Pharmacokinetic profiles of a biosimilar filgrastim and Amgen filgrastim: results from a randomized, phase I trial

Abstract

Recombinant human granulocyte colony-stimulating factor (filgrastim) has multiple hematologic and oncologic indications as Neupogen® (Amgen filgrastim). Hospira has developed a biosimilar filgrastim (Nivestim™). Here, results are reported from a phase I trial, primarily designed to compare the pharmacokinetic profiles of Hospira filgrastim and Amgen filgrastim. A phase I, single-center, open-label, randomized trial was undertaken to demonstrate equivalence of the pharmacokinetic characteristics of Hospira filgrastim and Amgen filgrastim. Forty-eight healthy volunteers were randomized to receive intravenous (i.v.) or subcutaneous (s.c.) dosing and then further randomized to order of treatment. Volunteers in each of the two dosing groups received a single 10µg/kg dose of Hospira filgrastim or Amgen filgrastim, with subsequent crossover. 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-six volunteers completed the study. Geometric mean area under the curve from time 0 to the last time point (primary endpoint) was similar in volunteers given Hospira filgrastim or Amgen filgrastim following i.v. (ratio of means: 0.96; 90% CI: 0.90–1.02) or s.c. (ratio of means: 1.02; 90% CI: 0.95–1.09) dosing; 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 in terms of its pharmacokinetic properties and may provide a clinically effective alternative.

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.…”

Pharmacokinetic and pharmacodynamic properties of a new biosimilar filgrastim TPI G-CSF in comparison to the marketed reference filgrastim Neupogen®: a double-blind, single-dose, two-period crossover trial

“…Overall, the findings from this study are consistent with those of similarly-designed studies of other newly developed biosimilar filgrastim products that have been approved in Europe or the US. 5,8,29,30 Establishing bioequivalence in terms of pharmacokinetics and pharmacodynamics is a key step in regulatory approval pathways (in the US and elsewhere), which is usually followed by establishing comparable efficacy and safety in patients. 31 ANC may be considered a surrogate marker for efficacy; it is relevant in not only diagnosis of neutropenia, but also prognosis and assessment of treatment response.…”

“…4 The pharmacokinetic characteristics of filgrastim are widely reported. [5][6][7] The absorption is bi-segmental, and total body clearance of filgrastim follows a first-order pharmacokinetic model. 7 A positive linear correlation is demonstrated between the parenteral dose administered and the serum concentration, as well as the areas under the concentrationtime curves (AUCs).…”

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.…”