Abstract
PurposeThe objectives of this analysis were to characterize the population pharmacokinetics (PK) of PF-06439535 (a bevacizumab biosimilar) and reference bevacizumab (Avastin®) sourced from the European Union (bevacizumab-EU) in patients with advanced non-squamous non-small cell lung cancer (NSCLC), and to quantify the difference in PK parameters between the two drug products via covariate analysis.MethodsPooled PF-06439535 and bevacizumab-EU serum concentration data from a comparative clinical efficacy and safety study (NCT02364999) in patients with NSCLC (N = 719) were analyzed using a non-linear mixed-effects modeling approach. Patients received PF-06439535 plus chemotherapy or bevacizumab-EU plus chemotherapy every 21 days for 4–6 cycles, followed by monotherapy with PF-06439535 or bevacizumab-EU. PF-06439535 or bevacizumab-EU was administered intravenously at a dose of 15 mg/kg. Effects of patient and disease covariates, as well as the drug product (PF-06439535 versus bevacizumab-EU), on PK were investigated.ResultsOverall, 8632 serum bevacizumab concentrations from 351 patients in the PF-06439535 group and 354 patients in the bevacizumab-EU group were included in the analysis. A two-compartment model adequately described the combined data. Clearance (CL) and central volume of distribution (V1) estimates were 0.0113 L/h and 2.99 L for a typical 71-kg female patient with NSCLC administered bevacizumab-EU. CL and V1 increased with body weight and were higher in males than females even after accounting for differences in body weight. The 95% confidence intervals for the effect of drug product on CL and V1 encompassed unity.ConclusionsThe population PK of PF-06439535 and bevacizumab-EU were well characterized by a two-compartment model. Covariate analysis did not reveal any appreciable differences between PK parameters for PF-06439535 and bevacizumab-EU in patients with NSCLC.Clinical trial registrationClinicalTrials.gov, NCT02364999.
Highlights
Bevacizumab (Avastin®) is a recombinant humanized immunoglobulin G1 monoclonal antibody that inhibits angiogenesis by binding to and neutralizing the biological activity of human vascular endothelial growth factor [1, 2]
In the United States (US), for example, bevacizumab is licensed for the treatment of metastatic colorectal cancer; unresectable, locally advanced, recurrent, or metastatic nonsquamous non-small cell lung cancer (NSCLC); recurrent glioblastoma; metastatic renal cell carcinoma; persistent, 1 3 Vol.:(0123456789)
The concentration–time profiles appeared to be similar between the PF-06439535 and bevacizumabEU treatment groups
Summary
Bevacizumab (Avastin®) is a recombinant humanized immunoglobulin G1 monoclonal antibody that inhibits angiogenesis by binding to and neutralizing the biological activity of human vascular endothelial growth factor [1, 2]. Biosimilars are biological products that are highly similar to a licensed reference product in terms of structure, biological activity, pharmacokinetics (PK) and pharmacodynamics (PD), and efficacy, safety, and immunogenicity profile [3,4,5]. In the US, for example, biosimilarity is defined as meaning that “the [biosimilar] product is highly similar to the reference product notwithstanding minor differences in clinically inactive components”, and that “there are no clinically meaningful differences between the [biosimilar] and the reference product in terms of the safety, purity, and potency of the product” [4]. The bevacizumab biosimilar PF-06439535 (ZirabevTM) has an identical primary structure and similar biologic function as compared with reference bevacizumab (Avastin®) sourced from the European Union (bevacizumab-EU) and US (bevacizumab-US) [6]. For the comparisons of PF-06439535 to each of the two bevacizumab reference products, and for the comparison of bevacizumab-EU to bevacizumab-US, the 90% confidence intervals (CIs) for the test-to-reference ratios of maximum observed concentration (Cmax), area under the concentration–time curve from time zero to the last quantifiable concentration (AUCt), and area under the concentration–time curve from time zero to infinity (AUCinf) were all within the predefined bioequivalence window of 80.00–125.00% [7]
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