Pharmacokinetics and Hepatic Extraction of Recombinant Human Parathyroid Hormone, hPTH (1–34), in Rat, Dog, and Monkey

• Published in: Journal of pharmaceutical sciences 2006-11, Vol.95 (11), p.2499-2506
• Main Authors: Jones, Karen O., Owusu-Ababio, Godfried, Vick, Andrew M., Khan, M.Amin
• Format: Article
• Language: English
• Subjects: Animals; Area Under Curve; AUC0-(area under the serum concentration—time curve from 0 to infinity; AUC0-lastarea under the serum concentration—time curve from 0 to last timepoint; AUCIPOarea under the serum concentration—time curve, intraportal administration; AUCIVarea under the serum concentration—time curve, IV administration; Biological and medical sciences; Biological Availability; CL/FIPOtime-average clearance as a function of bioavailability from portal vein; CLtime-average clearance; Cmaxmaximum observed serum concentration; Data Interpretation, Statistical; Dogs; EHhepatic extraction ratio; FIPObioavailability from portal vein administration (calculated from AUC0 − ∞); General pharmacology; hepatic extraction; hPTH (1–34); Indicators and Reagents; Injections, Intraperitoneal; Injections, Intravenous; intraportal vein administration; IPO intraportal vein administration; IRMA immunoradiometric assay; IV intravenous administration; Liver - metabolism; Macaca mulatta; Male; Medical sciences; Parathyroid Hormone - administration & dosage; Parathyroid Hormone - metabolism; Parathyroid Hormone - pharmacokinetics; peptide delivery; Peptide Fragments - administration & dosage; Peptide Fragments - metabolism; Peptide Fragments - pharmacokinetics; Pharmaceutical technology. Pharmaceutical industry; pharmacokinetics; Pharmacology. Drug treatments; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Recombinant Proteins - metabolism; Recombinant Proteins - pharmacokinetics; saturation; t½elimination half-life
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.20720

The pharmacokinetics (PK) and hepatic extraction (EH) of human PTH (1–34), hPTH (1–34), were characterized in rat, dog, and monkey, following intraportal (IPO) and intravenous (IV) bolus administration. hPTH (1–34) was administered to Sprague–Dawley rats (2, 10, 100 µg/kg), beagle dogs (3, 6 µg/kg), and rhesus monkeys (6, 30 µg/kg). Serum concentrations of immunoreactive hPTH (1–34) were used to derive PK parameters. IPO bioavailability (FIPO) was determined by comparing dose-normalized serum exposure (i.e., AUCIPO/AUCIV). EH was estimated as 1−FIPO. In all species, greater than dose-proportional increases in exposure (i.e., Cmax and AUC) were observed for both routes. Dose-dependent disposition (i.e., time-average clearance (CL) and half-life (t½) were observed in all three species. In rats, EH values of 71% (2 µg/kg), 35% (10 µg/kg), and