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

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