Toxicity and pharmacokinetics of actinomycin-D and vincristine in children and adolescents: Children's Oncology Group Study ADVL06B1

Abstract

Actinomycin-D and vincristine are cytotoxic drugs commonly used to treat cancers in children. This prospective study assessed pharmacokinetic variability and toxicity of these drugs in children. Blood samples were collected in 158 patients. Actinomycin-D or vincristine concentrations were quantified using high-performance liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were estimated using non-compartmental methods. Target toxicities were collected prospectively. Actinomycin-D pharmacokinetics (n = 52 patients) were highly variable. The median (coefficient of variation, CV%) area under the concentration-time curve (AUC) was 332 ng/mL·h. (110%); clearance was 4.6 L/h/m² (90%); half-life was 25 h (60%). No patient met the defined criteria for myelosuppression. In multivariate analysis, none of the demographic nor pharmacokinetic parameters was predictors of acute hepatotoxicity. Vincristine pharmacokinetics (n = 132 patients) demonstrated substantial variability. The median (CV%) AUC was 78 ng/mL·h (98%); clearance was 17.2 L/h/m² (67%); half-life was 14.6 h (73%). In multivariate analysis, the effect of increasing age for a given BSA was an increase in neuropathy while the effect of increasing BSA for a given age was a decrease in neuropathy. Conclusion: Pharmacokinetics of both drugs were highly variable. For actinomycin-D, there was no correlation between demographic or pharmacokinetic parameters and target toxicities. For vincristine, the correlations of age and BSA and neuropathy are confounded by the correlation between age and BSA in children and the ability to ascertain neuropathy in infants. Variability may be attributed to dose reductions and capped doses for both drugs. Investigation of BSA-based dosing in young children is warranted to decrease variability of exposure.

Keywords: Actinomycin-D; Childhood cancer; Pharmacokinetics; Vincristine.

Figure 1:. Exposure (AUC_inf) and Clearance of Actinomycin-D and Vincristine.

(A) Actual actinomycin-D dose (mg) administered to each patient versus exposure. (B) Actinomycin-D weigh-based dose (mg/kg) versus exposure. (C) Actinomycin-D BSA-based dose (mg/m²) versus exposure. (D) Actinomycin-D clearance for each age cohort, lines indicate median clearance. (E) Actual vincristine dose (mg) administered to each patient versus exposure (F) Vincristine weigh-based dose (mg/kg) versus exposure. (G) Vincristine BSA-based dose (mg/m²) versus exposure. (H) Vincristine clearance in each age cohort, lines indicate median clearance.