Biomedical subjects

Chee M Ng

Publications and source records attributed to Chee M Ng.

5 recordsLinked to original sources

PubMed2006

Pharmacokinetics/pharmacodynamics of nondepleting anti-CD4 monoclonal antibody (TRX1) in healthy human volunteers.

PURPOSE: TRX1 is a nondepleting anti-CD4 monoclonal IgG1 antibody being developed to induce tolerance by blocking CD4-mediated functions. The purpose of this study is to describe the pharmacokinetics (PK) and pharmacodynamics (PD) of TRX1 and to develop a receptor-mediated PK/PD model that characterizes the relationships between serum TRX1 concentration and total and free CD4 expression in healthy male volunteers. METHODS: Nine subjects from three dosing cohorts in double-blinded, placebo-controlled phase I clinical study was included in the analysis. Serum TRX1 levels were determined using enzyme-linked immunosorbent assay. Blood total and free CD4 receptor levels were determined by using flow cytometric analyses. The receptor-mediated PK/PD model was developed to describe the dynamic interaction of TRX1 binding with CD4 receptors. RESULTS AND CONCLUSIONS: TRX1 displayed nonlinear pharmacokinetic behavior and the CD4 receptors on T cells were saturated and down-modulated following treatment with TRX1. Results from in vitro studies using purified human T cells suggested that CD4-mediated internalization may constitute one pathway by which CD4 is down-modulated and TRX1 is cleared in vivo. The developed receptor-mediated PK/PD model adequately described the data. This PK/PD model was used to simulate PK/PD time profiles after different dosing regimens to help guide the dose selection in future clinical studies.

Algorithms↗

PubMed2006

Rationale for fixed dosing of pertuzumab in cancer patients based on population pharmacokinetic analysis.

OBJECTIVE: Our objectives were to develop the population pharmacokinetic (PK) for pertuzumab and examine the variability of steady-state trough serum concentrations (C(SS,trough)) and exposure after fixed, body-weight-based, or body-surface area (BSA)-based dosing methods in cancer patients. METHODS: Pertuzumab was administered by i.v. infusion (every 3 weeks) either as a weight-based dose (0.5-15 mg/kg) or a fixed dose (420 or 1050 mg). Data from three clinical studies, comprising 153 patients and 1458 concentration-time points, were pooled for this analysis using NONMEM. RESULTS: A linear two-compartment model best described the data. Body weight and BSA were significant covariates affecting clearance (CL) and distribution volume (Vc), respectively. However, weight and BSA only explained small percentage of interpatient variability for CL and Vc, respectively. Simulation results indicated that PK profiles were very similar after the three dosing methods. Compared to fixed dosing, weight- and BSA-based dosing only reduced the population variability of C(SS,trough) moderately. CONCLUSION: A population PK model was developed for pertuzumab, the first monoclonal IgG1 antibody in a new class of agents known as HER dimerization inhibitors. In addition, our analyses demonstrate the feasibility of administering pertuzumab using a fixed dose in women with ovarian and breast cancers.

Adult↗

PubMed2005

Pharmacokinetic-pharmacodynamic-efficacy analysis of efalizumab in patients with moderate to severe psoriasis.

PURPOSE: Efalizumab is a humanized anti-CD11a monoclonal antibody that demonstrated efficacy in the treatment of patients with psoriasis. The objective of this study was to perform a pharmacokinetic (PK)-pharmacodynamic (PD)-efficacy (E) modeling analysis with intersubject variability assessment to increase our understanding of the interaction of efalizumab with CD11a on T cells and consequent reduction in severity of disease in psoriasis patients. METHODS: A total of 6,329 samples from 240 patients in five Phase I and II clinical studies were used in the analysis. For the analysis, plasma efalizumab concentration was used as the PK measurement, the percent of predose CD11a was used as the PD measurement, and the psoriasis area and severity index was used as the measure of efficacy. A receptor-mediated PK/PD model was developed that describes the dynamic interaction of efalizumab binding with CD11a. In the efficacy model, the rate of psoriasis skin production is directly proportional to the amount of free surface CD11a on T cells, which is offset by the rate of skin healing. An additional CD11a-independent component to psoriasis skin production accounted for incomplete response to efalizumab therapy. A Monte Carlo parametric expectation maximization method implemented in the ADAPT II program was used to obtain the estimate of population parameters and inter- and intrasubject variability. RESULTS AND CONCLUSIONS: The final model described the PK/PD/E data in psoriasis patients reasonably well. In addition, simulations using the final model suggested that efalizumab administered less frequently could possibly be more convenient with similar efficacy.

Adult↗

PubMed2005

Population pharmacokinetics of rituximab (anti-CD20 monoclonal antibody) in rheumatoid arthritis patients during a phase II clinical trial.

Rituximab is a B cell-depleting anti-CD20 chimeric IgGkappa monoclonal antibody being investigated for the treatment of rheumatoid arthritis. The purpose of this study was to develop a population pharmacokinetic model in rheumatoid arthritis patients. In addition, the final pharmacokinetic model was used to assess the variability in drug exposure (AUC0-infinity) for fixed versus body surface area-based dosing. A total of 102 patients were included in this population pharmacokinetic analysis. A 2-compartment pharmacokinetic model described the data reasonably well. Body surface area and gender were the most significant covariates for both CL and Vc. Body surface area alone only explained about 19.7% of the total interindividual variability of CL. In a simulation study, body surface area-based dosing normalized drug exposure over a wide range of body surface area but did not seem to improve the predictability of rituximab AUC0-infinity in rheumatoid arthritis patients. Therefore, no rationale for body surface area-based dosing for rituximab in rheumatoid arthritis patients was found.

Adult↗

PubMed2003

Comparison of neural network, Bayesian, and multiple stepwise regression-based limited sampling models to estimate area under the curve.

This study compared limited sampling methods (LSM) of estimating area under the plasma concentration versus time curve (AUC) based on a Bayesian regularized neural network, the Bayesian approach, and multiple forward stepwise regression models from selected concentration-time points. Plasma concentration versus time data sets with a linear two-compartmental pharmacokinetic model were simulated. A limited sampling method based on the forward stepwise regression model was developed and validated. Plasma concentration-time points selected by the stepwise regression model were used for neural network and Bayesian evaluation. In addition, 55 plasma concentration-time profiles from two clinical studies were used to develop and compare the predicted AUC(last) for the three approaches. From simulated data sets, mean prediction errors for AUC(last) estimation were 0.00, -5.32, and -6.06 for the neural network, Bayesian approach, and forward stepwise regression LSM, respectively. Mean square errors were 581, 588, and 618, respectively. For clinical data set, model mean prediction errors were 0.00, 3.51, and 3.87, respectively. Model mean square errors were 30.6, 109, and 76, respectively. For both simulated and clinical data sets, the neural network approach to estimate AUC(last) from selected time points was numerically more precise and significantly less biased than the other two methods.

Antiviral Agents↗