Bioavailability of a New Generic Formulation of Mycophenolate Mofetil MMF 500 Versus CellCept in Healthy Adult Volunteers

Masri, Marwan; Rizk, S; Attia, M.L.E.; Barbouch, H.; Rost, M.

doi:10.1016/j.transproceed.2007.03.055

Cited by 12 publications

(9 citation statements)

References 14 publications

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“…23,161 An enteric-coated form of MMF's active metabolite MPA is currently being used, and is FDA approved, in transplant patients with hopes to decrease the severity of GI side effects and increasing tolerability. [162][163][164] Although pharmacokinetics of the enteric-coated form differ slightly, it appears to be a promising improvement while maintaining equivalent MPA exposure and may become a more popular choice in the future.…”

Section: Future Considerationsmentioning

confidence: 99%

Mycophenolate mofetil in dermatology

Orvis

Wesson

Breza

et al. 2009

Journal of the American Academy of Dermatology

114

106

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Section: Future Considerationsmentioning

confidence: 99%

Mycophenolate mofetil in dermatology

Orvis

Wesson

Breza

et al. 2009

Journal of the American Academy of Dermatology

114

106

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“…The relative bioavailability of generic MMF was studied in 5 single-dose cross-over trials [16, 18, 21, 26, 27]. CellCept® was compared to generic MMF500™, Linfonex™ or Suprimum 500®.…”

Section: Resultsmentioning

confidence: 99%

“…Five trials examined the relative bioavailability of generic MMF formulations to CellCept® [16, 18, 21, 26, 27]. Although the pooled C max of MMF generic formulations was significantly lower than that achieved by CellCept®, the FDA requirement for bioequivalence was met (pooled C max T/R ratio 0.98; 90% CI 0.96–1.01; p = 0.001; fig.…”

Section: Resultsmentioning

confidence: 99%

Bioavailability, Efficacy and Safety of Generic Immunosuppressive Drugs for Kidney Transplantation: A Systematic Review and Meta-Analysis

Tsipotis¹,

Gupta²,

Raman

et al. 2016

Am J Nephrol

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Background: Concerns exist over the extrapolation of bioavailability studies of generic immunosuppressive drugs in healthy volunteers, regarding their efficacy and safety in kidney transplant recipients. We conducted a meta-analysis of trials examining the bioavailability of generic (test) immunosuppressive drugs relative to their brand (reference) counterparts in healthy volunteers, based on the US Food and Drug Administration requirements for approval of generics, and their efficacy and safety in kidney transplant recipients. Methods: Eligible studies were identified in PubMed, Cochrane Central Register of Controlled Trials, Scopus, ClinicalTrials.gov, and conference abstracts. Results: Twenty crossover trials of healthy volunteers (n = 641) and 6 parallel-arm randomized controlled trials of kidney transplant recipients (n = 594) were identified. The 90% CI of the pooled test-to-reference drug ratio for maximum or peak plasma concentration (C_max) and area under the plasma concentration time-curve from time 0 to time of last determinable concentration (AUC_(0-t)) fell within the required range (0.80-1.25) for cyclosporine (C_max 0.91; 90% CI 0.86-0.95; and AUC_(0-t) 0.97; 90% CI 0.94-1.00), tacrolimus (C_max 1.17; 90% CI 1.09-1.24; and AUC_(0-t) 1.00; 90% CI 0.97-1.03) and mycophenolate mofetil (C_max 0.98; 90% CI 0.96-1.01; and AUC_(0-t) 1.00; 90% CI 0.99-1.01). In subgroup analyses, some generic cyclosporine formulations did not meet criteria for bioequivalence. No significant differences were observed in the time to maximum plasma concentration and terminal plasma half-life between generic and brand drugs. In parallel-arm trials, generic cyclosporine was non-inferior to brand counterpart in terms of acute allograft rejection, infections, and death. Conclusions: Not all generic immunosuppressive drugs have similar relative bioavailability to their brand name counterparts. Evidence on their efficacy and safety is inconclusive. Tighter regulatory requirement for approval of generic drugs with narrow therapeutic index is needed.

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“…While the economic need to limit healthcare costs by using generics is not questioned, it is important to ensure that patient health is not compromised. Equivalence has to be shown and is usually based on bioequivalence in healthy volunteers (1). However, as generic products are approved based on comparison with only the innovator product (2), one could argue that switching from one generic product to another might give rise to complications due to the potentially greater disparity between two generic products than between any single generic product and the innovator.…”

Section: Introductionmentioning

confidence: 99%

Mycophenolate Mofetil: Use of a Simple Dissolution Technique to Assess Generic Formulation Differences

Scheubel¹,

Adamy²,

Cardot³

2012

Dissolution Technol.

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Mycophenolate mofetil (MMF) is an immunosuppressive agent indicated for the prophylaxis of acute rejection in patients receiving allogeneic renal, cardiac, or hepatic transplants. It is a Biopharmaceutics Classification System Class II substance that has a strongly pH-dependent solubility profile. Consequently, differences in solid-state properties, formulation, and manufacturing processes of MMF can lead to disparities in bioavailability between brands of the same drug. This study was conducted to compare the in vitro dissolution profile of the original MMF innovator brand (CellCept, Roche) with available generic products. Two representative batches of CellCept 500-mg tablets and 14 different generic formulations were tested using different dissolution testing scenarios simulating conditions in the proximal gastrointestinal tract. These scenarios took into account stomach and small intestine media composition, surface tension, pH, increased buffer capacity, and osmolarity after food intake.Eight of the generic formulations tested passed the quality control dissolution test (pH 1.1) according to the specification Q = 75% after 5 min (i.e., all single units >80% dissolved), and 12 passed the specification Q = 85% after 15 min (i.e., all single units >90% dissolved). This suggests an almost homogenous dissolution rate between formulations in an acidic environment. However, at pH 4.5, large variations in the in vitro dissolution performance between generic formulations were observed (extremes resulting in greater than 60% dissolved difference after 30 min). Marked variability was seen among the different generic formulations and the innovator brand, CellCept. In conclusion, important differences exist among the different generic formulations with regard to in vitro performance. As MMF is required for life-long use, changes in drug performance as a result of switching between formulations may have serious clinical consequences (e.g., organ rejection). Therefore, clinical testing is necessary to evaluate the pharmacokinetics and the impact on clinical safety of a change of brands.

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Bioavailability of a New Generic Formulation of Mycophenolate Mofetil MMF 500 Versus CellCept in Healthy Adult Volunteers

Cited by 12 publications

References 14 publications

Mycophenolate mofetil in dermatology

Mycophenolate mofetil in dermatology

Bioavailability, Efficacy and Safety of Generic Immunosuppressive Drugs for Kidney Transplantation: A Systematic Review and Meta-Analysis

Mycophenolate Mofetil: Use of a Simple Dissolution Technique to Assess Generic Formulation Differences

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