Development of a Hospital Compounded, Taste-Masked, Temozolomide Oral Suspension and 5-Year Real-Life Experience in Treating Paediatric Patients

Abstract

The development of oral pediatric forms by pharmaceutical companies is still insufficient. In fact, many drugs used in paediatric oncology, such as temozolomide, are not labeled and adapted for paediatric use. Temozolomide (TMZ) is an alkylating agent used as the standard of care for many adult and pediatric brain tumours, such as neuroblastoma, glioblastoma and medulloblastoma. The present study was carried out to propose a suitable and palatable formulation of the oral liquid preparation of TMZ. The suspension is composed of TMZ suspended in SyrSpend SF pH 4, as well as TMZ crystallization stabilizing agents and sweetening agents. To reach this formulation, several taste-masking agents were evaluated. Here, we describe the method of preparation of the formation as well as the monocentric population treated with the formulation over a 5–year period. A 20 mg/mL TMZ suspension was developed. TMZ suspension is stable for 6 weeks, stored between 2 and 8 degrees, protected from light, and compatible with nasogastric tubes. Thirty-eight patients participated in the palatability study and choose cola flavour, and 104 patients were treated in Gustave Roussy with the developed suspension; no unexpected event was reported. To conclude, we propose here a new TMZ liquid formulation which is stable for at least 6 weeks and well-tolerated with extensive feedback.

Dispensing Oral Temozolomide in Children: Precision and Stability of a Novel and Ready to Use Liquid Formulation in Comparison with Capsule Derived Mixtures

“…For TMZ administration, caregivers open capsules and mix their contents with any kind of beverage or soft foods. This practice poses multiple risks, including exposure of the caregiver to a cytotoxic drug, imprecise delivery and dosing, partial drug intake if the food or beverage is not totally ingested or consumed, and uncontrolled stability of the active compound [ 8 , 15 , 20 ]. Here, we investigated the dosing accuracy and drug stability of TMZ in various food vehicles commonly used to aid administration to pediatric patients [ 18 , 29 ] and whether an investigational oral suspension of TMZ could offer improved dosage accuracy and stability.…”

“…In these cases, clinicians may often instruct caregivers to follow common administration practices in pediatrics [ 12 , 13 ] by opening the TMZ capsules and mixing the powder content into liquid and/or soft food before spoon-feeding or syringing the mixture to the child with the aim of improving swallowability and palatability [ 14 , 15 ]. Despite the lack of scientific information regarding the adverse effects associated with such drug manipulations or modifications [ 16 ], mixing medicines into foodstuffs to facilitate drug administration is frequent and occurs in one-third of medicines for oral administration to the pediatric population [ 11 , 17 ].…”

“…However, unless the impact of liquid or soft foods used as vehicles for drug administration on the drug product performance (i.e., drug product quality attributes) is appropriately assessed and justified [ 18 ], this approach should be avoided for several reasons. Firstly, TMZ is a cytotoxic and teratogenic alkylating agent, meaning that exposure to the powder can be harmful to caregivers and the family [ 8 , 15 ]. Secondly, administering the accurate dose may be inconsistent and compromised by incomplete food consumption by the child.…”

“…Manipulation and opening of the capsules may further increase the loss of TMZ (e.g., some powder left in the capsule shell) and thereby increase errors in accurate dosing. Third, as TMZ is unstable under light and at a pH of 7 or above, mixing the capsule contents with food may result in drug degradation and suboptimal dosing [ 15 ]. Finally, the co-administration of capsules with food may impact the bioavailability of TMZ [ 1 ] with the potential risk of subtherapeutic drug levels.…”

“…The objective of this study was to evaluate the impact of TMZ capsule manipulation on the main critical quality attributes, accuracy (assay), and stability of TMZ, compared with the ready-to-use Ped-TMZ suspension. Pediatric patients who require TMZ treatment typically receive doses of 80–120 mg [ 15 ]. For the purpose of this study, a dose of 90 mg was chosen corresponding to a child under the age of 6 exhibiting a BSA of 0.6 m 2 and treated with 150 mg/m 2 of TMZ.…”