Biodistribution and translational pharmacokinetic modeling of a human recombinant alkaline phosphatase

International Journal of Pharmaceutics
Esther PetersPeter Pickkers

Abstract

Clinical trials showed renal protective effects of bovine intestinal alkaline phosphatase (AP) in patients with sepsis-associated acute kidney injury (AKI). Subsequently, a human recombinant chimeric AP (recAP) was developed as a pharmaceutically acceptable alternative. Here, we investigated the biodistribution and pharmacokinetics (PK) of recAP and developed a translational population PK model. Biodistribution was studied during LPS-induced AKI in rats. Iodine-125-labeled recAP was primarily taken up by liver, spleen, adrenals, heart, lungs and kidneys followed by the gastro-intestinal tract and thyroid. Tissue distribution was not critically affected by endotoxemia. PK parameters were determined in rats and minipigs during IV bolus injections of recAP, administered once, or once daily during seven consecutive days. Plasma concentrations of recAP increased with increasing dose and disappeared in a biphasic manner. Exposure to recAP, estimated by AUC and Cmax, was similar on days 1 and 7. Subsequently, population approach nonlinear mixed effects modeling was performed with recAP rat and minipig and biAP phase I PK data. Concentration versus time data was accurately described in all species by a two-compartmental model with allo...Continue Reading

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Citations

Oct 1, 2016·Journal of the American College of Surgeons·Tetsuji Fujita
Oct 26, 2018·JAMA : the Journal of the American Medical Association·Peter PickkersUNKNOWN STOP-AKI Investigators
Jan 17, 2020·Scientific Reports·Cornelius EngelmannRajiv Jalan

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