Research Article: Sensitivity of Pegfilgrastim Pharmacokinetic and Pharmacodynamic Parameters to Product Differences in Similarity Studies

Date Published: July 8, 2019

Publisher: Springer International Publishing

Author(s): Ari Brekkan, Luis Lopez-Lazaro, Elodie L. Plan, Joakim Nyberg, Suresh Kankanwadi, Mats O. Karlsson.

http://doi.org/10.1208/s12248-019-0349-3

Abstract

In this work, a previously developed pegfilgrastim (PG) population pharmacokinetic-pharmacodynamic (PKPD) model was used to evaluate potential factors of importance in the assessment of PG PK and PD similarity. Absolute neutrophil count (ANC) was the modelled PD variable. A two-way cross-over study was simulated where a reference PG and a potentially biosimilar test product were administered to healthy volunteers. Differences in delivered dose amounts or potency between the products were simulated. A different baseline absolute neutrophil count (ANC) was also considered. Additionally, the power to conclude PK or PD similarity based on areas under the PG concentration-time curve (AUC) and ANC-time curve (AUEC) were calculated. Delivered dose differences between the products led to a greater than dose proportional differences in AUC but not in AUEC, respectively. A 10% dose difference from a 6 mg dose resulted in 51% and 7% differences in AUC and AUEC, respectively. These differences were more pronounced with low baseline ANC. Potency differences up to 50% were not associated with large differences in either AUCs or AUECs. The power to conclude PK similarity was affected by the simulated dose difference; with a 4% dose difference from 6 mg the power was approximately 29% with 250 subjects. The power to conclude PD similarity was high for all delivered dose differences and sample sizes.

Partial Text

Chemotherapy-induced neutropenia (CIN) is a major risk factor for infection-related morbidity and mortality, and also a significant dose-limiting toxicity in cancer treatment. Patients developing severe (grade 3/4) or febrile neutropenia (FN) during chemotherapy frequently receive dose reductions and/or delays to their chemotherapy. This may impact the success of treatment, particularly when treatment intent is either curative or to prolong survival (1). In patients undergoing cytotoxic chemotherapy, both primary and secondary prophylaxis with granulocyte colony-stimulating factors (GCSFs) have been demonstrated to reduce the incidence of severe and FN, length of neutropenia, neutropenia-associated complications, antibiotic use and the duration of hospitalization (2). Pegfilgrastim (PG) is a sustained-duration pegylated form of filgrastim, a recombinant methionyl form of human GCSF that is widely used in CIN management (3,4). Several biosimilar filgrastim (Neupogen®, Amgen) products have been approved by the European Medicines Agency (EMA) and US Food and Drug Administration (FDA) since 2008; however, the first approvals of PG biosimilars are very recent (5,6). One biosimilar PG product was approved by the FDA in June 2018 and five biosimilar PG products, including the product approved in the US, were recommended for approval by the EMA between July and September 2018 (6–8). Biosimilars are analogous to generics for small molecular weight drugs developed after the exclusive marketing period has expired although the regulatory requirements are very different due to the greater complexity of biological entities. Cost-effectiveness analyses have shown that the market entry of biosimilar filgrastim was associated with a treatment cost reduction (9,10). The approval of biosimilar PG will potentially also be associated with lower treatment costs thereby improving patient access to PG.

The entrance of biosimilar filgrastim products in the European Economic Area reduced the daily treatment price by between 8 and 62% (33). The result of such price reductions may be improved patient access to the therapies and a reduction of the impact of CIN (33). The approval of biosimilar PG has been comparatively slow, with the first approval in either the US or the EU coming in June 2018 (6). Difficulties in developing biosimilar PG may be explored using methods outlined in this work.

A simulation-based analysis demonstrated that PK similarity as assessed by AUC of PG was sensitive to bioavailable dose, baseline neutrophil count and, to a lesser degree, the EC50 of the administered products while AUEC was only sensitive to large differences in EC50. To demonstrate PK similarity, differences in dose content between the reference and test product need to be very small while other tested differences were somewhat less influential. The results of this work demonstrate that several factors need to be controlled and considered in the assessment of biosimilars for PG and that model-based simulations can be a valuable tool to assess factors of importance for biosimilar development.

 

Source:

http://doi.org/10.1208/s12248-019-0349-3

 

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