Model‐Based Approach to Selecting Pegfilgrastim Dose for Pharmacokinetic and Pharmacodynamic Similarity Studies in Biosimilar Development

Abstract

This study applied modeling and simulation (M&S) approaches to evaluate the sensitivity of pegfilgrastim pharmacokinetics (PKs) and pharmacodynamics (PDs) to changes in dose amount, and linear or nonlinear clearance (CL) over pegfilgrastim subcutaneous dose of 2-6 mg. A previously published model was adapted to better describe pegfilgrastim PK and PD data in healthy subjects and used in simulation. Nonlinear CL accounts for 98% and 77%, respectively, of the total CL of pegfilgrastim at 2 and 6 mg. The sensitivity analyses showed: (i) PK of 2 and 6 mg doses are similarly sensitive to detect differences for a 5% change in dose; (ii) PK of 2 mg dose is more sensitive to changes in receptor binding affinity, a model parameter for nonlinear CL, and a product quality attribute characterized with orthogonal methods as part of demonstrating analytical similarity between products; (iii) PK of approved 6 mg dose is more sensitive to changes in linear CL, which has not been associated with any specific product quality attributes, and (iv) the PDs are not sensitive to changes in linear or nonlinear CL. Taken together, our analyses support that the approved pegfilgrastim dose of 6 mg is appropriate for detecting differences between a biosimilar and the reference products in pegfilgrastim PK and PD similarity studies. The described M&S approaches can be adopted to support dose selection for biosimilars with nonlinear PK and complex PK-PD interplay.

A Critical Analysis of the FDA Omics Perspective on Pharma-codynamic Biomarkers to Support Biosimilarity, and its Surrogates.

“…Model-based Testing Markers [204] The FDA has also presented results on a Model-Based Approach for the Dose Selection of P e g f i l g r a s t i m , w h i c h t r e a t s n e u t r o p e n i a ( l o w w h i t e b l o o d c e l l c o u n t ) c a u s e d b y a n t i c a n c e r medications. There are several approved biosimilars for which PK and PD approaches, using the absolute neutrophil count biomarker, have been used to support biosimilar approval.…”

Advancing Innovations in Biosimilars

“…The primary results of these three trials are reported by Sheikhy et al (PSCK9 inhibitors), 5 Gershuny et al (IL-5 antagonists), 4 and Florian et al (interferon beta-1a products), 3 and Hyland et al reports the results of an evaluation of the utility of proteomics for identifying PD biomarkers from the interferon clinical trial. 14 In addition, Li et al 6 describe a model-based approach to inform dose selection, and Vaidyanathan et al 15 describe the evolution of regulatory requirements for insulin products to the current standard that stipulates PK and PD similarity data are sufficient to support approval of biosimilar insulin products.…”

“…One way to do this is to leverage the use of pharmacodynamic (PD) biomarkers in clinical pharmacology studies in place of comparative clinical studies with efficacy end point(s), which is discussed in multiple articles in this issue 1–5 . These articles and others 6 also discuss how modeling and simulation (or model‐informed drug development (MIDD)) can be used to optimize study design and analyses. Other articles focus on characterizing the relationship between product quality characteristics (e.g., structural and functional characterization) and clinical performance to further streamline clinical development 7–9 .…”

“…reports the results of an evaluation of the utility of proteomics for identifying PD biomarkers from the interferon clinical trial 14 . In addition, Li et al 6 . describe a model‐based approach to inform dose selection, and Vaidyanathan et al 15 .…”