Pharmacokinetic and Pharmacodynamic Characteristics of Tripegfilgrastim, a Pegylated G‐CSF, in Pediatric Patients with Solid Tumors

Abstract

A long-acting granulocyte colony-stimulating factor (G-CSF) has the benefit of reducing the incidence of febrile neutropenia and shortening the duration of hospitalization in patients with cancer, but its use in pediatric patients is limited due to the lack of clinical trials. WHAT QUESTION DID THIS STUDY ADDRESS? This study evaluated pharmacokinetic characteristics and exposure-response relationship of tripegfilgrastim, a longacting G-CSF, in pediatric patients with solid tumors. WHAT DOES THIS STUDY ADD TO OUR KNOW-LEDGE? Tripegfilgrastim was generally safe and well-tolerated in the pediatric patients, and the duration of grade 4 neutropenia in the 100 μg/kg dose group was reduced by ~ 2 days compared to that in the 60 μg/kg dose group. Higher systemic exposure in the early period before the absolute neutrophil count nadir was correlated with an improved neutrophil response. HOW MIGHT THIS CHANGE CLINICAL PHARMA-COLOGY OR TRANSLATIONAL SCIENCE? This study provides an enhanced understanding of how pediatric patients with solid tumor respond to long-acting G-CSF regarding the pharmacokinetic-pharmacodynamic relationship and added evidence to use tripegfilgrastim at 100 μg/ kg in pediatric patients.

Semimechanistic pharmacokinetic–pharmacodynamic model of tripegfilgrastim for pediatric patients after chemotherapy

“…[42][43][44] Our previous study showed that tripegfilgrastim 100 μg/kg reduced Grade 4 neutropenia and was generally tolerable in patients. 19 Although weight-based dosing is used, it has some disadvantages because of the inconvenience of administration and the nonlinear relationship between weight and dose. 45,46 Our simulation suggested that five weight-tiered fixed doses of tripegfilgrastim achieved a similar reduction in Grade 4 neutropenia duration compared with weight-based G-CSF treatment with 100 μg/kg.…”

“…A population PK‐PD model was developed to describe the ANC profiles after exposure to tripegfilgrastim in healthy adults and pediatric patients. PK‐PD data from two studies were used in this analysis 19,22 . Both studies were approved by the Institutional Review Board of Seoul National University Hospital and conducted in accordance with the Declaration of Helsinki and Good Clinical Practice.…”

“…The serum concentration of tripegfilgrastim was measured by solid‐phase sandwich enzyme‐linked immunosorbent assays (ELISA) with a lower limit of quantification (LLOQ) of 0.7 μg/L for healthy adults and 0.017 μg/L for pediatric patients 19,22 . Both assays were validated according to the bioanalytical method validation guidance but used different ELISA kits between the study.…”

“…The PK sample was obtained at 0, 3,6,9,12,24,36,48,72,96,120,144,168,192,240, and 312 h, and PD was obtained at 0, 6,12,24,48,72,96,120,144,168,192,240, and 312 h. In the pediatric study, patients aged between 6 and 19 years received a single subcutaneous dose of either 60 μg/kg or 100 μg/ kg tripegfilgrastim 24 h after the end of chemotherapy. 19 The PK sample was obtained at 0, 3,6,12,24,36,48,72,96,120,168,240,312, and 480 h, and PD was obtained at 0, 6,12,24,48,72,96,120,168,240, and 312 h.…”

“…Our recent work explored the pharmacokinetic (PK)–pharmacodynamic (PD) relationship for the long‐acting G‐CSF tripegfilgrastim in Korean pediatric patients. A single subcutaneous injection of tripegfilgrastim 100 μg/kg resulted in a reduced duration of Grade 4 neutropenia, whereas weighing less than 45 kg resulted in a higher risk of a prolonged neutropenia period when receiving 60 μg/kg tripegfilgrastim 19 . This finding implies that patient‐specific factors may affect the efficacy of tripegfilgrastim.…”