A pharmacokinetic model for predicting the concentration of methotrexate in plasma subsequent to intrathecal injection.

: A pharmacokinetic model has been established in which plasma methotrexate (MTX) concentrations following intrathecal administration are predicted. The model is based upon cerebrospinal fluid MTX concentrations following intrathecal injection of MTX, and plasma MTX levels subsequent to i.v. injection of the drug in dogs. Anticipated plasma MTX levels were compared with actual measured concentrations. The model predicts changes in the plasma MTX concentration curve as a result of varying of the injected dose, reduction in plasma MTX clearance, and reduced transfer of MTX from cerebrospinal fluid to the blood. It is suggested that plasma MTX levels be measured at 3, 5, 7 and 10 h following intrathecal injection to facilitate an early assessment of unusually slow plasma MTX decay. Thus, administration of leucovorin, to prevent systemic toxicity, may be more rapidly commenced. Also, if such measurements indicate that the transfer of MTX from cerebrospinal fluid to the blood is reduced. MTX dose of the subsequent intrathecal injections should be reduced to minimize risks of systemic toxicity and neurotoxicity.