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

Abstract

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.

Investigating the Role of Altered Systemic Albumin Concentration on the Disposition of Theophylline in Adult and Pediatric Patients with Asthma by Using the Physiologically Based Pharmacokinetic Approach

“…The physiologically based pharmacokinetic (PBPK) approach provides novel opportunities to incorporate the relevant pathophysiological changes occurring in various diseases for the construction of disease models (Li et al, 2012;Park et al, 2017). There are some published examples of drug-disease PBPK models that incorporate pathophysiological modifications occurring in different chronic conditions (Edginton and Willmann, 2008;Johnson et al, 2010;Rowland Yeo et al, 2011;Li et al, 2012Li et al, , 2015Schaller et al, 2013;Sayama et al, 2014;Vogt, 2014;Chadha and Morris, 2015;Rasool et al, 2016;Shah et al, 2019). Although there are a few published reports of PBPK models for theophylline in adults and children (Ginsberg et al, 2004;Björkman, 2005), until now there has been no published report of a theophyllineasthma PBPK model that has been used to predict drug exposure in adult and pediatric patients with asthma after incorporation of changes in human serum albumin concentrations.…”

Modeling Pharmacokinetics and Pharmacodynamics of Therapeutic Antibodies: Progress, Challenges, and Future Directions

“…The key determinants of antibody PK remained in the mPBPK models, such as convection as the major distribution pathway and the distribution space is limited in the interstitial fluid (ISF). The mPBPK models have been applied to characterize antibody PK profiles in various disease scenarios [ 25 , 26 , 27 , 28 , 29 , 30 , 31 ].…”

“…PBPK models are usually applied for more mechanistic exploration and species translation, while the mPBPK models could provide a simpler alternative at the systemic level but potential elaborations of tissue-of-interest. The mPBPK model has been adopted to assess the target binding dynamics in the target tissues and the effect of endosome trafficking on FcRn-mediated antibody recycling [ 23 , 25 , 26 , 27 , 28 , 30 , 115 ]. For example, Zheng et al investigated the distribution of an anti-TNF antibody candidate CNTO5048 and its TNF-suppression effect by developing an mPBPK model with an extended compartment representing mice colon [ 26 ].…”

Physiologically-based modeling of monoclonal antibody pharmacokinetics in drug discovery and development

“…In addit ion to these general examples demonstrating the utility of this model structure, Chen and colleagues have extended the mPBPK model to include a diseased tissue (synovial fluid) and have used this structure to characterize the time course of plasma and joint concentrations of CNTO 345 (anti-interleukin 6 (IL-6)) and IL-6 in a collagen-induced arthritis mouse model [79], as well as for the PK/PD of an anti-IL-23 mAb in a psoriasis model [27]. Another extension of the mPBPK model was proposed by Chadha and Morris, who linked a mechanistic kidney model to a mPBPK model to describe the influence of diabetic nephropathy on IgG PK in a rat model [80]. While these models do not have the capacity to predict drug concentrations in all tissues simultaneously, they do represent a potential platform for groups whose interest lies in characterization of mAb PK in plasma and a tissue of interest.…”