Preclinical examination of clofarabine in pediatric ependymoma: intratumoral concentrations insufficient to warrant further study.
Clofarabine, a deoxyadenosine analog, was an active anticancer drug in our in vitro high-throughput screening against mouse ependymoma neurospheres. To characterize the clofarabine disposition in mice for further preclinical efficacy studies, we evaluated the plasma and central nervous system disposition in a mouse model of ependymoma. A plasma pharmacokinetic study of clofarabine (45 mg/kg, IP) was performed in CD1 nude mice bearing ependymoma to obtain initial plasma pharmacokinetic parameters. These estimates were used to derive D-optimal plasma sampling time points for cerebral microdialysis studies. A simulation of clofarabine pharmacokinetics in mice and pediatric patients suggested that a dosage of 30 mg/kg IP in mice would give exposures comparable to that in children at a dosage of 148 mg/m(2). Cerebral microdialysis was performed to study the tumor extracellular fluid (ECF) disposition of clofarabine (30 mg/kg, IP) in the ependymoma cortical allografts. Plasma and tumor ECF concentration-time data were analyzed using a nonlinear mixed effects modeling approach. The median unbound fraction of clofarabine in mouse plasma was 0.79. The unbound tumor to plasma partition coefficient (K pt,uu: ratio of tumor to plasma AUCu,0-inf) of clofarabine was 0.12 ± 0.05. The model-predicted mean tumor ECF clofarabine concentrations were below the in vitro 1-h IC50 (407 ng/mL) for ependymoma neurospheres. Thus, our results show the clofarabine exposure reached in the tumor ECF was below that associated with an antitumor effect in our in vitro washout study. Therefore, clofarabine was de-prioritized as an agent to treat ependymoma, and further preclinical studies were not pursued.
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
Yogesh T
YT
Patel
Megan O
MO
Jacus
Nidal
N
Boulos
Jason D
JD
Dapper
Abigail D
AD
Davis
Pradeep K
PK
Vuppala
Burgess B
BB
Freeman
Kumarasamypet M
KM
Mohankumar
Stacy L
SL
Throm
Richard J
RJ
Gilbertson
Clinton F
CF
Stewart
D000227:Adenine Nucleotides / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000293:Adolescent; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D001087:Arabinonucleosides / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001798:Blood Proteins / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D001932:Brain Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D000077866:Clofarabine; D004806:Ependymoma / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000227:Adenine Nucleotides; D000964:Antimetabolites, Antineoplastic; D001087:Arabinonucleosides; D001798:Blood Proteins; D000077866:Clofarabine