Toxicokinetic Study of Recombinant Human Heparin-Binding Epidermal Growth Factor-Like Growth Factor (rhHB-EGF) in Female Sprague Dawley Rats

• Published in: Pharmaceutical research Vol. 25; no. 3; pp. 542 - 550
• Main Authors: Coowanitwong, Intira, Keay, Susan K., Natarajan, Karthika, Garimella, Tushar S., Mason, Clifford W., Grkovic, David, Bauer, Kenneth S.
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.03.2008; Springer; Springer Nature B.V
• Subjects: Administration, Intravesical; Animals; Area Under Curve; Biochemistry; Biological and medical sciences; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; General pharmacology; Heparin-binding EGF-like Growth Factor; Humans; Injections, Intravenous; Intercellular Signaling Peptides and Proteins - administration & dosage; Intercellular Signaling Peptides and Proteins - pharmacokinetics; Intercellular Signaling Peptides and Proteins - toxicity; Iodine Radioisotopes; Medical Law; Medical sciences; Models, Biological; Pharmaceutical technology. Pharmaceutical industry; Pharmacology; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pharmacy; Prescription drugs; Rats; Rats, Sprague-Dawley; Recombinant Proteins - pharmacokinetics; Recombinant Proteins - toxicity; Research Paper; Rodents; Toxicity; Urinary Bladder - drug effects; Urinary Bladder - metabolism; toxicity; HB-EGF; intrabladder instillation; toxicokinetics; interstitial cystitis; intravenous administration pharmacokinetics; NONMEM; Intravenous administration; Rat; Toxicity; Anticoagulant; Epidermal growth factor; Female; Interstitial cystitis; Human; Binding; Urinary system disease; Pharmaceutical technology; Rodentia; Urinary tract disease; Toxicokinetics; Vertebrata; Mammalia; Animal; Glycosaminoglycan; Heparin; Pharmacokinetics; Growth factor
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-007-9392-3

Purpose To determine the toxicity and pharmacokinetics of recombinant heparin-binding epidermal growth factor-like growth factor in female Sprague Dawley rats following intra-bladder and intravenous administration. Materials and Methods rhHB-EGF was administered once daily for 6 or 27 days at doses of 3, 10, or 30 μg/kg. 125 I-rhHB-EGF was administered on day 7 or 28 for pharmacokinetic analysis. Toxicity was assessed by general appearance and behavior, gross necropsy, blood chemistry and microscopic evaluation. Results Plasma AUCss of [ 125 I] rhHB-EGF equivalents following IB administration for 7 days were 4.28 ± 2.29, 7.75 ± 2.70, and 7.11 ± 1.42 ng ml −1 h −1 at doses of 3, 10, and 30 μg/kg, respectively. Following IV administration, the AUCss on day 7 increased from 27.0 ± 2.66 to 124 ± 5.09 and 385.11 ± 7.57 ng ml −1 h −1 with increasing the dose from 3 to 10 and 30 μg/kg. Similar AUCss data was obtained after 28 day administration. No toxicity was evident upon gross examination. Histologic examination revealed subacute inflammation and lymphocytic infiltration of the urinary bladder in animals from all groups dosed by the IB route. Conclusions Plasma and bladder concentrations of recombinant human [ 125 I] rhHB-EGF equivalents were significantly lower following the IB route than following IV administration. Histologic tissue examination indicated no toxicity attributable to rhHB-EGF.