The Use of Pharmacometrics to Optimize Biosimilar Development

Dodds, Mike; Chow, Vincent; Márkus, Richard; Pérez-Ruixo, Juan José; Shen, Danny D.; Gibbs, Megan

doi:10.1002/jps.23697

Cited by 8 publications

(5 citation statements)

References 22 publications

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“…M&S approaches are well-suited for evaluating and optimizing the study design for PK and PD similarity studies. 5,6,16…”

Section: Discussionmentioning

confidence: 99%

“…In the case of pegfilgrastim, there exists a PK and PD interplay where the rising pegfilgrastim concentration postdose leads to an increase in ANC (PD response), and in turn the increasing ANC presents a higher extent of receptor‐mediated elimination. M&S approaches are well‐suited for evaluating and optimizing the study design for PK and PD similarity studies 5,6,16 …”

Section: Discussionmentioning

confidence: 99%

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

Sun

et al. 2022

Clin Pharma and Therapeutics

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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.

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“…M&S approaches are well-suited for evaluating and optimizing the study design for PK and PD similarity studies. 5,6,16…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Sun

et al. 2022

Clin Pharma and Therapeutics

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“…Population PK/PD is also an integral part in the development of biosimilar products. Regulatory agencies require that the biosimilar products have a similar PK/PD profile to the reference product ( Zhu et al, 2018 , Dodds et al, 2013 ).…”

Section: Clinical Pharmacology Applications In Clinical Drug Developmmentioning

confidence: 99%

Clinical pharmacology applications in clinical drug development and clinical care: A focus on Saudi Arabia

Alsultan

Alghamdi

et al. 2020

Saudi Pharmaceutical Journal

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Drug development, from preclinical to clinical studies, is a lengthy and complex process. There is an increased interest in the Kingdom of Saudi Arabia (KSA) to promote innovation, research and local content including clinical trials (Phase I-IV). Currently, there are over 650 registered clinical trials in Saudi Arabia, and this number is expected to increase. An important part of drug development and clinical trials is to assure the safe and effective use of drugs. Clinical pharmacology plays a vital role in informed decision making during the drug development stage as it focuses on the effects of drugs in humans. Disciplines such as pharmacokinetics, pharmacodynamics and pharmacogenomics are components of clinical pharmacology. It is a growing discipline with a range of applications in all phases of drug development, including selecting optimal doses for Phase I, II and III studies, evaluating bioequivalence and biosimilar studies and designing clinical studies. Incorporating clinical pharmacology in research as well as in the requirements of regulatory agencies will improve the drug development process and accelerate the pipeline. Clinical pharmacology is also applied in direct patient care with the goal of personalizing treatment. Tools such as therapeutic drug monitoring, pharmacogenomics and model informed precision dosing are used to optimize dosing for patients at an individual level. In KSA, the science of clinical pharmacology is underutilized and we believe it is important to raise awareness and educate the scientific community and healthcare professionals in terms of its applications and potential. In this review paper, we provide an overview on the use and applications of clinical pharmacology in both drug development and clinical care.

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“…The focus of the biosimilar development program is not to establish patient benefit per se but to demonstrate comparability at the analytical, functional, and clinical levels, as the development of biosimilars relies on existing scientific knowledge about the safety and effectiveness of the approved reference products ( Weise et al, 2012 ). Nonetheless, conceptually, PK/PD (pharmacodynamic) modeling and simulation during biosimilar development can play a role similar to its role in the development of novel therapeutic proteins ( Dodds et al, 2013 ; Wang et al, 2019 ). Pharmacometric analysis can provide insights into the exposure range that would be sensitive enough to assess clinically meaningful differences between biosimilars and reference products and can optimize study designs accordingly.…”

Section: Introductionmentioning

confidence: 99%

Exposure–response analysis using time-to-event data for bevacizumab biosimilar SB8 and the reference bevacizumab

Park,

Jung,

et al. 2024

Front. Pharmacol.

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Purpose: This analysis aimed to characterize the exposure–response relationship of bevacizumab in non-small-cell lung cancer (NSCLC) and evaluate the efficacy of SB8, a bevacizumab biosimilar, and Avastin®, the reference bevacizumab sourced from the European Union (EU), based on the exposure reported in a comparative phase III efficacy and safety study (EudraCT, 2015-004026-34; NCT 02754882).Materials and methods: The overall survival (OS) and progression-free survival (PFS) data from 224 patients with steady-state trough concentrations (Css,trough) were analyzed. A parametric time-to-event (TTE) model was developed using NONMEM®, and the effects of treatments (SB8 and bevacizumab-EU) and patient demographic and clinical covariates on OS and PFS were evaluated. Simulations of median OS and PFS by bevacizumab Css,trough were conducted, and concentrations required to achieve 50% and 90% of the maximum median TTE were computed.Results: A log-logistics model with Css,trough best described the OS and PFS data. Treatment was not a predictor of the hazard for OS or PFS. Simulations revealed steep exposure–response curves with a phase of rapid rise before saturating to a plateau. The median Css,trough values of SB8 and bevacizumab-EU reported from the clinical study were on the plateaus of the exposure–response curves. The concentrations required to achieve 50% and 90% of the maximum effect were 82.4 and 92.2 μg/mL, respectively, for OS and 79.7 and 89.1 μg/mL, respectively, for PFS.Conclusion: Simulations based on the constructed TTE models for OS and PFS have well described the exposure–response relationship of bevacizumab in advanced NSCLC. The analysis demonstrated comparable efficacy between SB8 and bevacizumab-EU in terms of OS and PFS based on their exposure levels.

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The Use of Pharmacometrics to Optimize Biosimilar Development

Cited by 8 publications

References 22 publications

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

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

Clinical pharmacology applications in clinical drug development and clinical care: A focus on Saudi Arabia

Exposure–response analysis using time-to-event data for bevacizumab biosimilar SB8 and the reference bevacizumab

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