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Aims: Single‐dose pharmacokinetic (PK) studies in healthy subjects have been the design of choice for bioequivalence determination for decades. This preference has been recently extended to PK similarity studies of proposed biosimilars. However, PK similarity studies can be complicated by the effect of immunogenicity response on drug disposition. The impact is exacerbated when there is an imbalance in host‐specific immunological characteristics of subjects between the test and reference groups. Such complications remain poorly understood. The purpose of this communication is to show that the impact of immunogenicity response on PK similarity determination can be critical, using adalimumab as an example. Methods: Data for adalimumab concentrations and immunogenicity response over 10 weeks were obtained from 133 healthy subjects receiving a 40 mg dose of Humira® in a PK similarity study. Also, a population PK model with a mechanistic construct for delineating the interplay between adalimumab disposition and antidrug antibodies response was utilized to estimate via simulation the probability that a PK similarity study would fail in typical study settings. Results: The simulations showed that the immunogenicity response can have a profound impact on the outcome of PK similarity determination. As such, the probability of failing to achieve the similarity conclusion increased to 51.9%, from 13.8% in the absence of immunogenicity response. Conclusion: This study provides a model‐based framework for better understanding of how a PK similarity study can be optimally designed and for interpretation of the outcome of PK similarity determination when the drug disposition is affected in the presence of immunogenicity response. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: To demonstrate pharmacokinetic (PK) similarity of PF-06438179/GP1111, a potential biosimilar to Remicade®, to Remicade® sourced from European Union (infliximab-EU) and United States (infliximab-US), and of infliximab-EU to infliximab-US. Methods: In this phase I, parallel-group, three-arm trial, healthy adult subjects were randomized to receive a single 10-mg/kg intravenous infusion of PF-06438179/GP1111, infliximab-EU, or infliximab-US. PK, and safety and immunogenicity evaluations were performed over 8 and 12 weeks, respectively. PK similarity was established if the 90% confidence intervals (CIs) of the test-to-reference ratios for PK parameters, Cmax, AUCT, and AUCinf, were within the 80.00-125.00% pre-specified equivalence window. Results: Of 151 subjects randomized, 146 received study treatment; 130 were eligible for PK similarity assessment. Serum concentration-time profiles were similar across the three treatments. The 90% CIs for test-to-reference ratios for Cmax, AUCT, and AUCinf were within 80.00-125.00% for comparison of PF-06438179/GP1111 to infliximab-EU and infliximab-US, and of infliximab-EU to infliximab-US. Similar numbers of subjects across treatment groups experienced adverse events. Anti-drug and neutralizing antibody profiles were largely similar among groups. Conclusions: This study demonstrated PK similarity of PF-06438179/GP1111 to infliximab-EU and infliximab-US, and of infliximab-EU to infliximab-US. All three products displayed comparable safety and immunogenicity profiles. Trial registration: CT.gov identifier NCT01844804 [ABSTRACT FROM AUTHOR]

Aims To evaluate potential differences between PF-05280586 and rituximab sourced from the European Union (rituximab-EU) and USA (rituximab-US) in clinical response (Disease Activity Score in 28 Joints [DAS28] and American College of Rheumatology [ACR] criteria), as part of the overall biosimilarity assessment of PF-05280586. Methods A randomised, double-blind, pharmacokinetic similarity trial was conducted in patients with active rheumatoid arthritis refractory to anti-tumour necrosis factor therapy on a background of methotrexate. Patients were treated with 1000 mg of PF-05280586, rituximab-EU or rituximab-US on days 1 and 15 and followed over 24 weeks for pharmacokinetic, clinical response and safety assessments. Key secondary end points were the areas under effect curves for DAS28 and ACR responses. Mean differences in areas under effect curves were compared against respective reference ranges established by observed rituximab-EU and rituximab-US responses using longitudinal nonlinear mixed effects models. Results The analysis included 214 patients. Demographics were similar across groups with exceptions in some baseline disease characteristics. Baseline imbalances and group-to-group variation were accounted for by covariate effects in each model. Predictions from the DAS28 and ACR models tracked the central tendency and distribution of observations well. No point estimates of mean differences were outside the reference range for DAS28 or ACR scores. The probabilities that the predicted differences between PF-05280586 vs. rituximab-EU or rituximab-US lie outside the reference ranges were low. Conclusions No clinically meaningful differences were detected in DAS28 or ACR response between PF-05280586 and rituximab-EU or rituximab-US as the differences were within the pre-specified reference ranges. TRIAL REGISTRATION Number: NCT01526057. [ABSTRACT FROM AUTHOR]

Aims Pharmacokinetic (PK) similarity was assessed among PF-05280586 (a proposed biosimilar) vs. rituximab sourced from the European Union (rituximab-EU) and the United States (rituximab-US). Pharmacodynamics (PD), overall safety and immunogenicity were also evaluated. Methods Patients with active rheumatoid arthritis on a background of methotrexate and inadequate response to one or more tumour necrosis factor antagonist therapies were randomized to intravenous PF-05280586, rituximab-EU or rituximab-US 1000 mg doses on study days 1 and 15. Results A total of 220 patients were randomized to receive study treatment as assigned. Of these, 198 met per-protocol population criteria for inclusion in the PK data analysis. PF-05280586, rituximab-EU and rituximab-US exhibited similar PK profiles following administration of assigned study drug on days 1 and 15. The 90% confidence intervals of test-to-reference ratios for Cmax, AUCT, AUC0-∞ and AUC2-week were within the bioequivalence margin of 80.00-125.00% for comparisons of PF-05280586 with rituximab-EU, PF-05280586 with rituximab-US, and rituximab-EU with rituximab-US. All treatments resulted in a rapid and profound reduction in CD19+ B cells and sustained profound B cell suppression up to week 25. The incidence of antidrug antibody (ADA) response ( n = 7, 10 and 9 for PF-05280586, rituximab-EU and rituximab-US, respectively), time to ADA emergence and ADA titres were similar across treatments. None of the ADA-positive samples was positive for neutralizing activity. No clinically meaningful differences in adverse events were identified. Conclusions The study demonstrated PK similarity among PF-05280586, rituximab-EU and rituximab-US. In addition, all treatments showed comparable CD19+ B cell depletion PD responses, as well as safety and immunogenicity profiles. [ABSTRACT FROM AUTHOR]

Aims The pharmacokinetic ( PK) similarity between PF-05280014, a proposed trastuzumab biosimilar, trastuzumab sourced from European Union (trastuzumab- EU) or from United States (trastuzumab- US) was evaluated. Safety and immunogenicity were also assessed. Methods In this phase 1, double-blind trial ( NCT01603264), 105 healthy male volunteers were randomized 1:1:1 to receive a single 6 mg kg−1 intravenous dose of PF-05280014, trastuzumab- EU, or trastuzumab- US, and evaluated for 70 days. Drug concentration-time data were analyzed by non-compartmental methods. PK similarity for the comparisons of PF-05280014 to each of trastuzumab- EU and trastuzumab- US, and trastuzumab- EU to trastuzumab- US were determined using the standard 80.00% to 125.00% bioequivalence criteria. Results Baseline demographics for the 101 subjects evaluable for PK were similar across all arms. The three products exhibited similar PK profiles with target-mediated disposition. The 90% CIs for the ratios of Cmax [ABSTRACT FROM AUTHOR]

This study determined the pharmacokinetics (PK) of figitumumab and its effects on insulin-like growth factor (IGF) axis-related biomarkers, following a single intravenous dose (10 [n = 16] and 20 [n = 12] mg/kg) in healthy adults. Serial blood sampling for PK and biomarkers was conducted up to 84 days postdose. A dose increase from 10 to 20 mg/kg led to 1.9- and 2.4-fold increases in mean Cmax and AUC∞, respectively. Median disposition half-life was 21.1 and 27.8 days at 10 and 20 mg/kg, respectively. At 10 and 20 mg/kg, figitumumab increased total IGF-1, free IGF-1, IGF binding protein (IGFBP)-3, and insulin by 4.1- and 4.8-, 8.3- and 12.1-, 2.4- and 2.9-, and 7.3- and 9.8-fold, respectively; increases were sustained throughout the 84-day period. There was a slight and transient elevation in IGF-2. Mean plasma glucose increased by 18% and 16% at 10 and 20 mg/kg, respectively. Most treatment-related adverse events were mild in severity; the most common included dry eye (n = 9) and ocular hyperemia (n = 9) in the 20-mg/kg group. No antidrug antibodies were detected. Overall, figitumumab (10 or 20 mg/kg) demonstrated PK properties typical of IgG2 antibodies and produced substantial and sustained increases in IGF-1 (total and free), IGFBP-3, and insulin. [ABSTRACT FROM AUTHOR]

Summary: Background: Figitumumab is a fully human IgG2 monoclonal antibody targeting the insulin-like growth-factor-1 receptor (IGF-1R). Preclinical data suggest a dependence on insulin-like growth-factor signalling for sarcoma subtypes, including Ewing''s sarcoma, and early reports show antitumour activity of IGF-1R-targeting drugs in these diseases. Methods: Between January, 2006, and August, 2008, patients with refractory, advanced sarcomas received figitumumab (20 mg/kg) in two single-stage expansion cohorts within a solid-tumour phase 1 trial. The first cohort (n=15) included patients with multiple sarcoma subtypes, age 18 years or older, and the second cohort (n=14) consisted of patients with refractory Ewing''s sarcoma, age 9 years or older. The primary endpoint was to assess the safety and tolerability of figitumumab. Secondary endpoints included pharmacokinetic profiling and preliminary antitumour activity (best response by Response Evaluation Criteria in Solid Tumours [RECIST]) in evaluable patients who received at least one dose of medication. This study is registered with ClinicalTrials.gov, number NCT00474760. Findings: 29 patients, 16 of whom had Ewing''s sarcoma, were enrolled and received a total of 177 cycles of treatment (median 2, mean 6·1, range 1–24). Grade 3 deep venous thrombosis, grade 3 back pain, and grade 3 vomiting were each noted once in individual patients; one patient had grade 3 increases in aspartate aminotransferase and gammaglutamyltransferase concentrations. This patient also had grade 4 increases in alanine aminotransferase concentrations. The only other grade 4 adverse event was raised concentrations of uric acid, noted in one patient. Pharmacokinetics were comparable between patients with sarcoma and those with other solid tumours. 28 patients were assessed for response; two patients, both with Ewing''s sarcoma, had objective responses (one complete response and one partial response) and eight patients had disease stabilisation (six with Ewing''s sarcoma, one with synovial sarcoma, and one with fibrosarcoma) lasting 4 months or longer. Interpretation: Figitumumab is well tolerated and has antitumour activity in Ewing''s sarcoma, warranting further investigation in this disease. Funding: Pfizer Global Research and Development. [Copyright &y& Elsevier]