Bioequivalence of two preparations of ticlopidine evaluated using a pharmacodynamic end point.
OBJECTIVE
To evaluate the bio-equivalence of 2 ticlopidine preparations, 250 mg Iclopid tablets (Pabianickie Zaklady Farmaceutyczne, Polfa, Poland; test formulation) and 250 mg Ticlid tablets (Sanofi, France; reference formulation) using a pharmacodynamic end point, i.e the platelet aggregation test ex vivo.


METHODS
The study was open, randomized, multiple-dose, two-period, crossover with a four-week washout interval. Volunteers were screened for sensitivity towards the platelet aggregation (ex vivo) effect of ADP (30 micromol/l) and sensitivity to the antiplatelet activity of ticlopidine (250 mg daily, for 3 consecutive days). Only those responding to 30 micromol/l of ADP with aggregation in the range of 40 - 75% of control (0.9% NaCI), and those responding to ticlopidine within 40 - 75% of inhibition of platelet aggregation to ADP ex vivo were randomized to the study. The dose of ticlopidine in each phase was 250 mg daily for four days. Blood samples were taken on Day 0 and Days 2, 4 (last day of ticlopidine administration), 5, 6, 9, 11 and 16 in order to follow platelet recovery. The pharmacodynamic parameter measured was expressed as the percentage inhibition of ex vivo platelet aggregation calculated from the number of platelets in the sample of whole blood remaining after ADP (30 micromol/l) compared to the control sample. The following values were calculated: area under the inhibition curve of platelet aggregation (AUC(inh 1-16)), maximal inhibition of platelet aggregation (Max(inh)) and time at which maximal inhibition of aggregation occurred (T(max inh)).


RESULTS
The ratios (90% confidence intervals) of Iclopid/Ticlid for AUC(inh 1-16), Max(inh), and T(max inh) were: 1.008 (0.973 - 1.044), 1.009 (0.991 - 1.028) and 1.015 (0.988 - 1.043), respectively, satisfying the bioequivalence criteria.


CONCLUSIONS
The test and the reference products are bioequivalent on the basis of the ex vivo platelet aggregation test. Our study has shown that the bioequivalence of two different preparations can be assessed by measuring a pharmacodynamic end point in a suitably selected group of subjects.
Splawinski
J
J
National Institute of Public Health, Warsaw, Poland. splawinski@il.waw.pl
Kuzniar
J
J
Kurianowicz
R
R
Wanczura
P
P
D000328:Adult; D019540:Area Under Curve; D018592:Cross-Over Studies; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D013810:Therapeutic Equivalency; D013988:Ticlopidine / Q000493:pharmacokinetics / Q000494:pharmacology*
D010975:Platelet Aggregation Inhibitors; D013988:Ticlopidine