Hussein Khan

A comparison of the pharmacodynamic behavior of branded and biosimilar enoxaparin in primates.

Pharmacodynamic behavior of branded and biosimilar enoxaparin was compared in a crossover study in primates. Blood samples collected at baseline and at 1, 4, 6, and 28 hours post-subcutaneous administration of Lovenox or Fibrinox were evaluated using clot-based and amidolytic assays. Anti-Xa levels following Fibrinox and Lovenox administration were not different. Anti-IIa levels were significantly higher in Lovenox-treated animals 1 to 6 hours post-administration. Higher drug levels were measured by Heptest in Fibrinox-treated animals from 4 to 6 hours. Pharmacokinetic differences were not observed using anti-Xa or Heptest assays. The area under the curve (anti-IIa) following Lovenox treatment was significantly larger than following Fibrinox treatment. When drug levels (anti-IIa) were plotted against anti-Xa or Heptest drug levels, a hysteretic relationship which was distinct for Fibrinox- and Lovenox-treated primates was observed suggesting a lack of bioequivalence for the low-molecular-weight heparin tested. In vivo behavior is an important consideration for defining pharmacoequivalence of complex biologic drugs.

Comparative studies on branded enoxaparin and a US generic version of enoxaparin.

Enoxaparin, a complex, biologically derived low-molecular-weight heparin, is approved for a range of clinical indications. This study was carried out to compare the potency profile and pharmacodynamic responses of branded enoxaparin (Lovenox; Sanofi, US) with a generic enoxaparin (enoxaparin sodium injection, USP). Five batches of each product were tested. Although the average molecular weight, anti-factor Xa, and anti-factor IIa potencies were similar for the two products, differences were observed in the in vitro thrombin generation and kinetics of clot formation (P = .01) and in the ex vivo pharmacodynamics regarding thrombin generation inhibition (P = .029), tissue factor pathway inhibitor release (P = .006), and inhibition of the active form of thrombin-activated fibrinolysis inhibitor (P = .023). These findings suggest that simple analytical characterization can establish good quality control in manufacturing, but they may not assure similarity in biological performance between the branded and the generic enoxaparin.

Assessment of levels of vascular endothelial growth factor in patients with ESRD and its possible role in cardiovascular morbidity and mortality.

Patients with end-stage renal disease (ESRD) are known to have an elevation of a variety of abnormal thrombotic and inflammatory markers associated with high cardiovascular mortality. Vascular endothelial growth factor (VEGF) is also dysregulated in ESRD but not much is known about the serum levels of VEGF in patients with ESRD. Published reports suggest that elevated levels of VEGF may be protective to the kidney during periods of acute injury and may maintain local glomerular function. Impaired production of VEGF may lead to proteinuria, hypertension, and thrombotic microangiopathy. However, its role in chronic kidney disease or ESRD remains undefined. In our study, we analyzed blood samples of 52 patients with ESRD on stable hemodialysis regimen and measured predialysis serum levels of VEGF and compared these with blood samples obtained from 50 healthy volunteers in order to study differences between baseline levels of VEGF and also attempted to determine its role in ESRD-related cardiovascular mortality.

The effect of enoxaparin on inflammatory and thrombotic mediators in cancer patients as studied using protein and biochip array approaches.

2547 Background: The pathogenesis of cancer is known to upregulate inflammatory and thrombotic processes which contribute to the increased mortality. We hypothesized that the baseline inflammatory and thrombotic mediators are upregulated in cancer and treatment with LMWHs such as enoxaparin may downregulate them. METHODS To test this, plasma samples were retrospectively analyzed from an open label multi dose active comparator parallel design study in which all patients (n=110) were initially treated with enoxaparin (1-1.5 mg/kg sc) for 5 days. These patients were subdivided into two groups. Group A continued to receive enoxaparin whereas Group B received warfarin. Baseline blood samples, 5 days and 12 weeks post treatment samples were analyzed using bio chip arrays (Randox analyzer) and protein chip array using surface enhanced laser desorption ionization (SELDI) technique. RESULTS In the cerebral biochip array analysis, levels of CRP, TNFRI, D DIMER, NGAL and TM were elevated at baseline which reduced after treatment with enoxaparin at three months except for NSE and TNFRI. In the cytokine biochip array, IL2, IL4, IL6, IL8, IL10, VEGF, IFNG, TNFA, IL1A, IL1B, MCP1 and EGF showed marked upregulation at baseline with enoxaparin treatment resulting in a decrease of IL6 alone. The baseline plasma samples from the patients recruited with multiple cancers in the Oncenox study showed a greater prevalence of the 11.6kDa biomarker (76%) with average amplitude of 23.6. The samples collected after 3 Months of enoxaparin treatment revealed markedly reduced prevalence (38%) and average amplitude of 5.4. CONCLUSIONS These results confirm that inflammatory and thrombotic mediators are downregulated by treatment with enoxaparin. The biochip and protein arrays provide unique tools to profile the known mediators and identify newer biomarkers.