Abstract
Purpose. To describe the pharmacokinetics of SK&F 107647, a synthetichematoregulatory peptide, in healthy volunteers and in patientswith adenocarcinoma.Methods. SK&F 107647 pharmacokinetics were evaluated in 2dose-escalation studies. Volunteers received SK&F 107647 as single15-minute iv infusion doses of 1, 10, 100, 500, and 1000 μg/kg. Cancerpatients received 2-hour iv infusions of 0.001, 0.01, 0.1 and 1μg/kg once daily for 10 days. Drug concentrations were quantified in plasmaand urine of healthy volunteers and on days 1 and 10 in plasma ofcancer patients receiving the two top dose levels.Results. In volunteers, mean clearance (CL) ranged from 76.7 to 101ml/hour/kg; mean volume of distribution at steady-state (Vss)rangedfrom 175 to 268 ml/kg. Most of the administered dose was renallyexcreted as intact peptide within 24 hours postinfusion. In patients,mean CL was 57.6 ml/hour/kg, mean Vss ranged from 128 to 150ml/kg and terminal half-life from 2.1 to 3.4 hours. There was littleaccumulation of drug. In both studies, linear pharmacokinetics wasobserved. Clearance approached normal glomerular filtration rate(GFR) in volunteers and correlated with creatinine clearance incancer patients.Conclusions. SK&F 107647 exhibits linear pharmacokinetics, a smallVss, and clearance, primarily renal, approaching normal GFR.
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REFERENCES
J. M. Vose and J. O. Armitage. Clinical applications of hematopoietic growth factors. J. Clin. Oncol. 13:1023–1035 (1995).
W. P. Steward. Granulocyte and granulocyte-macrophage colony-stimulating factors. Lancet. 342:153–157 (1993).
D. R. Brocks, M. I. Freed, D. E. Martin, T. S. Sellers, N. Mehdi, D. R. Citerone, V. Boppana, B. Levitt, B. E. Davies, J. Nemunaitis, and D. K. Jorkasky. Interspecies pharmacokinetics of a novel hematoregulatory peptide (SK&F 107647) in rats, dogs, and oncologic patients. Pharm. Res. 13:794–797 (1996).
J. Nemunaitis, D. E. Martin, D. L. Willis, M. I. Freed, B. Levitt, D. A. Richards, J. V. Cox, G. T. Kimmel, W. J. Hyman, and D. K. Jorkasky. SK&F 107647: a synthetic hematoregulatory peptide in patients with solid tumor malignancies. A phase I trial. Am. J. Clin. Oncol. 21:189–194 (1998).
P. L. DeMarsh, S. K. Sucoloski, C. L. Frey, P. K. Bhatnagar, Y. Koltin, P. Actor, and S. R. Petteway. Efficacy of the hematoregulatory peptide SK&F 107647 in experimental systemic Candida albicans infections in normal and immunosuppressed mice. Immunopharmacology. 27:199–206 (1994).
P. L. DeMarsh, G. I. Wells, T. F. Lewandowski, C. L. Frey, P. K. Bhatnagar, and E. J. R. Ostovic. Treatment of experimental gram-negative and gram-positive bacterial sepsis with the hematoregulatory peptide SK&F 107647. J. Infect. Dis. 173:203–211 (1996).
L. M. Pelus, A. G. King, H. E. Broxmeyer, P. L. DeMarsh, S. R. Petteway, and P. K. Bhatnagar. In vivo modulation of hematopoiesis by a novel hematoregulatory peptide. Exp. Hematol. 22:239–247 (1994).
D. W. Cockcroft and M. H. Gault. Prediction of creatinine clearance from serum creatinine. Nephron. 16:31–41 (1976).
R. Rabkin and D. C. Dahl. Renal Uptake and Disposal of Proteins and Peptides. In K. L. Audus and T. J. Raub (eds.), Biological Barriers to Protein Delivery, New York, Plenum Press, 1993, pp. 299–338.
T. Maack, C. H. Park, and M. J. F. Gamaro. Renal filtration, transport, and metabolism of proteins. In D. W. Seldin and G. Giesbisch (eds.), The kidney, physiology and pathophysiology, 2nd edition, New York, Marcel Dekker, 1992, pp. 3005–3038.
J. Mordenti, S. A. Chen, J. A. Moore, B. L. Ferraiolo, and J. D. Green. Interspecies scaling of clearance and volume of distribution data for five therapeutic proteins. Pharm. Res. 8:1351–1359 (1991).
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Zia-Amirhosseini, P., Harris, R.Z., Cowley, H.C. et al. Pharmacokinetics of a Hematoregulatory Peptide (SK&F 107647) in Healthy Male Volunteers and in Patients with Colorectal or Pancreatic Adenocarcinoma Not Amenable to Standard Therapy. Pharm Res 17, 385–390 (2000). https://doi.org/10.1023/A:1007512617139
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DOI: https://doi.org/10.1023/A:1007512617139