Investigation of kinetics of methotrexate for therapeutic treatment of intraocular lymphoma.
OBJECTIVE
Primary intraocular lymphoma (PIOL) provides a therapeutic challenge because of its diverse clinical picture and variable clinical course. The main objective of this study was to evaluate the retinal permeability of methotrexate for rabbit and human eyes and then investigate its kinetics in a human eye following the standard induction-consolidation-maintenance (I-C-M) injection protocols for the treatment of PIOL. Additionally, the therapeutic release rate of a 90-day sustained-release methotrexate implant was also determined for the effective treatment of PIOL.


METHODS
The 3-dimensional model of a rabbit eye was adapted from our previous studies and a human eye model was constructed based on its physiological dimensions. The retinal permeability of methotrexate was the only unknown parameter in the numerical calculations and was determined by comparing the model simulated vitreous concentrations for rabbit and human eyes with the available in vivo and clinical data, respectively.


RESULTS
The retinal permeability values of methotrexate calculated for an albino rabbit and human eye were 1.1 × 10(-5) cm/s and 9.25 × 10(-6) cm/s, respectively. Given that the dosage above 0.1 µM is considered tumoricidal, the cytotoxic levels of methotrexate were consistently achieved only in the induction phase and the concentration levels dropped below the cytotoxic levels for part of the consolidation and maintenance phases of the treatment following the I-C-M protocols. A sustained-release implant with a mean release rate of 0.2 μg/day-2 μg/day should be designed in order to maintain tumoricidal levels of methotrexate inside the vitreous of the human eye for a period of 3 months.


CONCLUSIONS
By making use of the results of this study, one could select a dosing interval for serial injections of methotrexate or establish a treatment schedule using a controlled release methotrexate implant for the treatment of PIOL.
Department of Mechanical Engineering, University of Cincinnati, Cincinnati, Ohio, USA.
Nikhil Kumar
NK
Palakurthi
Mahesh
M
Krishnamoorthy
James J
JJ
Augsburger
Zelia M
ZM
Correa
Rupak K
RK
Banerjee
D000818:Animals; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D005134:Eye Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D008223:Lymphoma / Q000188:drug therapy* / Q000473:pathology; D008727:Methotrexate / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D008954:Models, Biological; D011817:Rabbits; D016896:Treatment Outcome; D014822:Vitreous Body / Q000187:drug effects
D007166:Immunosuppressive Agents; D008727:Methotrexate