Pharmacokinetic/Pharmacodynamic Modeling of Pegfilgrastim in Healthy Subjects

Roskos, Lorin; Lum, Peggy; Lockbaum, Pamela; Schwab, G.; Yang, Bing‐Bing

doi:10.1177/0091270006288731

Cited by 118 publications

(152 citation statements)

References 24 publications

Supporting

Mentioning

143

Contrasting

Order By: Relevance

“…From [Prol] compartment, a maturation-structured cytokinetic model was used to describe the development and maturation of platelets in blood. Similar concept has been exploited to deal with the dynamics of neutrophils and red blood cells following the administration of pegfilgrastim and erythropoietin, respectively (31,32). Briefly, platelets are represented by a series of sequential aging compartments (N PLT ) with transition rates k tr .…”

Section: Pharmacokinetic and Pharmacodynamic Modelmentioning

confidence: 99%

Platelet Dynamics in Peritoneal Carcinomatosis Patients Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Oxaliplatin

Pérez-Ruixo

Valenzuela

Peris

et al. 2015

AAPS J

View full text Add to dashboard Cite

Abstract. The aim of the study was to characterize the platelet count (PLT) dynamics in peritoneal carcinomatosis patients treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal oxaliplatin (HIO). Data from patients treated with CRS alone (N=18) or CRS and HIO (N=62) were used to estimate the baseline platelet count (PLT 0 ), rate constants for platelet maturation (k tr ) and platelet random destruction (k s ), feedback on progenitor cell proliferation (γ), and the drug-specific model parameters (α, β). Plasma oxaliplatin concentrations, C p , reduced the proliferation rate of progenitor cells (k prol ) according to a power function α×C p β . The surgery effect on k prol and k s was explored. The typical values (between subject variability) of the PLT 0 , k tr , k s , γ, α, and β were estimated to be 237×10 9 cells/L (32.9%), 7.09×10 −3 h −1 (47.1%), 8.86×10 −3 h −1 (80.0%), 0.621, 0.88 L/mg (56.9%), and 2.63. Surgery induced a maximal 2.09-fold increase in k prol that was attenuated with a half-life of 8.42 days. Splenectomy decreased k s by 47.5%. Age, sex, body surface area, sex, total proteins, and HIO carrier solution did not impact the model parameters. The model developed suggests that, following CRS and HIO, thrombocytopenia and thrombocytosis were reversible and short-lasting; the severity of the thrombocytopenia and thrombocytosis was inversely correlated, with splenectomized patients having thrombocytopenia of lower severity and thrombocytosis of higher severity; and the HIO dose and treatment duration determine the severity and duration of the thrombocytopenia. Higher HIO dose or longer treatment duration could be used without substantially increasing the risk of major hematological toxicity.

show abstract

Section: Pharmacokinetic and Pharmacodynamic Modelmentioning

confidence: 99%

Platelet Dynamics in Peritoneal Carcinomatosis Patients Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Oxaliplatin

Pérez-Ruixo

Valenzuela

Peris

et al. 2015

AAPS J

View full text Add to dashboard Cite

show abstract

“…Similar to small-molecule drugs, the relationship between the antibody dose or concentration(s) and the observed pharmacological response(s) can be characterized by linear and log-linear, sigmoid E max , biophase distribution, or indirect response models (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). The relationships between the drug dose or concentrations and the observed pharmacological effect can be characterized by linear or loglinear PD models in the form of E ¼ E 0 þ m C (or ln C), where E and E 0 denote the observed and baseline (no-drug) effects, respectively, and m is the slope of the concentrationeffect relationship.…”

Section: Introductionmentioning

confidence: 99%

“…Further complexities such as counterclockwise or clockwise hysteresis loops can be observed in the concentration-effect relationships at non-steady-state serum or tissue concentrations. The underlying causes for these additional complexities in the exposure-response relationships can be diverse and related to factors such as active or inhibitory metabolites, indirect response characteristics, a transient time delay between concentration and effect, or an equilibration delay in the distribution of drug to the biophase compartment (5,12,14,16,17,(22)(23)(24)(26)(27)(28). Additionally, target-mediated PK models (21,29) and bi-or tri-molecular interaction PK-PD models (4,30) that describe antibody PK, the interactions between antigen(s) and antibody, and the elimination of free antigen(s) are highly informative tools used for prediction of safe and effective dosing strategies (13,31).…”

Section: Introductionmentioning

confidence: 99%

Application of Quantitative Pharmacology in Development of Therapeutic Monoclonal Antibodies

Tabrizi

Funelas

Suria

2010

AAPS J

View full text Add to dashboard Cite

Abstract. The advancement of therapeutic monoclonal antibodies during various stages of the drug development process can be effectively streamlined when appropriate translational strategies are applied. Design of successful translational strategies for development of monoclonal antibodies should allow for understanding of the dose-and concentration-response relationships with respect to both beneficial and toxic effects from early phases of drug development. Evaluation of relevant biomarkers during early stages of drug development should facilitate the successful design of safe and effective dosing strategies. Moreover, application of quantitative pharmacology is critical for translation of exposure-response relationships early on.

show abstract

“…This seems unlikely, however, as studies in both healthy volunteers and cancer patients suggest that clinically relevant concentrations of pegfilgrastim are cleared within 12 days of administration. 22,23 This study was intended to investigate the feasibility of PBPC mobilization with pegfilgrastim in patients with solid tumours. Extrapolation of these findings to cell harvest is therefore speculative.…”

Section: Discussionmentioning

confidence: 99%

Pegfilgrastim for peripheral CD34+ mobilization in patients with solid tumours

Willis

Woll

Theti

et al. 2009

Bone Marrow Transplant

View full text Add to dashboard Cite

The efficacy of pegfilgrastim±chemotherapy for mobilizing stem cells in patients with solid tumours was assessed. In cycle 0, a 14-day prechemotherapy cycle, patients (N ¼ 61) were randomized open-label to single doses of pegfilgrastim (6, 12 or 18 mg) on day 1, or daily filgrastim (10 lg/kg) for p7 days. Mean peak peripheral CD34 þ cell counts increased with pegfilgrastim dose, but were significantly higher than filgrastim only at the 18 mg dose (10.17 vs 4.96 Â 10 4 /ml; P ¼ 0.014). In the clinically relevant period of days 3-7, both 12 and 18 mg pegfilgrastim doses produced significantly higher peak CD34 þ counts (8.18 and 9.96 vs 4.51 Â 10 4 /ml for filgrastim; P ¼ 0.034 and 0.006). In cycle 1, patients received carboplatin/paclitaxel on day 1, followed from day 2 by pegfilgrastim 6-18 mg or daily filgrastim (5 lg/ kg/day for p14 days) as per randomization in cycle 0. There were no significant differences in mean peak CD34 þ count between pegfilgrastim and filgrastim, but there was an advantage for pegfilgrastim 18 mg in the relevant period of days 7-12 (3.14 vs 1.19 Â 10 4 /ml; P ¼ 0.043). A single pegfilgrastim dose (X6 mg) could be substituted for daily filgrastim in cytokine-only peripheral CD34 þ cell mobilization.

show abstract

Pharmacokinetic/Pharmacodynamic Modeling of Pegfilgrastim in Healthy Subjects

Cited by 118 publications

References 24 publications

Platelet Dynamics in Peritoneal Carcinomatosis Patients Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Oxaliplatin

Platelet Dynamics in Peritoneal Carcinomatosis Patients Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Oxaliplatin

Application of Quantitative Pharmacology in Development of Therapeutic Monoclonal Antibodies

Pegfilgrastim for peripheral CD34+ mobilization in patients with solid tumours

Contact Info

Product

Resources

About