Bioequivalence of generic and branded subcutaneous enoxaparin: a single-dose, randomized-sequence, open-label, two-period crossover study in healthy Chinese male subjects.
BACKGROUND
Enoxaparin is a low-molecular-weight heparin (LMWH) indicated for antithrombosis. A branded formulation of subcutaneously administered enoxaparin has been available in China since 2000, and a generic formulation is being developed. In a literature search of the key term enoxaparin (publication years not restricted), no published data were identified regarding the pharmacokinetic profile of generic enoxaparin in Chinese subjects.


OBJECTIVE
The aim of this study was to determine the bioequivalence of generic (test) and branded (reference) formulations of enoxaparin 60 mg (6000 IU anti-Xa) SC in healthy subjects for the purpose of meeting regulatory requirements for marketing the generic formulation in China.


METHODS
Healthy Chinese male volunteers were eligible for this single-dose, randomized-sequence, open-label, 2-period crossover study. Participants were randomly assigned to receive the test and reference formulations of enoxaparin 60 mg SC injection (fasting state) in randomized order, with the 2 study periods separated by a 1-week washout period. For the assessment of anti-Xa and anti-IIa activities (surrogates used to describe the pharmacokinetic properties and bioavailability of LMWH), heparin clotting assay, and activated partial thromboplastin time (aPTT), blood samples were obtained before (hour 0; baseline) and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, and 24 hours after study drug administration. The 2 formulations were to be considered bioequivalent if the 90% CIs for the logarithm-transformed values of C(max), T(max), AUC(0-t), and AUC(0-infinity) fell within the predetermined range of 80% to 125%. Tolerability was assessed by questioning subjects about symptoms of possible adverse events and using laboratory analysis (hematology, biochemistry, hepatic function tests, and urinalysis).


RESULTS
Twenty-two subjects participated in the study (mean [SD] age, 21.10 [1.02] years [range, 19-23 years]; weight, 64.07 [5.93] kg [range, 54-75 kg]; and height, 173 [5] cm [range, 163-187 cm]). For anti-Xa activity, the 90% CIs of C(max), AUC(0-t), and AUC(0-infinity) were 100.4% to 106.7%, 100.7% to 105.8%, and 100.7% to 106.1%, respectively. Corresponding values for anti-IIa activity were 85.0% to 102.4%, 80.4% to 94.8%, and 80.1% to 96.0%. For the hepa-rin clotting assay, the values were 97.4% to 102.4%, 98.2% to 102.4%, and 96.0% to 102.7%; and for aPTT, values were 98.2% to 104.3%, 97.4% to 101.6%, and 93.4% to 117.4%. No adverse events were reported during the study.


CONCLUSIONS
Based on the 90% CIs of anti-Xa and anti-IIa activities, heparin clotting assay results, and aPTT in these healthy Chinese male subjects, the test and reference formulations of enoxaparin 60 mg SC met the regulatory requirements for bio-equivalence. Both formulations were well tolerated.
Feng
Limin
L
Clinical Laboratory, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China.
Shen-Tu
Jianzhong
J
Liu
Jian
J
Chen
Junchun
J
Wu
Lihua
L
Huang
Mingzhu
M
D000925:Anticoagulants / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D001682:Biological Availability; D001780:Blood Coagulation Tests; D002681:China; D018592:Cross-Over Studies; D016568:Drugs, Generic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D017984:Enoxaparin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D065427:Factor Xa Inhibitors; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D010314:Partial Thromboplastin Time / Q000379:methods; D011516:Prothrombin / Q000037:antagonists & inhibitors; D013810:Therapeutic Equivalency; D055815:Young Adult
D000925:Anticoagulants; D016568:Drugs, Generic; D017984:Enoxaparin; D065427:Factor Xa Inhibitors; D011516:Prothrombin; C025337:Factor IIa