Biodistribution and translational pharmacokinetic modeling of a human recombinant alkaline phosphatase.
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 allometric scaling based on body weight. This model provides a solid foundation for determining the optimal dose and duration of first-in-man recAP studies.
Department of Intensive Care Medicine, Radboud university medical center, PO Box 9101, Internal Mailbox 710, 6500HB Nijmegen, The Netherlandsc; Department of Pharmacology and Toxicology, Radboud university medical center, PO Box 9101, Internal Mailbox 149, 6500HB Nijmegen, The Netherlands.
Esther
E
Peters
Centre for Human Drug Research, Zernikedreef 8, 2333CL Leiden, The Netherlands.
Jasper
J
Stevens
AM-Pharma, Rumpsterweg 6, 3981AK Bunnik, The Netherlands.
Jacques
J
Arend
Centre for Human Drug Research, Zernikedreef 8, 2333CL Leiden, The Netherlands.
Zheng
Z
Guan
AM-Pharma, Rumpsterweg 6, 3981AK Bunnik, The Netherlands.
Willem
W
Raaben
Department of Radiology and Nuclear Medicine, Radboud university medical center, PO Box 9101, Internal Mailbox 756, 6500HB Nijmegen, The Netherlands.
Peter
P
Laverman
AM-Pharma, Rumpsterweg 6, 3981AK Bunnik, The Netherlands.
Andrea van
AV
Elsas
Department of Pharmacology and Toxicology, Radboud university medical center, PO Box 9101, Internal Mailbox 149, 6500HB Nijmegen, The Netherlands; Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, PO Box 80082, 3508TB Utrecht, The Netherlands.
Rosalinde
R
Masereeuw
Department of Intensive Care Medicine, Radboud university medical center, PO Box 9101, Internal Mailbox 710, 6500HB Nijmegen, The Netherlandsc. Electronic address: peter.pickkers@radboudumc.nl.
Peter
P
Pickkers
D058186:Acute Kidney Injury / Q000139:chemically induced / Q000000981:diagnostic imaging; D000469:Alkaline Phosphatase / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007457:Iodine Radioisotopes / Q000097:blood / Q000493:pharmacokinetics; D008070:Lipopolysaccharides; D008954:Models, Biological; D011877:Radionuclide Imaging; D051381:Rats; D011994:Recombinant Proteins / Q000097:blood / Q000493:pharmacokinetics*; D013552:Swine; D013556:Swine, Miniature; D014018:Tissue Distribution
D007457:Iodine Radioisotopes; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D000469:Alkaline Phosphatase
Acute kidney injury; Alkaline phosphatase; Biodistribution; Iodine-125 (PubChem CID: 104800); Lipopolysaccharide (PubChem CID: 11970143); NONMEM; Pharmacokinetics; Sepsis