Effect of Type 2 Diabetes Mellitus and Diabetic Nephropathy on IgG Pharmacokinetics and Subcutaneous Bioavailability in the Rat

Chadha, Gurkishan; Morris, Marilyn E.

doi:10.1208/s12248-015-9771-3

Cited by 13 publications

(13 citation statements)

References 55 publications

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“…Increases in mAb clearance were found to strongly correlate with urinary albumin excretion rate [348]. Similar results were obtained by Chadha and Morris with a 3.5-fold increase mAb clearance in the Zucker diabetic rat model [353].…”

Section: Proteinuria and Renal Protein Catabolismsupporting

confidence: 85%

Understanding Inter-Individual Variability in Monoclonal Antibody Disposition

Thomas

Balthasar

2019

Antibodies

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Monoclonal antibodies (mAbs) are currently the largest and most dominant class of therapeutic proteins. Inter-individual variability has been observed for several mAbs; however, an understanding of the underlying mechanisms and factors contributing to inter-subject differences in mAb disposition is still lacking. In this review, we analyze the mechanisms of antibody disposition and the putative mechanistic determinants of inter-individual variability. Results from in vitro, preclinical, and clinical studies were reviewed evaluate the role of the neonatal Fc receptor and Fc gamma receptors (expression and polymorphism), target properties (expression, shedding, turnover, internalization, heterogeneity, polymorphism), and the influence of anti-drug antibodies. Particular attention is given to the influence of co-administered drugs and disease, and to the physiological relevance of covariates identified by population pharmacokinetic modeling, as determinants of variability in mAb pharmacokinetics.

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Section: Proteinuria and Renal Protein Catabolismsupporting

confidence: 85%

Understanding Inter-Individual Variability in Monoclonal Antibody Disposition

Thomas

Balthasar

2019

Antibodies

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“…For the pioglitazone treatment diabetic group, the model estimated F r to be 72.9 and 69.2% during phases A and B, respectively. Similar to other antihyperglycemic drugs, pioglitazone treatment ameliorates the diabetes effects significantly; however, the reversal is incomplete (11,48). Although model 1 is unable to completely capture the plasma and urine profiles, the trends in model predictions are similar to those observed in the literature.…”

Section: Discussionsupporting

confidence: 50%

“…Previously, we had used a 2CM to describe hIgG concentration-time profiles in ZDF rats after the IV and SC administration of hIgG (11). A 2CM has been commonly used to describe and fit hIgG and mAb data in different species (19).…”

Section: Discussionmentioning

confidence: 99%

“…The data used in model development was obtained from a previous publication (11). In that study, ZDF rats were used as the animal model of Type 2 DM/DN as they exhibit the pertinent clinical signs of this disease including initial DM and progression to DN, allowing for assessment of the effects of DM with and without renal dysfunction, as well as with concomitant obesity.…”

Section: Methodsmentioning

confidence: 99%

“…Our previous studies have demonstrated that diabetes significantly impacts the renal and total clearance of human IgG (hIgG) in the T2DM Zucker Diabetic Fatty (ZDF) rat model (11). Since IgG is the most abundant antibody isotype found in the circulation, we dosed our animals with hIgG (12).…”

Section: Introductionmentioning

confidence: 99%

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An Extended Minimal Physiologically Based Pharmacokinetic Model: Evaluation of Type II Diabetes Mellitus and Diabetic Nephropathy on Human IgG Pharmacokinetics in Rats

Chadha

Morris

2015

AAPS J

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Abstract. Although many studies have evaluated the effects of type 2 diabetes mellitus (T2DM) on the pharmacokinetics (PK) of low molecular weight molecules, there is limited information regarding effects on monoclonal antibodies. Our previous studies have reported significant increases in total (2-4 fold) and renal (100-300 fold) clearance of human IgG, an antibody isotype, in Zucker diabetic fatty (ZDF) rats. Pioglitazone treatment incompletely reversed the disease-related PK changes. The objective of this study was to construct a mechanistic model for simultaneous fitting plasma and urine data, to yield physiologically relevant PK parameters. We propose an extended minimal physiologically based PK (mPBPK) model specifically for IgG by classifying organs as either leaky or tight vascular tissues, and adding a kidney compartment. The model incorporates convection as the primary mechanism of IgG movement from plasma into tissues, interstitial fluid (ISF) in extravascular distribution space, and glomerular filtration rate (GFR), sieving coefficient and fraction reabsorbed in the kidney. The model captured the plasma and urine PK profiles well, and simulated concentrations in ISF. The model estimated a 2-4 fold increase in nonrenal clearance from plasma and 30-120 fold increase in renal clearance with T2DM, consistent with the experimental findings, and these differences in renal clearance were related to changes in GFR, sieving coefficient, and proximal tubular reabsorption. In conclusion, the mPBPK model offers a more relevant approach for analyzing plasma and urine IgG concentration-time data than conventional models and provides insight regarding alterations in distributional and elimination parameters occurring with T2DM.

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Monoclonal Antibody Pharmacokinetics in Type 2 Diabetes Mellitus and Diabetic Nephropathy

Chadha

Morris

2016

Curr Pharmacol Rep

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The incidence of diabetes mellitus (DM) is increasing worldwide, and both type 1 as well as type 2 DM patients are at high risk of developing diabetic nephropathy (DN). Although the effects of DM and DN have been well documented for low molecular weight proteins and albumin, there is limited information regarding the changes in the clearance of higher molecular weight proteins, including monoclonal antibodies (mAbs) and IgG, an antibody isotype. This review compiles the available literature describing the effects of DM and DN on the pharmacokinetics and pharmacodynamics of IgG and mAbs and the potential mechanisms underlying the effects of DM and DN on IgG/mAb renal and catabolic clearances. This review also highlights the role of the neonatal Fc receptor (FcRn) and endocytic receptors (megalin and cubilin) and the influence of cytokines on renal function and expression/function of these proteins.

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Effect of Type 2 Diabetes Mellitus and Diabetic Nephropathy on IgG Pharmacokinetics and Subcutaneous Bioavailability in the Rat

Cited by 13 publications

References 55 publications

Understanding Inter-Individual Variability in Monoclonal Antibody Disposition

Understanding Inter-Individual Variability in Monoclonal Antibody Disposition

An Extended Minimal Physiologically Based Pharmacokinetic Model: Evaluation of Type II Diabetes Mellitus and Diabetic Nephropathy on Human IgG Pharmacokinetics in Rats

Monoclonal Antibody Pharmacokinetics in Type 2 Diabetes Mellitus and Diabetic Nephropathy

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