics , Immunosuppressive Agents/chemistry , Immunosuppressive Agents/pharmacokinetics , Immunosuppressive Agents/therapeutic use , Mice, Inbred BALB C , Microscopy, Atomic Force , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/drug effects , Signal Transduction/genetics , Signal Transduction/immunology , Spleen/cytology , Spleen/drug effects , Spleen/metabolism , Therapeutic Equivalency
2.
J Pharm Pharmacol ; 68(10): 1278-89, 2016 Oct.
Article in English | MEDLINE | ID: mdl-27465906

ABSTRACT

OBJECTIVES: While bioequivalence between enteric-coated and immediate-release formulations can be achieved in terms of AUC, gastric emptying of enteric-coated dosage forms is a stochastic event, usually leading to lower Cmax values than those observed with the corresponding immediate release. This article examines challenges of developing enteric-coated dosage forms which are bioequivalent to the corresponding immediate-release formulations in terms of both AUC and Cmax using rasagiline as a model compound. METHODS: In vitro drug release profiles of enteric-coated formulations were obtained and compared to those of the immediate-release formulation by dissolution testing. Pharmacokinetics was evaluated in bioequivalence studies in healthy human volunteers after single oral administration of enteric-coated and immediate-release formulations. KEY FINDINGS: The initial enteric-coated pellet formulation prototype was equivalent in terms of AUC, but differed in Cmax ; a second formulation prototype, consisting of a single-unit core and enteric-coating film, proved to be bioequivalent to immediate-release rasagiline tablets in terms of AUC and Cmax . In vitro, it released rasagiline rapidly at a pH of 6.8. CONCLUSIONS: Despite differences in gastric emptying between disintegrating immediate-release and enteric-coated solid dosage forms, bioequivalence in pharmacokinetic studies was achieved.


Subject(s)
Tablets, Enteric-Coated/pharmacokinetics , Administration, Oral , Adolescent , Adult , Area Under Curve , Biological Availability , Chemistry, Pharmaceutical/methods , Cross-Over Studies , Female , Half-Life , Humans , Male , Middle Aged , Therapeutic Equivalency , Young Adult
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