Abstract 4526: Age dependent disposition of cyclophosphamide (CTX) and metabolites in infants ≤ 1 year old with brain tumors
Authors: Daryani Vinay M. , Owens Thandranese S. , Harstead K. Elaine , Patel Yogesh T. , Turner David C. , Throm Stacy L. , Panetta John C. , Gajjar Amar , Stewart Clinton F. 
Published: August 2015

Abstract
An ongoing trial of risk-adapted therapy for infants and young children &lt; 3 yrs old diagnosed with brain tumors includes IV CTX (NCT00602667). One aim is to describe the pharmacokinetics (PK) of CTX, and 2 of its metabolites, the inactive carboxyethylphosphoramide mustard (CEPM) and the active 4-hydroxycyclophosphamide (4-OH CTX) in children &lt; 3 yrs old. This report describes the disposition of CTX and metabolites in infants ≤ 1 yr old. Induction therapy includes 1.5 gm/m2 CTX IV over 1 hr on day 9 of a 28 day course. PK studies for CTX were performed in consenting patients and samples were collected prior to drug infusion, at the end of the infusion (EOI), and 3, 6, and 24 h after EOI. Blood was processed to plasma for determination of CTX and CEPM using a LC-MS/MS method. For 4-OH CTX, samples were immediately derivatized using phenylhydrazine to ensure 4-OH CTX stability until analysis using a LC-MS/MS method. A model with one compartment for CTX and each metabolite was fit to the data using nonlinear mixed effects modeling. In 27 infants ≤ 1 yr, 133 samples were obtained and analyzed for CTX, CEPM, and 4-OH CTX. The median (range) age, BSA, and weight were 6.9 months (0.2 - 12 months), 0.4 m2 (0.2 - 0.6 m2), and 8.1 kg (3.6 - 14.1 kg), respectively. As depicted in the Table below, CTX and 4-OH CTX AUC were 50% and 30% higher in the youngest age group, respectively. Our preliminary analysis showed inclusion of age as a covariate on CTX clearance to 4-OH CTX improved model fits, decreasing the variability observed in 4-OH CTX AUC. Since high 4-OH CTX exposure is associated with increased toxicities, our results indicate the need for better models to accurately simulate 4-OH CTX exposures in infants with the goal of developing rational dosing approaches for CTX in this population. This is the first analysis of CTX and metabolite PK in infants ≤ 1 yr old with brain tumors. Future studies will include a full covariate analysis and an evaluation of exposure-toxicity relationships associated with CTX and metabolites.
Age group (months)# ptsCTX AUC0-∞ (μM*hr)4-OH CTX AUC0-∞ (μM*hr)0-363556 (2423-6170)†227 (158-263)†3-652854 (2174-3312)174 (170-237)6-972454 (2356-3281)179 (138-220)9-1292461 (1793-2735)175 (136-210)†Kruskal-Wallis, p&lt;0.05; Dunn's Multiple Comparison, p&lt;0.05†Kruskal-Wallis, p = 0.06
Citation Format: Vinay M. Daryani, Thandranese S. Owens, K. Elaine Harstead, Yogesh T. Patel, David C. Turner, Stacy L. Throm, John C. Panetta, Amar Gajjar, Clinton F. Stewart. Age dependent disposition of cyclophosphamide (CTX) and metabolites in infants ≤ 1 year old with brain tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4526. doi:10.1158/1538-7445.AM2015-4526