Abstract
The pharmacokinetic characteristics of a mouse/human chimeric monoclonal antibody (C-17-1A) were determined in 10 patients with metastatic adenocarcinoma following the administration of either 10-mg or 40-mg infusions as a single or multiple dose. The administration of single 10-mg (n = 5) and 40-mg (n = 5) doses infused over 1 hr resulted in mean apparent steady-state distribution volumes of 4.13 ± 0.97 and 5.16 ± 1.92 liters, respectively, indicating that C-17-1A appears to distribute throughout the vascular compartment and into limited extracellular fluid volume. The disposition of C-17-1A was adequately characterized using a two-compartment open model with mean distribution half-lives of 15.8 and 18.5 hr and mean elimination half-lives of 90.0 and 97.6 hr for the 10- and 40-mg groups, respectively. A linear relationship was observed between AUC and dose (µLg/kg). The clearance of C-17-1A was correlated linearly with total Ig, IgG, and tumor size. Multiple administration of either 10-mg (n = 3) or 40-mg (n = 3) doses of C-17-1A infused over 1 hr every 14 days for a total of three doses resulted in superimposable mean serum concentration versus time data and consistent mean pharmacokinetic characteristics. These data indicate that C-17-1A exhibits linear, nonsaturable distribution and elimination characteristics in man over the dose range studied (i.e., 130 to 880 µg/kg). The multiple-dose pharmacokinetics of C-17-1A were predictable, indicating a lack of an antibody response to C-17-1A over a period of 42 days. The clearance of C-17-1A exhibited large interindividual variability with significant correlations to circulating IgG levels and tumor size.
Similar content being viewed by others
REFERENCES
E. Haber. Annu. Rev. Med. 37:249–261 (1986).
G. Goldstein et al. (Ortho Multicenter Transplant Study Group). N. Engl. J. Med. 313:337–342 (1985).
A. E. Frankel, L. L. Houston, B. F. Issell, and G. Fathman. Annu. Rev. Med. 39:125–142 (1986).
R. A. Miller, D. G. Maloney, R. Warnke, and R. Levy. N. Engl. J. Med. 306:517–522 (1982).
D. C. Edwards. Pharm. Ther. 23:147–177 (1983).
F. M. Brodsky. Pharm. Res. 5:1–9 (1988).
S. Morrison. Science 229:1202–1207 (1985).
D. R. Shaw, M. B. Khazaeli, L. K. Sun, J. Ghrayeb, P. F. Daddona, S. McKinney, and A. F. LoBuglio. J. Immunol. 138:4534–4538 (1987).
A. F. LoBuglio, R. H. Wheeler, J. M. Trang, A. Haynes, K. Rogers, E. B. Harvey, L. Sun, J. Ghrayeb, and M. B. Khazaeli. Proc. Natl. Acad. Sci. USA 86:4220–4224 (1989).
H. F. Sears, D. Herlyn, Z. Steplewski, and H. Koprowski. J. Biol. Response Mod. 3:138–150 (1984).
A. F. LoBuglio, M. Saleh, L. Peterson, R. Wheeler, R. Carrano, W. Huster, and M. B. Khazaeli. Hybridoma 5:S117–S123 (1986).
L. K. Sun, P. Curtis, E. Rakowicz-Szulczynska, J. Ghrayeb, N. Chang, S. L. Morrison, and H. Koprowski. Proc. Natl. Acad. Sci. USA 84:214–218 (1987).
M. B. Khazaeli, M. N. Saleh, R. H. Wheeler, W. J. Huster, H. Holden, R. Carrano, and A. F. LoBuglio. J. Natl. Cancer Inst. 80:937–942 (1988).
A. LoBuglio, M. Saleh, J. Lee, M. B. Khazaeli, R. Carrano, H. Holden, and R. Wheeler. J. Natl. Cancer Inst. 80:932–937.
D. R. Shaw, G. Harrison, L. K. Sun, C. Shearman, J. Ghrayeb, S. McKinney, P. E. Daddona, and A. F. LoBuglio. J. Biol. Response Mod. 7:204–211 (1988).
A. Midgely. Endocrinology. 79:10–14 (1966).
R. Gomeni and C. Gomeni. Comput. Biol. Med. 9:38–48 (1979).
J. C. Loo and S. Riegelman. J. Pharm. Sci. 59:53–55 (1970).
D. W. Marquardt. J. Soc. Indust. Appl. Math. 11:431–441 (1963).
J. G. Wagner. J. Pharmacokinet. Biopharm. 4:443–467 (1976).
M. Gibaldi and D. Perrier. Pharmacokinetics, 2nd ed., Marcel Dekker, New York, 1982.
H. D. Batson. An Introduction to Statistics in the Medical Sciences, Burgess, Minneapolis, 1956.
W. J. Dixon and F. J. Massey (eds). Introduction to Statistical Analyses, McGraw-Hill, New York, 1969.
A. Morell, W. Terry, and T. Waldmann. J. Clin. Invest. 49:673–680 (1970).
R. Dillman, D. Shawler, J. Dillman, and R. Royston. J. Clin. Oncol. 2:881–891 (1984).
T. Meeker, J. Lowder, D. Maloney, R. Miller, K. Thielemans, R. Warnke, and R. Levy. Blood 65:1349–1363 (1985).
M. G. Rosenblum, J. L. Murray, T. P. Haynie, H. J. Glenn, M. F. Jahns, R. S. Benjamin, J. M. Frincke, D. J. Carlo, and E. M. Hersh. Cancer Res. 45:2382–2386 (1985).
K. Koizumi, G. L. DeNardo, S. J. DeNardo, M. T. Hays, H. H. Hines, P. O. Scheibe, J. S. Peng, D. J. Macey, N. Tomani, and K. Hisada. J. Nucl. Med. 27:1243–1254 (1986).
J. N. Lowder and R. Levy. West. J. Med. 143:810–818 (1985).
A. N. Houghton and D. A. Scheinberg. Semin. Oncol. 13:165–179 (1986).
A. Solomon, T. A. Waldmann, and J. L. Fahey. J. Lab. Clin. Med. 62:1–17 (1963).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Trang, J.M., LoBuglio, A.F., Wheeler, R.H. et al. Pharmacokinetics of a Mouse/Human Chimeric Monoclonal Antibody (C-17-1 A) in Metastatic Adenocarcinoma Patients. Pharm Res 7, 587–592 (1990). https://doi.org/10.1023/A:1015810009701
Issue Date:
DOI: https://doi.org/10.1023/A:1015810009701