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Comparison of dissolution profiles and serum concentrations of two lamotrigine tablet formulations.

Lalic M, Pilipovic A, Golocorbin-Kon S, Gebauer-Bukurov K, Bozic K, Mikov M, Cvejic J - Drugs R D (2011)

Bottom Line: There were no statistically significant differences in lamotrigine serum concentrations between the two groups, although formulation B had slightly higher mean concentration values (formulation A: 3.97 ± 4.1 μg/mL; formulation B: 5.78 ± 2.7 μg/mL).No significant changes in the serum concentrations of lamotrigine were seen between the two investigated formulations.It is evident that the doses of test formulation given to the patients were higher as a consequence of common assumption that generic products have a lower absorption rate, which is proven unnecessary in this study.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, Faculty of Medicine, University of Novi Sad, Novi Sad, Republic of Serbia.

ABSTRACT

Background: Since 2005, the antiepileptic drug lamotrigine has been present in the market in various generic products, in addition to the original brand of Lamictal®. The linear pharmacokinetics and wide therapeutic window of lamotrigine enable seizure-free patients to easily switch from brand to generic antiepileptic drugs.

Objective: The aim of this study was to investigate the extent of variations in lamotrigine serum concentrations between two immediate-release tablet formulations. Data were compared with in vitro difference and similarity tests on dissolution profiles of the two formulations.

Methods: Dissolution characteristics of formulations A (reference) and B (test) were evaluated at three points spanning the physiologic pH range (pH 1.2, pH 4.5, pH 6.8). A model-independent approach of difference (f1) and similarity (f2) tests were applied to dissolution data. A clinical study was performed with 16 patients who were divided into two groups - one group received formulation A (n = 9) and the other received formulation B (n = 7). Lamotrigine steady-state concentrations were determined by high-performance liquid chromatography on a reverse-phase column.

Results: There were no statistically significant differences in lamotrigine serum concentrations between the two groups, although formulation B had slightly higher mean concentration values (formulation A: 3.97 ± 4.1 μg/mL; formulation B: 5.78 ± 2.7 μg/mL). Dissolution profiles of the two formulations were similar in the pH 1.2 dissolution medium; however, the dissolution profiles of formulation B were outside the dissolution limit (≥85% at 15 minutes) in the pH 4.5 and 6.8 dissolution media.

Conclusions: No significant changes in the serum concentrations of lamotrigine were seen between the two investigated formulations. There is no evidence to suggest that the differences in dissolution profiles at pH 4.5 and pH 6.8 affect the therapeutic efficacy of the formulations. It is evident that the doses of test formulation given to the patients were higher as a consequence of common assumption that generic products have a lower absorption rate, which is proven unnecessary in this study. This investigation was a pilot study and thus further investigations with a larger sample size are necessary to determine if there is a connection between dissolution profiles and the therapeutic effect of investigated formulations.

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Difference (1) and similarity (2) factors for reference (formulation A – original formulation) vs test product (formulation B – generic formulation)
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Tab2: Difference (1) and similarity (2) factors for reference (formulation A – original formulation) vs test product (formulation B – generic formulation)

Mentions: A model-independent approach of difference (f1) and similarity (f2) tests were applied to dissolution data. The values of f1 and f2 factors for the test product (formulation B) versus the reference (formulation A) were calculated from the means of the percentage of drug dissolved at each timepoint (table I) by using equations 1 and 2.[24]1\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$f_1 =\bigg\lbrace {\lbrack\Sigma^n_{t=1} \mid R_t-T_t\mid\rbrack\over\lbrack\Sigma^n_t{R_t+T_t\over 2}\rbrack}\bigg\rbrace\times 100$$\end{document}2\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$log\bigg\lbrace \lbrack1+(1/n)\Sigma^n_{t=1} (R_t-T_t)^2\rbrack ^{-0.5} \times 100\bigg\rbrace$$\end{document}where n is the number of dissolution sample times, and Rt and Tt are the individual or mean percentage of drug dissolved at each timepoint (t), for the reference and test dissolution profiles, respectively. According to the US FDA guidance, f1 values generally vary between 0 and 15, and f2 values vary between 50 and 100, ensuring equivalence of the dissolution curves.[25] Dissolution profiles of formulations A and B were only similar in the pH 1.2 medium (table II).


Comparison of dissolution profiles and serum concentrations of two lamotrigine tablet formulations.

Lalic M, Pilipovic A, Golocorbin-Kon S, Gebauer-Bukurov K, Bozic K, Mikov M, Cvejic J - Drugs R D (2011)

Difference (1) and similarity (2) factors for reference (formulation A – original formulation) vs test product (formulation B – generic formulation)
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585764&req=5

Tab2: Difference (1) and similarity (2) factors for reference (formulation A – original formulation) vs test product (formulation B – generic formulation)
Mentions: A model-independent approach of difference (f1) and similarity (f2) tests were applied to dissolution data. The values of f1 and f2 factors for the test product (formulation B) versus the reference (formulation A) were calculated from the means of the percentage of drug dissolved at each timepoint (table I) by using equations 1 and 2.[24]1\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$f_1 =\bigg\lbrace {\lbrack\Sigma^n_{t=1} \mid R_t-T_t\mid\rbrack\over\lbrack\Sigma^n_t{R_t+T_t\over 2}\rbrack}\bigg\rbrace\times 100$$\end{document}2\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$log\bigg\lbrace \lbrack1+(1/n)\Sigma^n_{t=1} (R_t-T_t)^2\rbrack ^{-0.5} \times 100\bigg\rbrace$$\end{document}where n is the number of dissolution sample times, and Rt and Tt are the individual or mean percentage of drug dissolved at each timepoint (t), for the reference and test dissolution profiles, respectively. According to the US FDA guidance, f1 values generally vary between 0 and 15, and f2 values vary between 50 and 100, ensuring equivalence of the dissolution curves.[25] Dissolution profiles of formulations A and B were only similar in the pH 1.2 medium (table II).

Bottom Line: There were no statistically significant differences in lamotrigine serum concentrations between the two groups, although formulation B had slightly higher mean concentration values (formulation A: 3.97 ± 4.1 μg/mL; formulation B: 5.78 ± 2.7 μg/mL).No significant changes in the serum concentrations of lamotrigine were seen between the two investigated formulations.It is evident that the doses of test formulation given to the patients were higher as a consequence of common assumption that generic products have a lower absorption rate, which is proven unnecessary in this study.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, Faculty of Medicine, University of Novi Sad, Novi Sad, Republic of Serbia.

ABSTRACT

Background: Since 2005, the antiepileptic drug lamotrigine has been present in the market in various generic products, in addition to the original brand of Lamictal®. The linear pharmacokinetics and wide therapeutic window of lamotrigine enable seizure-free patients to easily switch from brand to generic antiepileptic drugs.

Objective: The aim of this study was to investigate the extent of variations in lamotrigine serum concentrations between two immediate-release tablet formulations. Data were compared with in vitro difference and similarity tests on dissolution profiles of the two formulations.

Methods: Dissolution characteristics of formulations A (reference) and B (test) were evaluated at three points spanning the physiologic pH range (pH 1.2, pH 4.5, pH 6.8). A model-independent approach of difference (f1) and similarity (f2) tests were applied to dissolution data. A clinical study was performed with 16 patients who were divided into two groups - one group received formulation A (n = 9) and the other received formulation B (n = 7). Lamotrigine steady-state concentrations were determined by high-performance liquid chromatography on a reverse-phase column.

Results: There were no statistically significant differences in lamotrigine serum concentrations between the two groups, although formulation B had slightly higher mean concentration values (formulation A: 3.97 ± 4.1 μg/mL; formulation B: 5.78 ± 2.7 μg/mL). Dissolution profiles of the two formulations were similar in the pH 1.2 dissolution medium; however, the dissolution profiles of formulation B were outside the dissolution limit (≥85% at 15 minutes) in the pH 4.5 and 6.8 dissolution media.

Conclusions: No significant changes in the serum concentrations of lamotrigine were seen between the two investigated formulations. There is no evidence to suggest that the differences in dissolution profiles at pH 4.5 and pH 6.8 affect the therapeutic efficacy of the formulations. It is evident that the doses of test formulation given to the patients were higher as a consequence of common assumption that generic products have a lower absorption rate, which is proven unnecessary in this study. This investigation was a pilot study and thus further investigations with a larger sample size are necessary to determine if there is a connection between dissolution profiles and the therapeutic effect of investigated formulations.

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