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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 -
Blood Cancer Journal May 2017The aim of this cohort study was to compare a condensed schedule of consolidation therapy with high-dose cytarabine on days 1, 2 and 3 (HDAC-123) with the HDAC schedule... (Comparative Study)
Comparative Study Randomized Controlled Trial
The aim of this cohort study was to compare a condensed schedule of consolidation therapy with high-dose cytarabine on days 1, 2 and 3 (HDAC-123) with the HDAC schedule given on days 1, 3 and 5 (HDAC-135) as well as to evaluate the prophylactic use of pegfilgrastim after chemotherapy in younger patients with acute myeloid leukemia in first complete remission. One hundred and seventy-six patients were treated with HDAC-135 and 392 patients with HDAC-123 with prophylactic pegfilgrastim at days 10 and 8, respectively, in the AMLSG 07-04 and the German AML Intergroup protocol. Time from start to chemotherapy until hematologic recovery with white blood cells >1.0 G/l and neutrophils >0.5 G/l was in median 4 days shorter in patients receiving HDAC-123 compared with HDAC-135 (P<0.0001, each), and further reduced by 2 days (P<0.0001) by pegfilgrastim. Rates of infections were reduced by HDAC-123 (P<0.0001) and pegfilgrastim (P=0.002). Days in hospital and platelet transfusions were significantly reduced by HDAC-123 compared with HDAC-135. Survival was neither affected by HDAC-123 versus HDAC-135 nor by pegfilgrastim. In conclusion, consolidation therapy with HDAC-123 leads to faster hematologic recovery and less infections, platelet transfusions as well as days in hospital without affecting survival.
Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Consolidation Chemotherapy; Cytarabine; Daunorubicin; Disease-Free Survival; Female; Filgrastim; Humans; Length of Stay; Leukemia, Myeloid, Acute; Male; Middle Aged; Platelet Transfusion; Polyethylene Glycols; Survival Rate
PubMed: 28548643
DOI: 10.1038/bcj.2017.45 -
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 -
Biologics : Targets & Therapy 2016Neutropenia and febrile neutropenia (FN) are frequent and potentially fatal toxicities of myelosuppressive anticancer treatments. The introduction of granulocyte... (Review)
Review
Neutropenia and febrile neutropenia (FN) are frequent and potentially fatal toxicities of myelosuppressive anticancer treatments. The introduction of granulocyte colony-stimulating factors (G-CSFs) in clinical practice has remarkably reduced the duration and severity of neutropenia, as well as the incidence of FN, thus allowing the administration of chemotherapeutic agents at the optimal dose and time with lower risk. The current scenario of G-CSFs in Europe includes filgrastim, lenograstim, some G-CSF biosimilars, and pegfilgrastim. Recently, a novel long-acting G-CSF, lipegfilgrastim, became available. Lipegfilgrastim is a glycopegylated G-CSF, alternative to pegfilgrastim, and has shown in randomized trials, to be equivalent to pegfilgrastim in reducing the incidence of severe neutropenia and FN in patients with breast cancer receiving chemotherapy, with a similar safety profile. Furthermore, lipegfilgrastim was more effective than the placebo in reducing the incidence of severe neutropenia, its duration, and time to absolute neutrophil count recovery, in patients with non-small cell lung cancer receiving myelosuppressive therapy. Although the number of studies currently published is still limited, lipegfilgrastim seems to be a promising drug in the management of chemotherapy-induced neutropenia.
PubMed: 26858523
DOI: 10.2147/BTT.S58597 -
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 -
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