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e14070 Background: Selumetinib (AZD6244 hyd sulfate) is an orally bioavailable agent targeting mitogen-activated protein kinase (MEK) 1/2. Selumetinib has shown activity in children with NF1 plexiform neurofibromas and refractory low-grade gliomas. The central nervous system (CNS) penetration of selumetinib in humans is unknown. Methods: We analyzed selumetinib in the cerebrospinal fluid (CSF) of NHP as a surrogate for CNS penetration. Four adult male rhesus macaques were each given a single dose of selumetinib capsules 2.5 mg/kg (human equivalent dose 50 mg/m2) by mouth on an empty stomach. Selumetinib was quantified in serial paired plasma and CSF samples from 0 to 48 hours after administration by Covance Bioanalytical Services (lower limit of quantification 0.5 ng/mL). Free selumetinib was estimated at 2.3% of total based on reported plasma protein binding of 97.7% in NHP. Pharmacokinetic parameters including area under the concentration x time curve (AUC) of selumetinib were calculated using non-compartmental methods and CSF penetration was calculated from the ratio of AUC (CSF): AUC (plasma). Results: Selumetinib was detected in plasma in all four NHPs, but in the CSF of only one NHP (ZH60). The mean (± SD) AUC0-∞ and half-life (t1/2) in plasma were 3350 ± 489 ng•h/mL and 10.8 ± 2.5 hours, respectively. In ZH60, the CSF AUC0-48 hr was 10.6 ng•h/mL. The CSF penetration of total and free selumetinib in this animal was 0.4%, and 14%, respectively. The mean plasma AUC and t1/2 were comparable to that of children (2842 ng•h/mL and 6.9 hours, respectively) at a similar dose in a phase I trial. However, the average peak concentration in children occurred at approximately 1 hour with a Cmax of 841 ng/mL, while the Cmax in NHP plasma ranged from 1 – 4 hours and averaged 198.8 ng/mL. Conclusions: The CSF penetration of oral selumetinib is limited; in one NHP it was 0.4% and 14% when corrected for plasma protein binding of selumetinib. The fact that plasma AUC0-∞ and half-lives in NHP were similar to previously reported human plasma PK indicates that this model may accurately reflect human CSF penetration as well.

The pharmacokinetics of subcutaneously administered methotrexate was studied as a parenteral alternative to oral administration. An initial feasibility study was performed in Rhesus monkeys comparing the subcutaneous route to intravenous (IV) injection and oral administration. The subcutaneous dose was completely absorbed and a sustained-release effect was observed when compared with the IV dose. No local or systemic toxicities resulted from subcutaneous methotrexate in the animals. Twelve children with acute lymphoblastic leukemia on maintenance therapy protocols prescribing either 7.5 mg/m2 biweekly or 40 mg/m2 weekly were also monitored after both a subcutaneous and an oral dose of methotrexate. Four children at the higher dosage level were also studied after an equal IV dose. The subcutaneous dose was again completely absorbed in these children at both dose levels, whereas the oral dose, which produced comparable plasma drug concentrations at the lower dosage level, resulted in a total drug exposure (area under the plasma concentration-time curve) that was one third that of the equal subcutaneous dose at the higher dosage level. No local or systemic toxicity was attributed to the subcutaneous methotrexate. Subcutaneous administration of methotrexate is well tolerated and well absorbed and appears to overcome the problems associated with oral administration, including variable absorption and saturation of the absorption mechanism with increasing doses.