[Ip-health] Bioequivalence of two film-coated tablets of imatinib mesylate 400 mg.......... comparison in healthy male South American volunteers

[Joana Ramos]

The new generic  in the study was Imatinib Elea, from Argentina.

Joana

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 www.clinicaltherapeutics.com/articles/2224_cam.pdf

Clin Ther. 2009 Oct;31(10):2224-2232.
Bioequivalence of two film-coated tablets of imatinib mesylate 400 mg: A
randomized, open-label, single-dose, fasting, two-period, two-sequence
crossover comparison in healthy male South American volunteers.

Parrillo-Campiglia S, Ercoli MC, Umpierrez O, Rodr=EDguez P, M=E1rquez S,
Guarneri C, Estevez-Parrillo FT, Laurenz M, Estevez-Carrizo FE.

Center for Clinical Pharmacology, Bdbeq S.A., Hospital Italiano Umberto
Primo, Montevideo, Uruguay; Center for Biomedical Sciences, University
of Montevideo, Montevideo, Uruguay.

Background: Imatinib is a tyrosine kinase inhibitor that has been
established as a highly effective therapy for chronic myelogenous
leukemia and gastrointestinal stromal tumors. A new generic, once-daily
400-mg tablet of imatinib has been developed by a pharmaceutical company
in Argentina, where the regulatory standard for marketing authorization
of an imatinib generic is in vitro dissolution testing. Objective: The
aim of this study was to assess the bioequivalence of a new generic
film-coated test tablet formulation versus a film-coated reference
tablet formulation of imatinib 400 mg. The local manufacturer seeks to
validate the in vitro performance of this new formulation with a
bioequivalence study. Methods: A randomized, open-label, single-dose,
fasting, 2-period, 2-sequence crossover design with a 2-week washout
period was used in this study. The study population consisted of healthy
male South American (Uruguayan) volunteers, who were assigned in a 1:1
ratio to a randomized sequence (test-reference or reference-test). In
each period, the test or reference formulation was administered after an
overnight fast. During the 72-hour follow-up period, participants were
monitored for vital signs and symptoms. Blood samples were collected at
15 time points, including baseline, until 72 hours. Physical examination
and laboratory tests (blood, urine) were repeated 1 week after study
completion. A noncompartmental model was used to determine the
pharmacokinetic parameters of imatinib. The 90% CIs of the
test/reference ratios for AUC(0-infinity) and C(max) were determined;
the test and reference formulations were considered bioequivalent if the
90% CIs were between 0.80 and 1.25. Adverse events were assessed by a
nurse who administered a questionnaire while the healthy volunteers were
admitted in the unit. Results: The bioequivalence study was conducted in
30 Uruguayan male volunteers. Demographic characteristics (mean [SD])
included age, 27.8 (6.5) years; weight, 71.2 (9.8) kg; height, 1.71
(0.09) m; and body mass index, 24.3 (3.0) kg/m2. The mean (SD) of
AUC(0-infinity) was 38,179 (15,504) ng/mL . h(-1) for the test
formulation and 40,554 (17,027) ng/mL . h(-1) for the reference
formulation. The mean of Cmax for the test formulation was 2472 (933)
ng/mL, and the mean Tmax was 3.28 (0.93) hours. The mean of Cmax for the
reference formulation was 2566 (963) ng/mL, and the mean T(max) was 3.63
(1.20) hours. The point estimates (90% CIs) for the test/reference
ratios of the log-transformed AUC- and C(max) mean values were 0.95
(0.87-1.03) and 0.97 (0.89-1.05), respectively, which met the regulatory
criteria for bioequiv-alence. Thirty-four mild to moderate adverse
events were reported (13 with the test formulation and 21 with the
reference formulation), and no serious or unexpected adverse events were
observed during the study. The adverse events included 16 cases of
headache, 13 cases of nausea, 4 cases of vomiting, and 1 episode of
diarrhea. Conclusions: The results of this study suggest that the test
formulation of imatinib met the regulatory criteria for bioequivalence
to the reference formulation in these healthy fasting male volunteers.
Both formulations were generally well tolerated and appeared to have a
similar adverse-event profile.


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Joana Ramos, MSW
Cancer Resources & Advocacy
Seattle WA USA
+1-206-229-2420
http://ramoslink.info/
www.bmtbasics.org