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.
Highlights
Chemotherapy-induced neutropenia (CIN) is a major risk factor for infection-related morbidity and mortality, and a significant dose-limiting toxicity in cancer treatment
The area under the effect curve (AUEC) differences for a 10% delivered dose difference were all ≤ 7%, with the largest difference observed for the 4 mg dose (7%)
Simulations from a previously developed bidirectional population PKPD model describing the timecourse of PG concentrations and absolute neutrophil count (ANC) were used in this work to demonstrate model sensitivity to different drug and patient-specific parameter perturbations potentially influencing PK and PD similarity [28]
Summary
Chemotherapy-induced neutropenia (CIN) is a major risk factor for infection-related morbidity and mortality, and 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, when treatment intent is either curative or to prolong survival [1]. Several biosimilar filgrastim (Neupogen®, Amgen) products have been approved by the European Medicines Agency (EMA) and US Food and Drug Administration (FDA) since 2008; the first approvals of PG biosimilars are very recent [5,6]. Costeffectiveness analyses have shown that the market entry of biosimilar filgrastim was associated with a treatment cost reduction [9,10].
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