Clinical Pharmacokinetics of Amifostine and WR1065 in Pediatric Patients with Medulloblastoma

Abstract

Purpose: We evaluated the pharmacokinetics of amifostine and WR1065 in pediatric patients with newly diagnosed medulloblastoma to assess the influence of patient covariates, including demographics, clinical characteristics, and genetic polymorphisms, on amifostine and WR1065 pharmacokinetic parameters.Experimental Design: We assessed the pharmacokinetics of amifostine and WR1065 in 33 children who received amifostine (1-minute infusion, 600 mg/m 2 ) just before the start of and 3 hours into a 6-hour cisplatin infusion. Serial blood samples were collected after doses 1 (0 hour) and 2 (3 hours) of course 1. Amifostine and WR1065 were quantitated by high performance liquid chromatography with electrochemical detection. A pharmacokinetic model was simultaneously fit to amifostine and WR1065 plasma or whole blood concentration-versus-time data. The influence of demographic, biochemical, and pharmacogenetic covariates on amifostine and WR1065 disposition was evaluated.Results: Body surface area was the primary size-based covariate for amifostine pharmacokinetics explaining 53% and 56% of interindividual variability in plasma and whole-blood amifostine clearance, respectively. , and 12.5 L/h/m 2 . Conclusions: These results support using body surface area for calculating doses of amifostine in children. Similar to data in adults, amifostine and WR1065 are rapidly cleared from plasma and whole blood in children.

Evaluation of amifostine for protection against cisplatin-induced serious hearing loss in children treated for average-risk or high-risk medulloblastoma

“…In addition, the results of our published pharmacokinetic study of amifostine and WR1065 in this patient population further lead credence to the selection of the amifostine dosage and schedule for this patient population. 10 We also used a standardized coding method, the Chang ototoxicity grading scale, 21 to assess hearing level for all participants, which has notable advantages over the NCI CTCAE v3.0 method and other earlier ototoxicity scales 3,20 including the scale used in our previous analysis.…”

“…7 Currently, no established treatments or procedures exist to prevent platinum-induced hearing loss in children or adults. 3,8,9 Amifostine, a prodrug metabolized in humans to WR-1065, 10 is a thiol-reducing agent and potent free-radical scavenger with demonstrated otoprotective properties against cisplatin in experiments using hamsters 11 and guinea pigs. 12 Evaluation of amifostine as a cisplatin otoprotectant in childhood cancer treatment has been limited to small studies with results suggesting no positive effect.…”

Concordance between the chang and the International Society of Pediatric Oncology (SIOP) ototoxicity grading scales in patients treated with cisplatin for medulloblastoma

“…Cisplatin dose included 75 mg/m 2 each cycle totaling 300 mg/m 2 cumulative dose. The SJMB96 protocol began enrolling patients in October 1996 and was amended in August 1999 to include amifostine , a thiophosphate cytoprotective agent given to reduce toxicities associated with radiotherapy and alkylating and platinum‐containing agents . Amifostine was administered immediately prior to and again three hours into each of the four cycles of cisplatin treatments to minimize ototoxic effects .…”

Amifostine (WR-2721) Mitigates Cognitive Injury Induced by Heavy Ion Radiation in Male Mice and Alters Behavior and Brain Connectivity

“…Research into the effects of amifostine in females is glaringly lacking, though. Females clear plasma amifostine faster than males ( McKibbin et al, 2010 ). However, to the best of our knowledge, there are no reports of the effects of amifostine on learning and memory outcomes in females.…”