Real-world utilization of darbepoetin alfa in cancer chemotherapy patients.

OBJECTIVES: To provide an understanding of darbepoetin alfa dose patterns in cancer patients undergoing myelosuppressive chemotherapy starting from 2011. STUDY DESIGN: This is a retrospective cohort study using a proprietary outpatient oncology database. METHODS: Metastatic, solid tumor cancer patients receiving concomitant myelosuppressive chemotherapy and darbepoetin alfa with an associated hemoglobin <10 g/dL during 2011-2015 were identified. The analysis was restricted to the first continuous exposure to chemotherapy agents (maximum allowable gap of 90 days between consecutive exposures) with darbepoetin alfa for each eligible patient. Initial, maintenance, weekly, and cumulative doses of darbepoetin alfa were examined across all darbepoetin alfa users. Subgroup analyses were conducted by chemotherapy type, baseline hemoglobin level, year of chemotherapy, solid tumor type, and initial dosing schedule. Differences in weekly doses across subgroups were evaluated using Wilcoxon rank-sum tests. RESULTS: Among 835 eligible patients, over 90% were 50 years or older. Mean chemotherapy course duration was 248 days, and mean duration of darbepoetin alfa treatment was 106 days. The mean weekly darbepoetin alfa dose was 110 µg. Patients received a mean of 4.3 darbepoetin alfa injections in the first chemotherapy course. There were no statistically significant differences (all P values > .05) in weekly dose by chemotherapy type, baseline hemoglobin level, year of chemotherapy, or solid tumor type. CONCLUSION: The average weekly darbepoetin alfa dose among metastatic cancer patients with chemotherapy-induced anemia from this study was 110 µg, which was lower than the labeled dosage for most adults. This estimate did not differ over time, across chemotherapy regimens, baseline hemoglobin levels, or solid tumor types.

Population Pharmacokinetics of Darbepoetin in Infants Following Single Intravenous and Subcutaneous Dosing.

Darbepoetin alfa (Darbe) is a hyperglycosylated analogue of recombinant human erythropoietin (Epo). The aim of this study was to develop a population pharmacokinetic model for Darbe following intravenous (i.v.) and subcutaneous (s.c.) administration to infants. Data from 2 infant clinical studies (a single i.v. dose study following a 4 µg/kg dose of Darbe, and a single s.c. dose study following 1 µg/kg or 4 µg/kg dose of Darbe) were combined and analyzed simultaneously using nonlinear mixed-effect modeling approach. Darbe population pharmacokinetics was well described by a 2-compartment model with first-order elimination. The covariate analysis identified significant impact of gender on clearance and bodyweight on volume of distribution. The clearance of Darbe was estimated to be 0.050 L/h/kg in male infants and 0.031 L/h/kg in female infants. The predicted population mean value of Vp is 0.84 L/kg, which is associated with the subject's bodyweight (p < 0.05). Following s.c. administration, the estimated absorption rate (i.e., ka) of Darbe was 0.062 L/h. The model provides a suitable starting point for the development of further pharmacokinetic-pharmacodynamic models in infants in a variety of disease settings. Because the covariate-pharmacokinetic parameter relationships were identified in only 22 infants, further investigation with larger sample size is warranted.

Population Pharmacokinetics of Darbepoetin Alfa in Conjunction with Hypothermia for the Treatment of Neonatal Hypoxic-Ischemic Encephalopathy.

AIM: The aim of this study was to determine the population pharmacokinetics of darbepoetin alfa in hypothermic neonates with hypoxic-ischemic encephalopathy treated with hypothermia. METHODS: Neonates ≥36 weeks gestation and <12 h postpartum with moderate to severe hypoxic-ischemic encephalopathy who were undergoing hypothermia treatment were recruited in this randomized, multicenter, investigational, new drug pharmacokinetic study. Two intravenous darbepoetin alfa treatment groups were evaluated: 2 and 10 µg/kg. Serum erythropoietin concentrations were measured using an enzyme-linked immunosorbent assay. Monolix 4.3.1 was used to estimate darbepoetin alfa clearance and volume of distribution. Covariates tested included: birthweight, gestational age, postnatal age, postmenstrual age, sex, Sarnat score, and study site. RESULTS: Darbepoetin alfa pharmacokinetics were well described by a one-compartment model with exponential error. Clearance and the volume of distribution were scaled by birthweight (centered on the mean) a priori. Additionally, gestational age (also centered on the mean) significantly affected darbepoetin alfa clearance. Clearance and volume of distribution were estimated as 0.0465 L/h (95% confidence interval 0.0392-0.0537) and 1.58 L (95% confidence interval 1.29-1.87), respectively. CONCLUSIONS: A one-compartment model successfully described the pharmacokinetics of darbepoetin alfa among hypothermic neonates treated for hypoxic-ischemic encephalopathy. Clearance decreased with increasing gestational age.