A pharmacokinetic model for radioimmunotherapy delivered through cerebrospinal fluid for the treatment of leptomeningeal metastases.

UNLABELLED

Radioimmunotherapy can effectively treat leptomeningeal metastases when radiolabeled antibodies are administered into the cerebrospinal fluid (CSF). We developed a pharmacokinetic model to evaluate the role of kinetic and transport parameters of radioimmunotherapy in maximizing the therapeutic ratio, the ratio of the area under the curve for the concentration of the bound antibodies versus time (AUC[C(IAR)]), to that for unbound antibodies (AUC[C(IA)]).

METHODS

We simplified the CSF space as a single compartment and considered the binding of antibodies to antigens on tumor cells lining the surface of the CSF space. Mass conservation was applied to set up the equations for C(IAR), C(IA), and other pharmacokinetic variables. A Runge-Kutta method was used to solve the equations.

RESULTS

This model agreed with the measured data in 10 of 14 patients in the phase I trial of intra-Ommaya radioimmunotherapy using (131)I-3F8. Using this model, we predicted that increasing the affinity of antibodies to antigens greatly increases AUC(C(IAR)) but not AUC(C(IA)); for the same amount of isotope administered, the smaller antibody dose and the higher specific activity improves therapeutic ratio. When the isotope half-life (t(1/2-I)) was 0.77 h, increasing the antibody association constant enhanced AUC(C(IAR)) much more than did decreasing the dissociation constant, even if overall affinity was unchanged. When t(1/2-I) reached 240 h, decreasing the dissociation constant would slightly enhance AUC(C(IAR)). Other predictions were that decreasing the CSF bulk flow rate would increase AUC(C(IAR)), with 3 mL/h being optimal; at the same amount of antibody administered by continuous infusion and by split administrations, compared with that by the single bolus administration, one could improve AUC(C(IAR)) by up to 1.8- and 1.7-fold, respectively; and for an antibody affinity of 10(-8) M, increasing t(1/2-I) from 0.77 up to 64 h could greatly enhance the therapeutic ratio.

CONCLUSION

The strong agreement between model predictions and patient data supports the validity of the assumptions and simplifications in our model. The predictions using this model are not intuitive and need to be validated in future clinical trials. The improved therapeutic ratio by optimized kinetic and transport parameters may enhance the clinical efficacy of this new treatment modality.