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A pharmacokinetics phase 1 bioequivalence study of the trastuzumab biosimilar MYL-1401O vs. EU-trastuzumab and US-trastuzumab.

ABSTRACT: AIMS:Trastuzumab is a humanized monoclonal antibody that binds the human epidermal growth factor receptor 2 (HER2) oncoprotein and is an effective therapy for HER2-overexpressing breast cancer. MYL-1401O is a trastuzumab biosimilar. Here, we report results from a phase 1 study that investigated bioequivalence among MYL-1401O, reference EU-trastuzumab and US-trastuzumab. METHODS:This single-centre, randomized, double-blind, three-arm, parallel-group, phase 1 study was conducted in healthy adult male volunteers. Subjects were randomized 1:1:1 to receive a single 8 mg kg-1 dose of MYL-1401O, EU-trastuzumab or US-trastuzumab as a 90-min intravenous infusion. The primary objective was to assess PK similarity among all three products. Primary endpoints assessed were peak serum concentration (Cmax), area under the serum concentration-time curve from time of dosing to time of last quantifiable concentration and from time of dosing to infinity. Secondary endpoints included time of Cmax, elimination rate constant, half-life, safety and immunogenicity. RESULTS:Of 132 subjects enrolled (44/treatment), 120 (MYL-1401O, n = 42; EU-trastuzumab, n = 41; US-trastuzumab, n = 37) were included in the PK analysis. The 90% confidence intervals of the ratios of geometric means for the primary endpoints were bounded within the predefined bioequivalence criterion of 80-125%. Secondary endpoints time of Cmax, elimination rate constant and half-life were similar among groups. All treatment-emergent adverse events were mild or moderate, similar across groups and no serious adverse events were reported. No treatment-related antidrug antibodies were detected. CONCLUSIONS:MYL-1401O was well tolerated and demonstrated PK and safety profiles similar to EU-trastuzumab and US-trastuzumab in healthy volunteers (ClinicalTrials.gov, NCT02594761).

SUBMITTER: Waller CF

PROVIDER: S-EPMC6138509 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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A pharmacokinetics phase 1 bioequivalence study of the trastuzumab biosimilar MYL-1401O vs. EU-trastuzumab and US-trastuzumab.

Waller Cornelius F CF Vutikullird Apinya A Lawrence Tracey E TE Shaw Andrew A Liu Mark Shiyao MS Baczkowski Mark M Sharma Rajiv R Barve Abhijit A Goyal Parag P Donnelly Charles C Sengupta Nilanjan N Pennella Eduardo J EJ

British journal of clinical pharmacology 20180731 10

<h4>Aims</h4>Trastuzumab is a humanized monoclonal antibody that binds the human epidermal growth factor receptor 2 (HER2) oncoprotein and is an effective therapy for HER2-overexpressing breast cancer. MYL-1401O is a trastuzumab biosimilar. Here, we report results from a phase 1 study that investigated bioequivalence among MYL-1401O, reference EU-trastuzumab and US-trastuzumab.<h4>Methods</h4>This single-centre, randomized, double-blind, three-arm, parallel-group, phase 1 study was conducted in ...[more]

PMID: 29926514

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Project description:PurposeBevacizumab is a recombinant humanized monoclonal antibody that inhibits vascular endothelial growth factor-specific angiogenesis in some cancers. MYL-1402O is a proposed bevacizumab biosimilar.MethodsThe primary objective of this single-center, randomized, double-blind, three-arm, parallel-group, phase 1 study in healthy male volunteers was to evaluate bioequivalence of MYL-1402O to EU and US-reference bevacizumab, and EU-reference bevacizumab to US-reference bevacizumab. The primary pharmacokinetic parameter was area under the serum concentration-time curve from 0 extrapolated to infinity (AUC0-∞). Pharmacokinetic parameters were analyzed using general linear models of analysis of variance. Secondary endpoints included safety and tolerability.ResultsOf 111 enrolled subjects, 110 were included in the pharmacokinetic analysis (MYL-1402O, n = 37; EU-reference bevacizumab, n = 36; US-reference bevacizumab, n = 37). Bioequivalence was demonstrated between MYL-1402O and EU-reference bevacizumab, MYL-1402O and US-reference bevacizumab, and between EU- and US-reference bevacizumab where least squares mean ratios of AUC0-∞ were close to 1, and 90% CIs were within the equivalence range (0.80-1.25). Secondary pharmacokinetic parameters (AUC from 0 to time of last quantifiable concentration [AUC0-t], peak serum concentration [Cmax], time to Cmax, elimination rate constant, and elimination half-life) were also comparable, with 90% CIs for ratios of AUC0-t and Cmax within 80-125%. Treatment-emergent adverse events were similar across all three treatment groups and were consistent with clinical data for bevacizumab.ConclusionMYL-1402O was well tolerated and demonstrated pharmacokinetic and safety profiles similar to EU-reference bevacizumab and US-reference bevacizumab in healthy male volunteers. No new significant safety issues emerged (ClinicalTrials.gov, NCT02469987; ClinicalTrialsRegister.eu EudraCT, 2014-005621-12; June 12, 2015).

Project description:IntroductionThis study evaluated the pharmacokinetic (PK) equivalence between BP02 (a proposed trastuzumab biosimilar) and the reference trastuzumab approved in the EU (EU-trastuzumab) and the US (US-trastuzumab).MethodsIn this phase 1, double-blind, parallel-group trial, 111 healthy male volunteers were randomized 1:1:1 to receive a single 6-mg/kg intravenous infusion of BP02, EU-trastuzumab, or US-trastuzumab and were evaluated for 78 days. Serum drug concentration-time data were analyzed by non-compartmental methods. The PK similarity of BP02 to the two reference products, and between EU-trastuzumab and US-trastuzumab, was determined using the standard 80-125% bioequivalence criteria.ResultsBaseline demographics for the 111 subjects with evaluable pharmacokinetics were similar across all treatment groups. PK profiles were similar for the three products. The 90% confidence intervals (CIs) for the ratios of area under the serum concentration-time curve (AUC) from the time of dosing to infinity (AUC0-inf), AUC from the time of dosing until the time of the last quantifiable concentration (AUC0-t), and peak serum concentration of trastuzumab (Cmax) were within 80% to 125% for all three pairwise comparisons. Adverse events (AEs) were similar across all arms, with treatment-related AEs reported by 73.0%, 73.0%, and 89.2% of the subjects in the BP02, EU-trastuzumab, and US-trastuzumab groups, respectively. The most common AEs were headache, infusion-related reactions, and upper-respiratory-tract infections. Four subjects-three in the US-trastuzumab group and one in the BP02 group-discontinued the study due to AEs. All post-dose samples except for two tested negative for anti-drug antibodies.ConclusionThis study demonstrates the PK similarity among BP02, EU-trastuzumab, and US-trastuzumab. The safety and immunogenicity profiles observed for the three products in this study are consistent with previous reports for trastuzumab.Trial registrationANZCTR number: ACTRN12621000573853.

Project description:PURPOSE:PF-05280014 is a biosimilar to trastuzumab (Herceptin®). Following demonstration of pharmacokinetic (PK) similarity in healthy volunteers, a comparative clinical study in patients with HER2-positive metastatic breast cancer (mBC) compared the efficacy, safety and immunogenicity of PF-05280014 and trastuzumab sourced from the EU (trastuzumab-EU), both with paclitaxel. METHODS:Population PK of PF-05280014 and trastuzumab-EU was evaluated. RESULTS:Overall, 702 patients were treated: PF-05280014 (n?=?349) and trastuzumab-EU (n?=?353). Peak-and-trough serum drug concentration samples were collected (selected doses) following repeated intravenous administration of PF-05280014 or trastuzumab-EU. Population PK analysis was performed with drug concentration-time data to cycle 17 for each compound, using nonlinear mixed effect modeling. Potential baseline covariates (circulating HER2 concentrations, body weight, Japanese race, Eastern Cooperative Oncology Group status, number of metastatic sites and antidrug antibody status) were evaluated. Concentration-time data of PF-05280014 and trastuzumab-EU were adequately described by a two-compartment model with first-order elimination, with inter-individual variability (IIV) on clearance (CL), volumes of distribution in central compartment (V1) and peripheral compartments, and intercompartment clearance. Similar estimated PK parameters and IIV were obtained for both treatments. For PF-05280014 and trastuzumab-EU, baseline body weight was an influential covariate on CL and V1; the magnitude was comparable between treatments. PK was consistent between the limited number of Japanese and non-Japanese patients for both compounds. CONCLUSIONS:PF-05280014 and trastuzumab-EU had similar PK parameters and influential PK covariates in patients with HER2-positive mBC. These results provided further evidence in patients for PK similarity between PF-05280014 and trastuzumab-EU. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov, NCT01989676.

Dataset Information

A pharmacokinetics phase 1 bioequivalence study of the trastuzumab biosimilar MYL-1401O vs. EU-trastuzumab and US-trastuzumab.

Publications

A pharmacokinetics phase 1 bioequivalence study of the trastuzumab biosimilar MYL-1401O vs. EU-trastuzumab and US-trastuzumab.

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