Risk assessment of drug interaction potential and concomitant dosing pattern on targeted toxicities in pediatric cancer patients

Abstract

This investigation evaluated the impact of potential drug interactions on the incidence of reported toxicities seen with common dosing patterns in children with cancer, with the intent of being able to screen and reduce the incidence of adverse drug reactions (ADRs) in the future. Toxicity reported in pediatric cancer patients treated at the Children's Hospital of Philadelphia from 2004 to 2010 were abstracted from a cancer tumor registry and merged with drug order profiles from the medical record system. Analysis datasets were created in SAS and permutation algorithms were used to identify pairwise drug combinations associated with specific toxicity occurrence. Relative risk of toxicity based on dosing pattern was assessed via comparison to control patients. A total of 326 of 1,713 patients (19%) had reportable toxicities. Neutrophil count decreases and alanine aminotransferase increases represented the highest occurring, corresponding to 28.8% and 31.9% prevalence among patients reporting toxicity, respectively. Of coadministered drug pairs, acetaminophen-diphenhydramine occurred most frequently; however, methotrexate-vincristine was the highest occurring pair linked to a single toxicity (hepatotoxicity). Toxicity was highly associated with the diagnoses of leukemia (52.1%) or neuroblastoma (28.5%). Comparison of the dosing interval (≤30 versus >30 min) suggested that risk of toxicity can be associated with the timing of coadministration, with ≤30 min increasing the risk of hepatotoxicity with fentanyl-midazolam and methotrexate-midazolam combinations. Knowledge of drug interactions in children with cancer may help reduce the incidence of ADRs by providing pharmacotherapy options that may reduce the likelihood of toxicity.

Fig. 1

Data abstraction flow diagram illustrating subset sample size and analyses

Fig. 2

Cumulative frequency time to toxicity profiles over a 28-day observation window based on the first occurrence of study protocol initiation

Fig. 3

Representative patient drug coadministration and toxicity profile

Fig. 4

Dose time between drug pairs for ADR and control patients

Fig. 5

a RR rate comparing ADR and control patients based on whether they received drug pairs simultaneously or in a staggered manner (>30 min gap). b RR rate comparing ADR and control patients controlling for cancer diagnosis of leukemia (predominantly ALL patients based on CHOP population). 95% confidence intervals provided