Comparison of Bioavailability and Metabolism with Two Commercial Formulations of Cyclosporine A in Rats

Koehler, Jens; Kuehnel, Thomas; Kees, Frieder; Hoecherl, Klaus; Grobecker, H.

doi:10.1124/dmd.30.6.658

Cited by 14 publications

(8 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The use of healthy volunteers, rather than patients, to determine the bioequivalence of immunosuppressants has recently been criticized (36) and evidence is now becoming available to show that there are differences in metabolism between formulations (37), that independent researchers are unable to confirm bioequivalence of formulations in repeated studies Data set 2302a had the data from one subject and 2302b data from two subjects omitted from the data, in line with FDA guidance, due to high predose MPA concentrations. (38), and that therapeutic equivalence has not been shown for some formulations (39).…”

Section: Discussionmentioning

confidence: 93%

Bioequivalence of Enteric-Coated Mycophenolate Sodium and Mycophenolate Mofetil: A Meta-Analysis of Three Studies in Stable Renal Transplant Recipients

Johnston

Holt

2006

Transplantation

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 93%

Bioequivalence of Enteric-Coated Mycophenolate Sodium and Mycophenolate Mofetil: A Meta-Analysis of Three Studies in Stable Renal Transplant Recipients

Johnston

Holt

2006

Transplantation

View full text Add to dashboard Cite

show abstract

“…Koehler et al reported that the bioavailability of a CsA generic product (Eon Labs) in rats was lower than that of Neoral, whereas the plasma AM4N level was significantly elevated in groups receiving Eon compared to that in another group receiving Neoral. 17) In our data, a significantly elevated AM4N blood level was not observed in groups treated with generic products compared with that of the group treated with Neoral, Product B. In rats, CsA undergoes first-pass metabolism by CYP3A, which is located in the gastrointestinal mucosa and in the liver.…”

Section: Pharmacokinetics Of Csa and Its Metabolites In Ratsmentioning

confidence: 65%

“…16) In addition, another group reported that after oral administration in rats, the pharmacokinetics of CsA metabolites differed between the innovator and generics. 17) Thus, as we describe above, there are concerns about the quality and efficacy of generics due to the formulation specificity of the innovator and the narrow therapeutic window of CsA. To our knowledge, there have been no direct comparisons of innovator and generics using both in vitro and in vivo assessment.…”

mentioning

confidence: 99%

Comparison of Particle Size and Dispersion State among Commercial Cyclosporine Formulations and Their Effects on Pharmacokinetics in Rats

Shibata¹,

Saito²,

Kawanishi³

et al. 2012

CHEMICAL & PHARMACEUTICAL BULLETIN

View full text Add to dashboard Cite

Generic versions of Neoral, a microemulsion capsule formulation of cyclosporine, have been approved worldwide. However, there are concerns about the quality and efficacy of the generics due to the formulation specificity and differences in inactive ingredients among products. In this study, we measured the physicochemical properties of both the innovator and the generic formulations, and compared their bioavailability in rats. When the capsule contents were dispersed in water, the absorbance (600 nm wavelength) of generic products was higher than that of the innovator. Whereas the dispersion solution of the innovator in Fed State Simulated Intestinal Fluid was nearly clear, that of all the generics became white and turbid. The mean diameter of the microemulsion (or emulsion) formed in water by the generics was 39.7, 57.7, 64.5, and 74.8 nm, all of which were larger than that of the innovator (26.4 nm). Although the T max of the generics tended to be long relative to that of the innovator, there were no significant differences between the innovator and generics with regard to maximum blood concentration (C max ) or area under the curve (AUC). These results suggest that the physicochemical differences between the innovator and the generics will not have a significant effect on C max or AUC, which is necessary to ensure bioequivalence.

show abstract

“…Although a number of bioequivalent assessments for various drugs were conducted in the rat model [27-29], considerable variability of drug level in population or series time points sampling have been observed in early studies, which has hampered the precision of bioequivalence studies [30-32]. Recently, in spite of the many successful reports of bioequivalence/bioavailability studies in rats by using microdialysis, there are a few challenges that need to be addressed before microdialysis can be regarded as a generally applicable routine technique for assaying drug delivery [33].…”

Section: Resultsmentioning

confidence: 99%

Bioequivalence of Two Intravenous Artesunate Products with Its Active Metabolite Following Single and Multiple Injections

Xie

Meléndez

et al. 2011

Pharmaceuticals

View full text Add to dashboard Cite

In animal species and humans, artesunate (AS) undergoes extensive and complex biotransformation to an active metabolite, dihydroartemisinin (DHA). The bioequivalence of two intravenous AS pharmaceutical products with 5% NaHCO3 (China Formulation) or 0.3 M PBS (WRAIR Formulation) was determined in rats in a two-formulation, two-period, and two-sequence crossover experimental design. Following single and multiple intravenous administrations, a series of blood samples was collected by using an automated blood sampler and drug concentrations were analyzed by LC-MS/MS. The 90% CI of the difference between the two intravenous formulations was contained within 80–125% of the geometric mean of pharmacokinetic parameters for AS and DHA in all animals dosed. Hematological effects were studied on days 1 and 3 after the final dosing, and a rapidly reversible hematological toxicity (significant reductions in reticulocyte levels) was seen in the peripheral blood of the rats treated with each formulation. The results showed that bioequivalence with the parent compound and active metabolite was fulfilled in the 82.3–117.7% ranges of all parameters (AUC0−t, Cmax, concentration average and degree of fluctuation) in the two-period and two-sequence crossover studies following single and repeated intravenous injections. For the metabolite, the equivalence was satisfied in most pharmacokinetic parameters tested due to the variability in the hydrolysis rate of AS to DHA. The WRAIR formulation of AS was considered to be bioequivalent to the Chinese formulation at steady-state according to the total drug exposure, in terms of both parent drug and active metabolite, rapidly reversal in reticulocyte decline, and extension of single and multiple administrations. Therefore, the parent drug and active metabolites should play similar important roles in the determination of efficacy and safety of the drug.

show abstract

Comparison of Bioavailability and Metabolism with Two Commercial Formulations of Cyclosporine A in Rats

Abstract: ABSTRACT:The bioavailability and metabolism of cyclosporine A (CsA) capsules were compared with two bioequivalent (Food and Drug Administration approved) preparations in rats. Two groups of WistarKyoto rats were given 10 mg/kg q.

Cited by 14 publications

References 17 publications

Bioequivalence of Enteric-Coated Mycophenolate Sodium and Mycophenolate Mofetil: A Meta-Analysis of Three Studies in Stable Renal Transplant Recipients

Bioequivalence of Enteric-Coated Mycophenolate Sodium and Mycophenolate Mofetil: A Meta-Analysis of Three Studies in Stable Renal Transplant Recipients

Comparison of Particle Size and Dispersion State among Commercial Cyclosporine Formulations and Their Effects on Pharmacokinetics in Rats

Bioequivalence of Two Intravenous Artesunate Products with Its Active Metabolite Following Single and Multiple Injections

Contact Info

Product

Resources

About