Population PK and IgE Pharmacodynamic Analysis of a Fully Human Monoclonal Antibody Against IL4 Receptor

Kakkar, Tarundeep; Sung, Cynthia; Gibiansky, Leonid; Vu, Thuy; Narayanan, Adimoolam; Lin, Shao-Lee; Vincent, Michael S.; Banfield, Christopher; Colbert, Alex; Hoofring, Sarah A; Starcevic, Marta; Ma, Pelosi

doi:10.1007/s11095-011-0481-y

Cited by 46 publications

(44 citation statements)

References 31 publications

(41 reference statements)

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“…Many physiologic factors such as age, body weight, and injection sites have been reported as covariates for subcutaneous bioavailability in humans (Macdougall et al, 1991;Chan et al, 2003;Silva et al, 2006;Fishbane et al, 2007;Olsson-Gisleskog et al, 2007;Kakkar et al, 2011). In this investigation, we show that physiologic factors such as fat content and physical activity can have a profound impact on subcutaneous absorption of PEGylated proteins in preclinical species.…”

Section: Lymphatic Transport After Subcutaneous Administrationmentioning

confidence: 54%

“…Many physiologic factors, e.g., age, body weight, and injection site, have been identified as covariants for the pharmacokinetics (PK) of macromolecules administered subcutaneously in humans (Macdougall et al, 1991;Chan et al, 2003;Fishbane et al, 2007;Olsson-Gisleskog et al, 2007;Kakkar et al, 2011). However, the type of factors and extent of their impact are apparently compound-dependent.…”

Section: Introductionmentioning

confidence: 99%

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Lymphatic Transport and Catabolism of Therapeutic Proteins after Subcutaneous Administration to Rats and Dogs

Wang¹,

Chen²,

Shen³

et al. 2012

Drug Metab Dispos

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ABSTRACT:The mechanism underlying subcutaneous absorption of macromolecules and factors that can influence this process were studied in rats using PEGylated erythropoietins (EPOs) as model compounds. Using a thoracic lymph duct cannulation (LDC) model, we showed that PEGylated EPO was absorbed from the subcutaneous injection site mainly via the lymphatic system in rats, which is similar to previous reports in sheep. After subcutaneous administration, the serum exposure was reduced by ϳ70% in LDC animals compared with that in the control animals, and most of the systemically available dose was recovered in the lymph. In both LDC and intact rats, the total radioactivity recoveries in excreta after subcutaneous administration were high (70-80%), indicating that catabolism, not poor absorption, was the main cause for the observed low bioavailability (30-40%). Moreover, catabolism of PEGylated EPO was found with both rat subcutaneous tissue homogenate and lymph node cell suspensions, and a significant amount of dose-related breakdown fragments was found in the lymph of LDC rats. In addition, the bioavailability of PEGylated EPOs was shown to be 2-to 4-fold lower in "fat rats," indicating that physiologic features pertinent to lymphatic transport can have a profound impact on subcutaneous absorption. Limited studies in dogs also suggested similar subcutaneous absorption mechanisms. Collectively, our results suggest that the lymphatic absorption mechanism for macromolecules is probably conserved among commonly used preclinical species, e.g., rats and dogs, and that mechanistic understanding of the subcutaneous absorption mechanism and associated determinants should be helpful in biologic drug discovery and development.

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Section: Lymphatic Transport After Subcutaneous Administrationmentioning

confidence: 54%

Section: Introductionmentioning

confidence: 99%

Lymphatic Transport and Catabolism of Therapeutic Proteins after Subcutaneous Administration to Rats and Dogs

Wang¹,

Chen²,

Shen³

et al. 2012

Drug Metab Dispos

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“…45 Of note, the influence of age on absorption was reported for an anti-interleukin 4 receptor monoclonal antibody administered subcutaneously, the absorption rate decreasing with age. 46 The infliximab pharmacokinetic parameters estimated in our study were used to predict the distribution of infliximab trough concentrations at steady-state and compare them with cut-off concentrations predictive of good clinical response. In RA, the published cut-off value is 2.5 mg/L.…”

Section: Discussionmentioning

confidence: 99%

The underlying inflammatory chronic disease influences infliximab pharmacokinetics

Passot

Mulleman

Bejan-Angoulvant

et al. 2016

mAbs

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Infliximab is an anti-tumor necrosis factor monoclonal antibody approved in chronic inflammatory diseases such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohn's disease (CD) and ulcerative colitis (UC). Infliximab pharmacokinetics is variable between patients, but influence of the underlying disease was never assessed. This study aimed at assessing this influence using a cohort of patients monitored in a single center and with the same assay. Infliximab trough concentrations were determined on samples collected between weeks 0 and 22 after treatment initiation in 218 patients treated for RA, PsA, AS, CD or UC. Infliximab pharmacokinetics was analyzed by a onecompartment population model with first-order elimination rate constant. In AS patients, volume of distribution (V) and elimination clearance (CL) were 5.4 L and 0.24 L/day, respectively. In CD and UC patients, V was 49% and 52% higher than in AS, respectively, and CL was 47% and 60% higher than in AS, respectively. In RA patients, CL was 49% higher than in AS patients. Simulations showed that without methotrexate, a 3 mg/kg dosing regimen would lead only 16% of RA patients to reach the target concentration (2.5 mg/L) at week 22, whereas target concentrations would be reached in approximately half of RA patients cotreated with methotrexate, as well as half of CD (3.5 mg/L) and UC (3.7 mg/L) patients. The suboptimality of approved dosing regimens supports the development of dosing optimization based on concentration measurements.

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“…The concentration of AMG 317 in plasma samples was determined using a validated enzyme-linked immunosorbent assay, as previously described (19). After pretreatment to a dilution factor of 50 with SuperBlock® T20 Buffer (Thermo Fisher Scientific/Pierce), study samples, standards, and quality controls (prepared in human K2-EDTA plasma pool) were added to microplate wells coated with human IL-4R fused to recombinant human Fc (IL-4R:Fc).…”

Section: Amg 317 Concentration Assaymentioning

confidence: 99%

“…A twocompartment model with quasi-steady-state approximation of target-mediated drug disposition and first-order absorption rate was used to describe the PK of the compound (21). The population PK analysis model development and evaluation were performed as described previously (19). The ADA effect on drug elimination parameters was investigated by direct testing of ADA status (e.g., negative or positive) as a covariate in the PK model.…”

Section: Population Pk Analysis Of the Impact Of Ada On Amg 317 Clearmentioning

confidence: 99%

Stratification of Antibody-Positive Subjects by Antibody Level Reveals an Impact of Immunogenicity on Pharmacokinetics

Zhou

Hoofring

et al. 2012

AAPS J

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Abstract. The availability of highly sensitive immunoassays enables the detection of antidrug antibody (ADA) responses of various concentrations and affinities. The analysis of the impact of antibody status on drug pharmacokinetics (PK) is confounded by the presence of low-affinity or low-concentration antibody responses within the dataset. In a phase 2 clinical trial, a large proportion of subjects (45%) developed ADA following weekly dosing with AMG 317, a fully human monoclonal antibody therapeutic. The antibody responses displayed a wide range of relative concentrations (30 ng/mL to >13 μg/mL) and peaked at various times during the study. To evaluate the impact of immunogenicity on PK, AMG 317 concentration data were analyzed following stratification by dose group, time point, antibody status (positive or negative), and antibody level (relative concentration). With dose group as a stratifying variable, a moderate reduction in AMG 317 levels (<50%) was observed in antibody-positive subjects when compared to antibody-negative subjects, but the difference was not statistically significant in all dose groups. The most significant reduction in AMG 317 levels was revealed when antibody data was stratified by both time point and antibody level. In general, high ADA concentrations (>500 ng/mL) and later time points (week 12) were associated with significantly (up to 97%) lower trough AMG 317 concentrations. The use of quasi-quantitative antibody data and appropriate statistical methods was critical for the most comprehensive evaluation of the impact of immunogenicity on PK.

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Population PK and IgE Pharmacodynamic Analysis of a Fully Human Monoclonal Antibody Against IL4 Receptor

Cited by 46 publications

References 31 publications

Lymphatic Transport and Catabolism of Therapeutic Proteins after Subcutaneous Administration to Rats and Dogs

Lymphatic Transport and Catabolism of Therapeutic Proteins after Subcutaneous Administration to Rats and Dogs

The underlying inflammatory chronic disease influences infliximab pharmacokinetics

Stratification of Antibody-Positive Subjects by Antibody Level Reveals an Impact of Immunogenicity on Pharmacokinetics

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