Monoclonal Antibody Pharmacokinetics in Type 2 Diabetes Mellitus and Diabetic Nephropathy

Chadha, Gurkishan; Morris, Marilyn E.

doi:10.1007/s40495-016-0048-z

Cited by 31 publications

(10 citation statements)

References 108 publications

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“…However, the effect is not considered clinically relevant. The cause of the increased CL/F of guselkumab in patients with diabetes is unclear, although enhanced elimination of macromolecules (IgG), proteins, and mAbs is not uncommon in these patients . It has been reported that glycation can result in an increase in the clearance of IgG .…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetic Modeling of Guselkumab, a Human IgG1λ Monoclonal Antibody Targeting IL‐23, in Patients with Moderate to Severe Plaque Psoriasis

Yao

Zhu

et al. 2018

The Journal of Clinical Pharma

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Psoriasis is a common inflammatory skin disorder that requires chronic treatment and is associated with multiple comorbidities. Guselkumab, a human immunoglobulin-G1-lambda monoclonal antibody, binds to interleukin-23 with high specificity and affinity and is effective in treating moderate to severe plaque psoriasis. As part of the guselkumab psoriasis clinical trial program, using a confirmatory approach, a population pharmacokinetics (PopPK) model was established using 13 014 PK samples from 1454 guselkumab-treated patients across 3 phase 2/3 trials. Observed serum guselkumab concentrations were adequately described by a 1-compartment linear PK model with first-order absorption and elimination. The final PK model was robust and stable, with apparent clearance (CL/F), apparent volume of distribution (V/F), and absorption rate constant (ka) estimates of 0.516 L/day, 13.5 L, and 1.11 day , respectively. A model-derived elimination half-life of 18.1 days indicated achievement of steady-state serum guselkumab concentrations within 12-14 weeks. The primary covariate contributing to the observed PK variability was body weight, which accounted for only 28% (CL/F) and 32% (V/F) of the interindividual proportion of variance. Diabetes was identified to marginally reduce guselkumab exposure, owing to 12% higher CL/F in diabetic versus nondiabetic patients, but its contribution was not clinically relevant. None of the other covariates tested (eg, age, sex, ethnicity, immune response to guselkumab, or concomitant medications) had a clinically relevant effect on guselkumab exposure.

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Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetic Modeling of Guselkumab, a Human IgG1λ Monoclonal Antibody Targeting IL‐23, in Patients with Moderate to Severe Plaque Psoriasis

Yao

Zhu

et al. 2018

The Journal of Clinical Pharma

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“…The cause of the increased CL/F of sirukumab in patients of diabetic comorbidity is unclear, and could come from an increased renal and/or catabolic clearance. 28 Proteinuria as a consequence of microvascular changes within the kidney is common among diabetic patients. Potential contribution factors for the enhanced clearance of sirukumab in diabetic patients may also involve altered lymphatic flow and particle transport, altered capillary permeability, increased interstitial fluid volume, and accelerated clearance of the antibody resulting from increased glycation.…”

Section: Discussionmentioning

confidence: 99%

“…Because patients with diabetic comorbidity tend to be obese, the combined effect of diabetic comorbidity and weight was evaluated via simulation, which indicates that the effects of diabetes and weight on the systemic exposure to sirukumab were additive. The cause of the increased CL/F of sirukumab in patients of diabetic comorbidity is unclear, and could come from an increased renal and/or catabolic clearance . Proteinuria as a consequence of microvascular changes within the kidney is common among diabetic patients.…”

Section: Discussionmentioning

confidence: 99%

“…The study duration was 120 weeks including a 104-week double-blind treatment phase and a 16-week follow-up phase. PK and immunogenicity data collected through week 52 were included in this analysis, including blood samplings for PK at weeks 0, 2,4,6,8,12,16,18,20,24,28,40, and 52 (plus a random sample between weeks 0 and 16), and immunogenicity samplings at weeks 0, 24, and 52. Approximately 70% of the patients randomized to the sirukumab treatment arms had PK samples collected, and thus, only data from these patients were included for the analysis.…”

Section: Study Design and Sample Collectionmentioning

confidence: 99%

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Confirmatory Population Pharmacokinetic Analysis for Sirukumab, a Human Monoclonal Antibody Targeting Interleukin‐6, in Patients With Moderately to Severely Active Rheumatoid Arthritis

Zhuang

et al. 2018

The Journal of Clinical Pharma

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The population pharmacokinetics of sirukumab, a human immunoglobulin G1κ monoclonal antibody against interleukin-6, were characterized in patients with moderately to severely active rheumatoid arthritis in 4 phase 3 studies (SIRROUND-D, -T, -H, and -M). A total of 17 034 serum concentrations were analyzed from 1991 rheumatoid arthritis patients who received subcutaneous administration of sirukumab 50 mg every 4 weeks or 100 mg every 2 weeks. A stepwise confirmatory population PK analysis was conducted to accommodate the staged data release and the sparse sampling nature of phase 3 studies and to assess the potential covariate influences in an unbiased and timely manner. The base model, that is, a 1-compartment linear model with first-order absorption and first-order elimination, was prespecified based on prior information from a phase 2 study along with information about phase 3 study design. The covariate model was also prespecified based on pharmacological/physiological relevance and sample size. After the primary covariate analysis, a simplified model was produced by removing covariates with effect sizes <10%. The estimated apparent clearance (CL/F) and volume of distribution were 0.641 L/day and 16.1 L, respectively, at standard body weights of 70 kg. The terminal elimination half-life was approximately 17.4 days. Sirukumab CL/F and volume of distribution increased with body weight, and CL/F was higher in patients with diabetic comorbidity. Simulations suggest that the effects of diabetic comorbidity and weight on sirukumab exposure were additive. To fully understand the clinical relevance including potential dose adjustment, current covariate findings need to be evaluated concurrently with the efficacy and safety data.

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“…IgG transcytosis by FcRn is believed to serve two purposes: (i) to clear IgG and IgG-based ICs from the GBM and (ii) to provide antigen-free protective IgG to the urinary tract. 9,49 The latter purpose must additionally be linked to antigen destruction inside the podocyte to free IgG that is bound in ICs. This model of action of FcRn was supported by the observation that Fcgrt À/À mice (the gene that encodes FcRn) exhibited accumulation of IgG in the GBM and developed serum-induced nephritis.…”

Section: Fcrn In Igg and Albumin Recovery; Its Influence On Immune Re...mentioning

confidence: 99%

Presence and possible impact of Fcγ receptors on resident kidney cells in health and disease

2022

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Fcγ receptors (FcγRs) bind the Fc fragment of immunoglobulin G (IgG), mostly after IgG opsonizes a bacterial or viral antigen or danger/damage‐associated molecule. Consequently, classic FcγRs initiate phagocytosis of the IgG–antigen immune complex and stimulate an immune reaction against the threat. Signals from activating FcγRs (FcγRI, FcγRIIa/c, FcγRIIIa/b) are balanced by inhibitory FcγRIIb and likely also by two FcR‐like proteins (FCRL4 and FCRL5). The neonatal Fc receptor (FcRn) recirculates IgG and increases its half‐life. The last FcγR that has been identified in humans, tripartite motif‐containing protein 21 (TRIM21), acts toward pathogen destruction via the proteasomal or autophagic pathway. The expression of FcγRs occurs almost exclusively in immune cells. However, podocytes, key cells in the glomerular filtration barrier, also possess several features of an immune cell and express receptors for IgG. The presence of FcγRs in glomeruli was analyzed in the Human Protein Atlas project. FcγR occurrence in whole glomeruli or in particular resident kidney cells was also showed in a few original articles. In human podocytes only FcRn has been studied extensively, and the presence and role of other FcγRs remain obscure. Research on the genetic background of kidney diseases revealed a connection between FcγRs and several nephropathies. Investigations of FcγR expression in podocytes appear to be of great clinical importance. The present review discusses the latest literature on FcγRs in kidney cells (especially podocytes), with an emphasis on their involvement in kidney health and disease.

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Monoclonal Antibody Pharmacokinetics in Type 2 Diabetes Mellitus and Diabetic Nephropathy

Cited by 31 publications

References 108 publications

Population Pharmacokinetic Modeling of Guselkumab, a Human IgG1λ Monoclonal Antibody Targeting IL‐23, in Patients with Moderate to Severe Plaque Psoriasis

Population Pharmacokinetic Modeling of Guselkumab, a Human IgG1λ Monoclonal Antibody Targeting IL‐23, in Patients with Moderate to Severe Plaque Psoriasis

Confirmatory Population Pharmacokinetic Analysis for Sirukumab, a Human Monoclonal Antibody Targeting Interleukin‐6, in Patients With Moderately to Severely Active Rheumatoid Arthritis

Presence and possible impact of Fcγ receptors on resident kidney cells in health and disease

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