Lorin Roskos

Elimination mechanisms of therapeutic monoclonal antibodies.

Targeted therapies using monoclonal antibodies have achieved important therapeutic applications in the treatment of various human diseases. Understanding the factors that impact the pharmacokinetics of monoclonal antibodies is of high importance for effective therapy. Many factors related to the target antigen, antibody and patients can affect antibody elimination. Evaluation of these factors will facilitate the understanding of the processes involved in antibody elimination.

Randomized, Dose-Escalation Study of SD/01 Compared With Daily Filgrastim in Patients Receiving Chemotherapy

PURPOSE To explore the use of SD/01 (a polyethylene glycol-conjugated filgrastim shown in preclinical studies to have a prolonged half-life) in patients with chemotherapy-induced neutropenia. PATIENTS AND METHODS Thirteen patients with non-small-cell lung cancer were randomized to receive daily filgrastim (5 microg/kg/d) or a single injection of SD/01 (30, 100, or 300 microg/kg) 2 weeks before chemotherapy and again 24 hours after administration of carboplatin and paclitaxel. Pharmacodynamic, pharmacokinetic, and safety analyses were performed. RESULTS Peak serum concentrations of SD/01 and the duration of increased serum concentrations were dependent on the SD/01 dose. SD/01 concentrations remained increased longer in patients with chemotherapy-induced neutropenia. Prechemotherapy median absolute neutrophil counts (ANCs) in patients receiving SD/01 were increased in a dose-dependent fashion, with the duration of this effect also being dose dependent. After chemotherapy, median ANC nadirs were similar in the filgrastim cohort and the cohort receiving SD/01 30 microg/kg, with higher nadirs seen in the cohorts receiving SD/01 100 or 300 microg/kg. Dose-limiting toxicities were not noted. CD34(+) cells were mobilized in all cohorts. CONCLUSION A single dose of SD/01 increases the serum concentration of SD/01 for several days in a dose-dependent fashion and is not associated with significant toxicity. The effects of SD/01 on ANC and CD34(+) cell mobilization are comparable or greater than those achieved with daily filgrastim. The self-regulation of this molecule provides a potential therapeutic advantage in a variety of clinical settings associated with neutropenia.

Pharmacokinetic/Pharmacodynamic Modeling of Pegfilgrastim in Healthy Subjects

This analysis was conducted to characterize the pharmacokinetics and pharmacodynamics of pegfilgrastim and to develop a pharmacokinetic‐pharmacodynamic model to describe the granulopoietic effects of pegfilgrastim and the homeostatic regulation of pegfilgrastim clearance in healthy subjects. Pegfilgrastim serum concentration data and differential white cell counts were obtained from an open‐label, single‐dose, dose escalation study. Healthy subjects (8 subjects/dose group) received a single subcutaneous dose of 30, 60, 100, or 300 μg/kg pegfilgrastim. Pegfilgrastim exhibited nonlinear pharmacokinetics; clearance decreased with increasing dose. A dose‐dependent increase in absolute neutrophil count with an increase in the percentage of band cells was observed. A pharmacokinetic‐pharmacodynamic model was developed that adequately described the nonlinear pharmacokinetics of pegfilgrastim, feedback regulation of pegfilgrastim clearance by neutrophils, and the differential effects of pegfilgrastim on neutrophil populations in blood.

Pharmacokinetic and Pharmacodynamic Perspectives on the Clinical Drug Development of Panitumumab

Panitumumab is a recombinant, fully human IgG2 monoclonal antibody directed against the epidermal growth factor receptor (EGFR). It is indicated for use as monotherapy in the treatment of patients with EGFR-expressing metastatic colorectal cancer after disease progression with standard chemotherapy. The currently indicated dose is 6mg/kg given every 2 weeks.Panitumumab is mainly distributed into the vascular space and exhibits nonlinear pharmacokinetics that are consistent with target-mediated drug disposition, involving saturable binding to EGFR and subsequent internalization and degradation inside the cells. Panitumumab is also cleared in a linear fashion by the reticuloendothelial system, similarly to other endogenous immunoglobulins. After single-dose administration of panitumumab as a 1-hour intravenous infusion, the area under the serum concentration-time curve increases in a greater-than-dose-proportional manner asthe dose increases from 0.75 to 5mg/kg; however, at doses above 2mg/kg, the exposure to panitumumab increases in a dose-proportional manner. Panitumumab pharmacokinetics are not meaningfully affected by the tumour type, EGFR membrane expression, tumour KRAS mutation, sex, age, race or renal or hepatic dysfunction. In addition, irinotecan-containing and paclitaxel/carboplatin-containing chemotherapeutic regimens do not appear to affect panitumumab pharmacokinetics. The results of population pharmacokinetic analyses have shown that bodyweight is the most influential covariate on panitumumab exposure, supporting the current use of bodyweight-adjusted doses (mg/kg). The relationship between the weekly dose of panitumumab and skin rash, an on-target pharmacodynamic effect of EGFR inhibition, reaches a plateau at 2.5 mg/kg, indicating that this is the optimal weekly dose. Two less-frequent dosing regimens (6 mg/kg given every 2 weeks and 9mg/kg given every 3 weeks) achieve steady-state serum trough concentrations similar to those achievedby 2.5mg/kg given every week, ensuring maximal EGFR coverage. Anti-panitumumab antibody production is uncommon and does not appear to have an impact on the pharmacokinetics of panitumumab.

Population pharmacokinetic-pharmacodynamic modeling of filgrastim (r-metHuG-CSF) in healthy volunteers.

AbstractThe pharmacokinetic–pharmacodynamic (PK–PD) relationship of the granulopoietic effects of Filgrastim in healthy volunteers was characterized via a population approach. Healthy male volunteers were enrolled into a four-way crossover clinical trial. Subjects received four single doses of Filgrastim (375 and 750 μg iv and sc) with an intervening washout period of 7 days. Serum concentrations of Filgrastim were determined using an enzyme-linked immunosorbent assay. Absolute neutrophil count (ANC) was determined. Data analysis was performed using mixed-effects modeling as implemented in the NONMEM software package. The final PKPD model incorporates a two-compartment PK model with bisegmental absorption from the sc site, first-order and saturable elimination pathways, and an indirect PD model. A sigmoidal Emax model for the stimulation of ANC input rate kin) was superior to the conventional Emax model (

Integration of pharmacokinetic and pharmacodynamic studies in the discovery, development, and review of protein therapeutic agents: A conference report

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Translational strategies for development of monoclonal antibodies from discovery to the clinic

±SE: Emax=12.7 ± 1.7; EC50=4.72 ± 0.72 ng/ml; Hill=1.34 ± 0.19). In addition, a time-variant scaling factor for ANC observations was introduced to account for the early transient depression of ANC after Filgrastim administration. The absolute bioavailability of subcutaneously administered Filgrastim was estimated to be 0.619±0.058 and 0.717±0.028 for 375 μg and 750 μg sc doses, respectively. The time profiles of concentration and ANC, as well as the concentration∼ANC relationship of Filgrastim in healthy volunteers were well described by the developed population PK–PD model.

An open‐label, single‐dose bioavailability study of the pharmacokinetics of CAT‐354 after subcutaneous and intravenous administration in healthy males

Pharmacokinetic-pharmacodynamic (PK-PD) modeling is an integral part of the preclinical and clinical development of protein drugs. Bioanalytical data from appropriately selected and well-characterized PK and PD biomarker assays can be incorporated into mechanistic PK-PD models and allow a quantitative relationship between protein drug exposure, target modulation, and biochemical, physiological and pathophysiological effects to be established. The selection of PD biomarkers that assess target engagement and modulation in the extracellular milieu and downstream cellular effects can provide proof-of-mechanism and define the magnitude and duration of target modulation following drug administration. The PK-PD data can provide an important link between magnitude of target modulation and clinical efficacy and safety outcomes, and guide the selection of doses and dosing schedules for clinical trials. In this article, approaches to the selection and development of fit-for-purpose, PK and PD assays for protein drugs are reviewed, and the applications of the assay results in PK-PD models are discussed.