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A Pharmacokinetic Model for Radioimmunotherapy Delivered Through Cerebrospinal Fluid for the Treatment of Leptomeningeal Metastases

¹ Department of Biomedical Engineering, The City College of New York, New York, New York; and ² Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York

View larger version (16K): [in this window] [in a new window]   FIGURE 1.  Schematic of our pharmacokinetic model for radioimmunotherapy through CSF administration. CSF space was simplified as compartment of volume V with surface area S. Radioactive isotope–loaded antibodies are injected into CSF space and assumed to be well mixed immediately. Binding of antibodies to receptors (antigens) on tumor cells occurs at surface of CSF compartment.

View larger version (15K): [in this window] [in a new window]   FIGURE 2.  Comparison of model predictions and clinical results for time-changing radioactivity of free antibodies CIA in CSF compartment. Symbols are clinical results for 2 representative patients, and curves are model predictions. CI0 was 185 MBq/mg-protein, V was 140 mL, CLCSF was 20 mL/h, Kd was 10–8 M (), and t1/2-I was 193 h.

View larger version (15K): [in this window] [in a new window]   FIGURE 3.  Time-changing radioactivity of bound antibodies CIAR (A) and free antibodies CIA (B) as function of kAR and k–AR rate constants of antibodies to antigens. (C) AUC(CIAR) and AUC(CIAR)/AUC(CIA). Kd equaled , and V was 140 mL, CLCSF was 20 mL/h, tumor CR0 was 5.73 x 1014 antigens/mL, DoseA was 2 mg, CI0 was 370 MBq/mg, and t1/2-I was 193 h.

View larger version (12K): [in this window] [in a new window]   FIGURE 4.  AUC(CIAR) and AUC(CIAR)/AUC(CIA) as function of CLCSF. V was 140 mL, Kd was 10–8 M (), tumor CR0 was 5.73 x 1014 antigens/mL, DoseA was 2 mg, CI0 was 370 MBq/mg, and t1/2-I was 193 h.

View larger version (14K): [in this window] [in a new window]   FIGURE 5.  AUC(CIAR) and AUC(CIAR)/AUC(CIA) as function of injected DoseA, CI0, and initial CR0. CI0 was 370 MBq/mg protein when DoseA was 2 mg, and CI0 was 3,700 MBq/mg protein when DoseA was 0.2 mg. V was 140 mL, Kd was 10–8 M (), and t1/2-I was 193 h.

View larger version (10K): [in this window] [in a new window]   FIGURE 6.  (A) CIAR as function of time in CSF compartment for single bolus administration and continuous infusion for 12, 24, and 48 h, correspondingly. (B) AUC(CIAR) and AUC(CIAR)/AUC(CIA) as function of infusion time for continuous infusion. (C) AUC(CIAR) and AUC(CIAR)/AUC(CIA) as function of time interval between dosing for 4 injections. Total dose of 2-mg antibody is same for different administration schedules. V was 140 mL, Kd was 10–8 M (), tumor CR0 was 5.73 x 1014 antigens/mL, CI0 was 370 MBq/mg, and t1/2-I was 193 h.

View larger version (27K): [in this window] [in a new window]   FIGURE 7.  AUC(CIAR) and AUC(CIAR)/AUC(CIA) as function of t1/2-I when Kd = 10–8M (A) and Kd = 10–10M (B). Normalized AUC(CIAR) as function of kAR and k–AR rate constants when t1/2-I = 0.77 (C) and t1/2-I = 240.0 h (D). Kd equaled , and V was 140 mL, tumor CR0 was 5.73 x 1014 antigens/mL, DoseA was 2 mg, and CI0 was 370 MBq/mg.