Safety and pharmacokinetics of intrathecal administration of pemetrexed in rats.
OBJECTIVE
Leptomeningeal carcinomatosis is a devastating complication of malignant disease. In this study, we evaluated the safety and pharmacokinetics of intrathecally administered pemetrexed in rats.


METHODS
Three levels of pemetrexed (0.3, 1, and 3 mg/kg) were administered to 15 rats per level (45 rats in total) twice a week for 2 weeks through specifically designed indwelling subarachnoid catheters. Presence of clinical and pathological neurotoxicity was evaluated. To evaluate the pharmacokinetics of pemetrexed, independent cohorts of 30 rats were treated with 1 mg/kg of pemetrexed and its concentration in cerebrospinal fluid (CSF) and blood was measured using UPLC/MS/MS.


RESULTS
There were no cases of clinical or pathologic neurotoxicity after intrathecal administrations of pemetrexed at levels of 0.3 and 1 mg/kg; however, 5 of 15 (33%) rats died after administration of 3 mg/kg pemetrexed. The distribution/elimination of pemetrexed in CSF was best described by a two-compartment model, with initial and terminal half-lives of 0.43 and 1.43 h, respectively. The predicted maximal concentration in CSF was 588 μM, and high levels of pemetrexed appeared to be maintained for a long time. Area under the curve and volume of distribution at steady state were 560 μM h and 1.14 ml, respectively.


CONCLUSIONS
The no observed adverse effect level of intrathecal administration of pemetrexed was 1 mg/kg in rats. At this level, therapeutically high and durable pemetrexed concentrations could be achieved. Based on these results, further research on intrathecal pemetrexed in humans or non-human primates should be considered.
Department of Medicine, Sungkyunkwan University School of Medicine, Seoul, Korea.
Jong-Mu
JM
Sun
Mi Hyun
MH
Nam
Jae Yong
JY
Chung
Bohee
B
Im
Soo-Youn
SY
Lee
Youn-Lim
YL
Suh
Jin Seok
JS
Ahn
Keunchil
K
Park
Myung-Ju
MJ
Ahn
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects* / Q000032:analysis / Q000493:pharmacokinetics; D002408:Catheters, Indwelling; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005971:Glutamates / Q000008:administration & dosage* / Q000009:adverse effects* / Q000032:analysis / Q000493:pharmacokinetics; D006147:Guanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000032:analysis / Q000493:pharmacokinetics; D006207:Half-Life; D007278:Injections, Spinal; D008297:Male; D008657:Metabolic Clearance Rate; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D020258:Neurotoxicity Syndromes / Q000097:blood / Q000134:cerebrospinal fluid / Q000473:pathology; D019055:No-Observed-Adverse-Effect Level; D000068437:Pemetrexed; D051381:Rats; D017207:Rats, Sprague-Dawley; D013346:Subarachnoid Space; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution; D018675:Toxicity Tests
D000964:Antimetabolites, Antineoplastic; D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine