Comparison of the pharmacodynamic profiles of a biosimilar filgrastim and Amgen filgrastim: results from a randomized, phase I trial

Abstract

Further to the patent expiry of Neupogen® (Amgen filgrastim), Hospira has developed a biosimilar filgrastim (Nivestim™) that may offer a clinically effective alternative for multiple hematologic and oncologic indications. Here results are reported from a phase I trial, primarily designed to compare the pharmacodynamic profiles of Hospira filgrastim and Amgen filgrastim. A phase I, single-center, double-blind, randomized trial was undertaken to demonstrate equivalence of the pharmacodynamic characteristics of Hospira filgrastim and Amgen filgrastim. Fifty healthy volunteers were randomized to receive 5 or 10 µg/kg dosing, before further randomization to treatment sequence. All volunteers received five daily subcutaneous doses of Hospira filgrastim or Neupogen, with subsequent crossover to the alternative treatment. Bioequivalence was evaluated by analysis of variance; if the estimated 90% confidence intervals (CIs) for the ratio of ‘test’ to ‘reference’ treatment means were within the conventional equivalence limits of 0.80–1.25, then bioequivalence was concluded. Forty-eight volunteers completed the study. Geometric mean absolute neutrophil count area under the curve from time 0 to the last time point at day 5 (primary endpoint) was comparable in volunteers given Hospira filgrastim or Amgen filgrastim at 5 µg/kg (ratio of means, 0.98; 90% CI, 0.92–1.05) or 10 µg/kg (ratio, 0.97; 90% CI, 0.93–1.01); 90% CIs were within the predefined range necessary to demonstrate bioequivalence. Hospira filgrastim was well tolerated with no additional safety concerns over Amgen filgrastim. Hospira filgrastim is bioequivalent with Amgen filgrastim with regard to its pharmacodynamic characteristics.

A Phase III Randomized Equivalence Study of Biosimilar Filgrastim versus Amgen Filgrastim in Patients Receiving Myelosuppressive Chemotherapy for Breast Cancer

“…All stages of the preclinical and clinical development of Hospirafilgrastimwerecarefullydesignedinaccordancewith EMAguidelines [8][9][10].Asaresult,aseriesofrigorousanalyseshavenowdemonstratedthebioequivalenceofHospirafilgrastimandAmgenfilgrastimintermsoftheirphysicochemicalproperties,pharmacokineticandpharmacodynamiccharacteristics,andclinicalefficacyandsafetyprofiles [13,14,26]. EMA guidelines support the extrapolation of clinical data from one therapeutic indication to another, assuming that reasonablejustificationcanbemadefollowingconsideration of clinical experience, current literature, similarity of the mechanismsofaction,andanypossiblesafetyissuesindifferentpatientsubpopulations [9,10].Therefore,Hospirafilgras-…”

“…To address this issue, the European Medicines Agency (EMA) has recommended guidelines for the development of biosimilars [8][9][10][11][12]. The development program for Hospira filgrastim was carefully designed to fulfil these guideline requirements and ensure bioequivalence with Amgen filgrastim in terms of quality, safety,andefficacy.PreclinicalandphaseIstudiessupported thephysicochemical,pharmacokinetic,andpharmacodynamic bioequivalence of Hospira filgrastim and Amgen filgrastim [13,14,26].Furthertotheseencouragingearlierstudies,we report the results of a phase III, randomized, double-blind, therapeutic equivalence study designed to evaluate the efficacyandsafetyofHospirafilgrastimversusAmgenfilgrastim forthepreventionofneutropeniainpatientsreceivingmyelosuppressivechemotherapyforbreastcancer.…”

What is a biosimilar? How far does the similarity go?

“…L'étude de cas des deux biosimilaires du GCSF recombinant humain concerne Zarzio ® et Nivestim ® , biosimilaires développés respectivement par Sandoz et Hospira [5][6][7][8][9]. Le produit de référence utilisé pour le développement de ces deux biosimilaires est Neupogen ® , le filgrastim développé par Amgen.…”

“…Les mêmes résultats de bioéqui-valence pharmacodynamique ont été obtenus avec le biosimilaire Nivestim ® en comparaison avec Neupogen ® [9].…”

Comparability of Pharmacodynamics Profiles with an Application to a Biosimilar Study

“…Most biologics usually have multiple indications. A couple of papers used the same bioequivalence (BE) rule in PK analysis for PD comparison in terms of the area under the effect curve (AUEC) of the PD profile [6,7]. Recently, FDA [8] issued guidance for conducting PD comparability study using the same BE rule.…”