-
Journal of Clinical Pharmacology Feb 2020Target-mediated drug disposition (TMDD) is a term to describe a nonlinear pharmacokinetic (PK) phenomenon that is caused by high-affinity binding of a compound to its... (Review)
Review
Target-mediated drug disposition (TMDD) is a term to describe a nonlinear pharmacokinetic (PK) phenomenon that is caused by high-affinity binding of a compound to its pharmacologic targets. As the interaction between a drug and its pharmacologic target belongs to the process of pharmacodynamics (PD), TMDD can be viewed as a consequence of "PD affecting PK." Although there are numerous TMDD-related articles in the literature, most of them focus on characterizing TMDD using various mathematical models, which may not be suitable for those readers who have little interest in mathematical modeling and only want to have an understanding of the basic concept. The goal of this review is to serve as a "primer" on TMDD. This review explains (1) how TMDD happens; (2) why large-molecule and small-molecule compounds exhibiting TMDD demonstrate substantially different nonlinear PK behaviors; (3) what nonlinear PK profiles look like in large-molecule and small-molecule compounds exhibiting TMDD, using pegfilgrastim, erythropoietin, ABT-384, and linagliptin as case examples; and (4) how to identify whether the nonlinear PK of a compound is because of TMDD.
Topics: Animals; Drug Delivery Systems; Humans; Nonlinear Dynamics; Pharmaceutical Preparations; Pharmacokinetics; Tissue Distribution
PubMed: 31793004
DOI: 10.1002/jcph.1545 -
Cancer Medicine Sep 2020Our aim was to compare the efficacy and safety of two recently developed biosimilars of pegfilgrastim, a pegylated form of the recombinant human granulocyte-colony... (Comparative Study)
Comparative Study
Our aim was to compare the efficacy and safety of two recently developed biosimilars of pegfilgrastim, a pegylated form of the recombinant human granulocyte-colony stimulating factor (G-CSF) analog filgrastim with those of the reference pegfilgrastim. We retrospectively analyzed data from patients diagnosed with diffuse large B-cell lymphoma (DLBCL) who were treated with first-line R-CHOP chemotherapy and received pegylated G-CSF for primary prophylaxis. The following pegylated G-CSFs were analyzed in this study: reference pegfilgrastim (Neulasta ) and two of its biosimilars (tripegfilgrastim; Dulastin and pegteograstim; Neulapeg ). In total, 296 patients were enrolled. The number of patients with at least one episode of neutropenia during R-CHOP chemotherapy was the lowest in the reference cohort (pegfilgrastim: 127 of 193 patients, 65.8%; tripegfilgrastim: 64 of 69 patients, 92.8%; pegteograstim: 28 of 34 patients, 82.4%, P < .001). The number of patients with at least one episode of febrile neutropenia was also lowest in the reference cohort (pegfilgrastim: 67 of 193 patients, 34.7%; tripegfilgrastim: 38 of 69 patients, 55.1%; pegteograstim: 16 of 34 patients, 47.1%, P = .009). There were no differences in the duration of neutropenia and febrile neutropenia or treatment outcomes (rate of complete response or relapse and survival). There were no reports of grade 3 or higher adverse events requiring discontinuation of prophylactic pegylated G-CSF in any group. The safety of the pegfilgrastim biosimilars for prophylactic purposes was comparable to that of the reference pegfilgrastim; however, in terms of their efficacy, the incidence of neutropenia and febrile neutropenia tended to be higher than that when using pegfilgrastim. The clinical relevance of these results in the biosimilar cohorts should be explored.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bacterial Infections; Biosimilar Pharmaceuticals; Cyclophosphamide; Doxorubicin; Febrile Neutropenia; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Neutropenia; Polyethylene Glycols; Prednisone; Retrospective Studies; Rituximab; Treatment Outcome; Vincristine
PubMed: 32633471
DOI: 10.1002/cam4.3261 -
Cancer Reports (Hoboken, N.J.) Nov 2022Biologicals have become an integral part of cancer treatment both as therapeutic agents and as supportive care agents. It is important to know that biologics are large,... (Review)
Review
Biologicals have become an integral part of cancer treatment both as therapeutic agents and as supportive care agents. It is important to know that biologics are large, complex molecular entities requiring extensive immunogenicity testing and pharmacovigilance strategies to ensure no immune response is evoked in the body. Oncology's pharmacological market is dominated by biologics; however, their high development and manufacturing costs are burdensome to health care systems. Biologics being the most expensive prescription drugs on the market limit the accessibility for necessary treatment in the case of many patients. As biologics patents expire, the development of biosimilars is underway in an effort to lower costs and enable patients to access new cancer therapies. Regulatory guidelines for biosimilars have now been established and are constantly being revised to address any issues, facilitating their robust development. Moreover, many scientific societies offer guidance to help stakeholders better understand current regulations and biosimilar's safety. Despite the potential cost benefits, lack of knowledge about biosimilars, and the possibility of immunogenicity have created an uncertain environment for healthcare professionals and patients. In this review, we provide an overview of relevant legislation and regulations, pharmacoeconomics, and stakeholder perceptions regarding biosimilars. The article also describes biosimilars in development, as well as the ones currently available on the market.
Topics: Humans; Biosimilar Pharmaceuticals; Antineoplastic Agents; Medical Oncology
PubMed: 36195576
DOI: 10.1002/cnr2.1720 -
Journal of the Advanced Practitioner in... Jul 2021In 1991, the U.S. Food & Drug Administration (FDA) approved rmetHuGCSF for human use. This recombinant methionyl human granulocyte colony-stimulating factor, or...
In 1991, the U.S. Food & Drug Administration (FDA) approved rmetHuGCSF for human use. This recombinant methionyl human granulocyte colony-stimulating factor, or filgrastim, saw use in over 1 million patients in its first 5 years on the market. In 2002, the FDA approved a version of filgrastim with covalent linkage to a monomethoxypolyethylene glycol, increasing the molecular size and half-life to replace multiple days of dosing with a single injection. These medications remained standard of care for neutropenia until the Biologics Price Competition and Innovation Act of 2009 created an abbreviated pathway to licensure for biologic products. Practitioners now have their pick of numerous and expanding options for pegfilgrastim biosimilars.
PubMed: 34430064
DOI: 10.6004/jadpro.2021.12.5.9 -
Current Oncology (Toronto, Ont.) Mar 2023Lapelga was approved by Health Canada as a pegfilgrastim biosimilar in 2019 and remains the most commonly used biosimilar in Ontario and is fully reimbursed under the... (Review)
Review
BACKGROUND
Lapelga was approved by Health Canada as a pegfilgrastim biosimilar in 2019 and remains the most commonly used biosimilar in Ontario and is fully reimbursed under the Ontario Drug Benefit program in this category. We explored the efficacy and tolerability of Lapelga in a retrospective analysis of patients with early breast cancer who underwent adjuvant chemotherapy supported with Lapelga as a primary prophylaxis.
METHODS
Adult patients with early breast cancer treated with adjuvant chemotherapy at the London Regional Cancer Program in London, ON, Canada between May 2019 and June 2022 were included. All of these patients were supported with Lapelga as the primary prophylaxis. Patients' age, tumour, and nodal status, their type of chemotherapy, co-morbid conditions, and incidence of febrile neutropenia (FN) and its related details as well as any reported side effects to Lapelga were collected.
RESULTS
A total of 201 patients were included in this review with majority (78%) of patients under 65 years of age. One third of patients were treated with the adriamycin and cyclophosphamide (AC)-Paclitaxel dose dense chemotherapy and a quarter of patients with either a docetaxel and cyclophosphamide (TC) combination or an AC-dose dense with Paclitaxel weekly, and 10% or less patients had FEC-D (5-fluorouracil, epirubicin, and cyclophosphamide) and AC chemotherapy. FN incidence was only 3.48% in this review (7/201 patients). Patients with FN were admitted to hospital and recovered completely with no mortality reported. No cases of a switch to a different granulocyte colony growth factor were seen. The most frequent side effects from Lapelga included musculoskeletal pain, fever, and headache. However, the majority of patients (88.6%; 178/201) did not have any reported side effects specifically assigned to Lapelga.
CONCLUSIONS
In this single centre retrospective study, early breast cancer patients (n = 201) treated with adjuvant chemotherapy supported with primary prophylaxis with Lapelga had a low incidence of FN (3.48%). This supports Lapelga being an effective strategy as the primary prophylaxis when used with common chemotherapy regimens in the real-world setting.
Topics: Adult; Humans; Female; Breast Neoplasms; Retrospective Studies; Biosimilar Pharmaceuticals; Granulocyte Colony-Stimulating Factor; Cyclophosphamide; Doxorubicin; Paclitaxel; Ontario
PubMed: 36975457
DOI: 10.3390/curroncol30030244 -
BioDrugs : Clinical Immunotherapeutics,... Jun 2020Febrile neutropenia (FN) is a serious complication of chemotherapy, which can cause significant morbidity and mortality, result in dose delays and reductions and,... (Review)
Review
Febrile neutropenia (FN) is a serious complication of chemotherapy, which can cause significant morbidity and mortality, result in dose delays and reductions and, ultimately, reduce cancer survival. Over the past decade, the availability of biosimilar filgrastim (short-acting granulocyte colony-stimulating factor [G-CSF]) has transformed patient access, with clear evidence of clinical benefit at preventing FN at reduced costs. In 2019, seven biosimilar pegfilgrastims (long-acting G-CSFs) were licensed, creating optimal market conditions and choice for prescribers. FN affects up to 117 per 1000 cancer patients, with mortality rates in the range of 2-21%. By reducing FN incidence and improving chemotherapy relative dose intensity (RDI), G-CSF has been associated with a 3.2% absolute survival benefit. Guidelines recommend primary prophylaxis and that filgrastim be administered for 10-14 days, while pegfilgrastim is administered once per cycle. When taken according to the guidelines, pegfilgrastim and filgrastim are equally effective. However, in routine clinical practice, filgrastim is often under-dosed (< 7 days) and has been shown to be inferior to pegfilgrastim at reducing FN incidence, hospitalisations and maintaining RDI. Once-per-cycle administration with pegfilgrastim might also aid patient adherence. The introduction of biosimilar pegfilgrastim should instigate a rethink of neutropenia management. Biosimilar pegfilgrastim offers countries using biosimilar filgrastim opportunities to improve adherence and thus cancer survival, whilst offering economic benefits for countries using reference pegfilgrastim. These benefits can be realised in full if biosimilar pegfilgrastim becomes part of routine clinical practice supported by drug and therapeutic committees implementing guidelines with multidisciplinary support in the hospital.
Topics: Antineoplastic Agents; Biosimilar Pharmaceuticals; Chemotherapy-Induced Febrile Neutropenia; Filgrastim; Humans; Neoplasms; Polyethylene Glycols
PubMed: 32232676
DOI: 10.1007/s40259-020-00411-4 -
Advances in Therapy Mar 2022Biologic therapeutics can trigger immune responses in patients. As part of the totality of evidence that is required for regulatory approval of biosimilars,... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Biologic therapeutics can trigger immune responses in patients. As part of the totality of evidence that is required for regulatory approval of biosimilars, immunogenicity similarity must be assessed in the clinical programs. Pegfilgrastim-cbqv (UDENYCA) is a pegfilgrastim biosimilar approved in the USA and European Union. This article demonstrates the similar immunogenicity of pegfilgrastim-cbqv compared with its reference product, pegfilgrastim (Neulasta).
METHODS
The immunogenicity of pegfilgrastim-cbqv was assessed in three clinical studies in healthy subjects (one specifically designed to evaluate immunogenicity similarity and two studies to assess pharmacokinetics and pharmacodynamics bioequivalence) using a tiered approach, in which plasma samples were tested for the presence of antidrug antibodies (ADAs) as well as ADA binding-specificity, titer and neutralizing activity. To assess the clinical impact of ADAs, pharmacokinetics, pharmacodynamics and safety profiles were compared between ADA-positive and -negative subjects.
RESULTS
These studies demonstrated similar immunogenicity of pegfilgrastim-cbqv and pegfilgrastim. The small differences in ADA incidence between treatment groups observed in the immunogenicity study were driven by non-neutralizing, low-titer, polyethylene glycol (PEG)-reactive ADAs, which are commonly present in healthy subjects. No treatment-emergent neutralizing antibodies (NAbs) were detected in either treatment group, and there was no apparent impact of ADAs on pharmacokinetics, pharmacodynamics or safety.
CONCLUSION
Pegfilgrastim-cbqv has similar immunogenicity to pegfilgrastim. The presented immunogenicity, pharmacokinetics, pharmacodynamics and safety data support the overall demonstration of no clinically meaningful differences between pegfilgrastim-cbqv and pegfilgrastim.
CLINICAL TRIAL REGISTRATION
NCT02418104 (CHS-1701-04, April 2015), NCT02650973 (CHS-1701-05, February 2016) and NCT02385851 (CHS-1701-03, March 2015).
Topics: Biosimilar Pharmaceuticals; Case-Control Studies; Filgrastim; Healthy Volunteers; Humans; Polyethylene Glycols
PubMed: 35034311
DOI: 10.1007/s12325-021-02024-x -
Cancers Aug 2022Neutropenia and febrile neutropenia are common and potentially life-threating events associated with chemotherapy treatment in Hodgkin lymphoma (HL). Neutropenia-related...
Neutropenia and febrile neutropenia are common and potentially life-threating events associated with chemotherapy treatment in Hodgkin lymphoma (HL). Neutropenia-related infectious events could be an issue both for direct clinical consequences and for delay in treatment delivery, affecting final outcomes in a potentially highly curable disease. Pegfilgrastim is the pegylated form of filgrastim, the recombinant form of human G-CSF, capable of prevent and mitigate neutropenic effects of chemotherapy, when adopted as primary prophylaxis in several hematological malignancies. No updated version of major international guidelines provides clear indication on prophylaxis use of pegfilgrastim in HL to prevent febrile neutropenia episodes in HL. Moreover, to date, scarce and non-uniform clinical experiences evaluating pegfilgrastim as prophylaxis in HL are present in the literature. Herein, we propose a brief summary of the literature data about efficacy and safety of the use of pegfilgrastim as primary prophylaxis in HL during chemotherapy treatment.
PubMed: 36077600
DOI: 10.3390/cancers14174063