Population pharmacokinetics of the humanised monoclonal antibody, HuHMFG1 (AS1402), derived from a phase I study on breast cancer

Royer, Bernard; Wu, Yin; Pegram, Mark D.; Ibrahim, Nuhad K.; Villanueva, Carolina; Mir, D.; Erlandsson, Fredrik; Pivot, Xavier

doi:10.1038/sj.bjc.6605560

Cited by 16 publications

(8 citation statements)

References 23 publications

(33 reference statements)

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“…[19][20][21] At the highest dose, V 1 values (central distribution) corresponded to those reported for other For personal use only. on August 29, 2018.…”

Section: Discussionsupporting

confidence: 78%

Impact of in vivo alemtuzumab dose before reduced intensity conditioning and HLA-identical sibling stem cell transplantation: pharmacokinetics, GVHD, and immune reconstitution

Chakraverty

Ortí

Roughton

et al. 2010

Blood

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“…[19][20][21] At the highest dose, V 1 values (central distribution) corresponded to those reported for other For personal use only. on August 29, 2018.…”

Section: Discussionsupporting

confidence: 78%

Impact of in vivo alemtuzumab dose before reduced intensity conditioning and HLA-identical sibling stem cell transplantation: pharmacokinetics, GVHD, and immune reconstitution

Chakraverty

Ortí

Roughton

et al. 2010

Blood

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“…PK parameter estimates obtained from this model and the 95% CIs from the bootstrap analysis are shown in Table 2[27, 28]. The mean apparent volume of distribution ( V / F ) was 113 l (RSE, 4.18%).…”

Section: Resultsmentioning

confidence: 99%

“…It was considered appropriate to use the plots of the random effects (h) of PK parameters vs. covariates for screening potential covariates [26]. The structure of the final PK model was: Table 2 [27,28]. The mean apparent volume of distribution (V/F) was 113 l (RSE, 4.18%).…”

Section: Pk/pdmentioning

confidence: 99%

Population PK/PD analysis of metformin using the signal transduction model

Chae

Baek²,

Lee

et al. 2012

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Metformin, a biguanide glucose lowering agent, is commonly used to manage type 2 diabetes.• The molecular mechanisms of metformin have not been fully identified, but turnover of biomarkers such as glucose and signalling pathways or translocation of glucose transporters are closely related to the glucose-lowering effects of metformin.• The PK/PD of metformin have been investigated in healthy humans and patients with type 2 diabetes mellitus and modelling has been performed using an indirect response model. WHAT THIS STUDY ADDS• The purpose of this investigation was to develop a population PK/PD model for metformin using a signal transduction model in healthy humans and predict the PK/PD profile in patients with type 2 diabetes.• The aim was to compare a previous model (a biophase model) with the signal transduction model, and use a more appropriate model to follow the actions of metformin.• Additionally, our developed model was appropriate to predict the time course of plasma metformin and fasting plasma glucose (FPG) concentrations in patients with type 2 diabetes. • To our knowledge, this is the first published population PK/PD analysis using the signal transduction model for metformin. AIMSTo develop a population pharmacokinetic (PK) and pharmacodynamic (PD) model for metformin (500 mg) using the signal transduction model in healthy humans and to predict the PK/PD profile in patients with type 2 diabetes. METHODSFollowing the oral administration of 500 mg metformin to healthy humans, plasma concentrations of metformin were measured using LC-MS/MS. A sequential modelling approach using NONMEM VI was used to facilitate data analysis. Monte Carlo simulation was performed to predict the antihyperglycaemic effect in patients with type 2 diabetes. RESULTSForty-two healthy humans were included in the study. Population mean estimates (relative standard error, RSE) of apparent clearance, apparent volume of distribution and the absorption rate constant were 52.6 l h -1 (4.18%), 113 l (56.6%) and 0.41 h -1, respectively. Covariate analyses revealed that creatinine clearance (CLCR) significantly influenced metformin: CL/F = 52.6 ¥ (CLcr/106.5) 0.782 . The signal transduction model was applied to describe the antihyperglycaemic effect of metformin. The population means for efficacy, potency, transit time and the Hill coefficient were estimated to be 19.8 (3.17%), 3.68 mg ml -1 (3.89%), 0.5 h (2.89%) and 0.547 (9.05%), respectively. The developed model was used to predict the antihyperglycaemic effect in patients with type 2 diabetes. The predicted plasma glucose concentration value was similar to previous values. CONCLUSIONSThe population signal transduction model was developed and evaluated for metformin use in healthy volunteers. Model evaluation by non-parametric bootstrap analysis suggested that the proposed model was robust and parameter values were estimated with good precision.

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“…Pharmacokinetic (PK) samples were collected according to a previously described limited sampling scheme (21). Plasma levels of AS1402 were determined at Covance Laboratories Ltd.…”

Section: Translational Relevancementioning

confidence: 99%

Randomized Phase II Trial of Letrozole plus Anti-MUC1 Antibody AS1402 in Hormone Receptor–Positive Locally Advanced or Metastatic Breast Cancer

Ibrahim

Yariz

Bondarenko

et al. 2011

Clinical Cancer Research

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Purpose: AS1402 is a humanized immunoglobulin G1 antibody that targets the aberrantly glycosylated antigen MUC1, which is overexpressed in 90% of breast tumors and contributes to estrogen-mediated growth and survival of breast cancer cells in vitro by modulating estrogen receptor (ER) activity. Aromatase inhibitors have been reported to enhance antibody-dependent cell-mediated cytotoxicity elicited by antibodies in vitro. We compared the outcomes of patients with breast cancer treated with letrozole with or without AS1402.Experimental Design: The study population included 110 patients with locally advanced or metastatic hormone receptor-positive breast cancer randomized to receive 2.5 mg letrozole only once daily or with a weekly 9 mg/kg AS1402 infusion. The primary endpoint was overall response rate. Secondary endpoints included progression-free survival, time to progression, and safety. AS1402 exposure and influence of allotypes of FcgRIIIa, FcgRIIa, and MUC1 were evaluated.

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Population pharmacokinetics of the humanised monoclonal antibody, HuHMFG1 (AS1402), derived from a phase I study on breast cancer

Cited by 16 publications

References 23 publications

Impact of in vivo alemtuzumab dose before reduced intensity conditioning and HLA-identical sibling stem cell transplantation: pharmacokinetics, GVHD, and immune reconstitution

Impact of in vivo alemtuzumab dose before reduced intensity conditioning and HLA-identical sibling stem cell transplantation: pharmacokinetics, GVHD, and immune reconstitution

Population PK/PD analysis of metformin using the signal transduction model

Randomized Phase II Trial of Letrozole plus Anti-MUC1 Antibody AS1402 in Hormone Receptor–Positive Locally Advanced or Metastatic Breast Cancer

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