Purpose: Quizartinib pharmacokinetics in FLT3-ITD negative acute myeloid leukemia (AML) remain largely unexplored. This study aims to validate a population pharmacokinetics model (popPK) for quizartinib in plasma samples of FLT3-ITD negative AML patients. To do so, an ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) method has been developed and validated for the quantification of quizartinib. Methods: Plasma samples were collected from FLT3-ITD negative newly diagnosed AML patients undergoing quizartinib therapy at induction in the QUIWI phase II clinical trial [NCT04107727, PETHEMA group] between March 2020 and February 2022. The UPLC-MS/MS method was developed and validated. A previously described popPK model was validated using external validation techniques and implemented using the software NONMEM v7.5. Results: The developed UPLC-MS/MS method demonstrated high accuracy and precision with a linear range of 6 to 200 ng/mL, with relative standard deviation between 3–11 and accuracy of 88–97% from nominal values. The external validation of the quizartinib popPK model showed minimal bias at the population level (MdPE: -9.86%; ME: 0.50 ng/mL, p = 0.964), but moderate imprecision (MdAPE: 32.28%) and suboptimal accuracy (F20: 24.5%; F30: 43.4%). Individual predictions improved performance, with negligible bias (MdPE: -0.50%), acceptable precision (MdAPE: 11.27%), and F20 (64.2%) and F30 (77.4%) exceeding predefined thresholds. Visual predictive checks confirmed adequate prediction of median concentrations, though some deviations occurred at extremes. Conclusion: This study presents a replicable UPLC-MS/MS method for the determination of quizartinib in plasma. The validated popPK model can be used to optimize dosing strategies in future clinical studies.

A 53-year-old male with recovering alcohol dependency, diagnosed with bipolar disorder and recurrent episodes of diverticulitis, came to the emergency department with disorientation and confusion after 3 days of treatment with metronidazole 250 mg/12 hours and ciprofloxacin 500 mg/12 hours for acute diverticulitis. In the hospital emergency department, he presented moments of agitation, fluctuations of attitude, increased basal tremor, with rhythmic movement of the left arm and leg, as well as generalised rigidity with an episode of tonic-clonic seizure of 1.5-2 min duration. After performing different diagnostic tests, significant brain findings were ruled out. The pharmacy department recommended the discontinuation of one of the two drugs. As a result, the on-call doctor adjusted the patient’s treatment: disulfiram and previous antibiotic therapy (metronidazole and ciprofloxacin) were discontinued, and amoxicillin/clavulanic acid 2 g/8 hour was prescribed instead. The patient progressed well and fully recovered.

Objective: This study aimed to analyze pharmacokinetic and clinical parameters (bleeding rates and joint health) before and after switching from standard half-life (SHL) factor VIII (FVIII) to extended half-life (EHL) PEGylated turoctocog alfa pegol in patients with severe/moderate hemophilia A (HA) on prophylaxis, one year prior to and following the switch in a real-world setting. Methods: A single-center, comparative, observational, sequential, retrospective, multidisciplinary study was designed. The population pharmacokinetic parameters were estimated using the WAPPS-Hemo^® platform. The annualized bleeding rate (including total and joint bleeds), joint health (Hemophilia Joint Health Score), FVIII consumption, administration frequency, and treatment costs were analyzed. Results: Eight patients with severe (n = 7) or moderate (n = 1) HA on prophylaxis were included after switching to turoctocog alfa pegol. With this regimen, the median FVIII half-life was 16.8 (15.2–19.1) hours, the area under the curve (AUC) was 18,182 (12,879–21,214) IU·h/dL, and the incremental recovery was 2.2 IU/dL per (1.6–2.4) IU/kg. The patients required a median of 2.0 infusions per week (2.0–2.0), corresponding to a weekly consumption of 57.8 (54.2–61.1) IU/kg. Clinically, the prophylactic regimen was associated with fewer infusions per week, stable joint health, and a reduction in overall treatment costs. Conclusions: Prophylaxis with turoctocog alfa pegol provided the expected pharmacokinetic profile of an EHL-FVIII concentrate, enabled a lower infusion frequency, and was linked to a decreased treatment burden and cost while maintaining joint health.

To analyze the differences in pharmacokinetic and clinical parameters (bleeding rates and joint health) before and after switching from standard half-life factor VIII (FVIII) to extended half-life pegylated FVIII in patients with severe/moderate hemophilia A on prophylaxis, one year before and after the switch in real-life. This is a single-center, comparative, observational, sequential, retrospective, and multidisciplinary study. Population pharmacokinetic models from the WAPPS-Hemo® application were used to calculate pharmacokinetic parameters and individualize prophylaxis. The annual rate of total and joint bleeds, joint health (Hemophilia Joint Health Score), plasma half-life and area under the curve ratios, FVIII consumption, administration frequency, and cost were analyzed. Thirty-eight adult patients with hemophilia A who switched from standard half-life FVIII to extended half-life pegylated FVIII were analyzed. Significant improvements (p < 0.05) were observed in all pharmacokinetic parameters, with plasma half-life and area under the curve improvement ratios of 1.5 and 1.9, respectively, as well as reductions in annual total and joint bleeding rates were registered. A higher number of patients with zero total (16.0 vs. 29.0) and joint bleeds (23.0 vs. 33.0) was also observed. The median reductions in administration frequency and dose/kg/week were 30.0% and 19.7%, respectively, avoiding 44.3 infusions/patient/year, resulting in savings of 20,843 €/patient/year. Furthermore, joint health improved (23.0 vs. 21.0; p = 0.017), and target joints resolved after the switch. The pharmacokinetically guided switch from standard half-life FVIII to pegylated FVIII demonstrated significant clinical benefits with reduced bleeding rates and improvements in joint health. Additionally, improvements in pharmacokinetic parameters were observed, allowing for reduced treatment burden by decreasing administration frequency, as well as lower consumption and costs.