Selección de dosis en el desarrollo de fármacos para el tratamiento del cáncer en pacientes con insuficiencia renal y hepática

Abstract

Patients with cancer and renal impairment (RI) and /or hepatic impairment (HI) are one of the main challenges in cancer treatment since anti-cancer agents are mainly metabolized by the liver and eliminated by the kidneys and the doses and regimens for treatments were investigated mostly in patients with normal kidney and liver function. RI and HI may affect drug pharmacokinetics unpredictably. In this context, a dose reduction is required to avoid excessive toxicity even it could put the efficacy of the treatment at risk. Assuming the hypothesis that organ dysfunction affects pharmacokinetics of anti-cancer drugs in patients with cancer and RI/HI and that it may modify the safety of these drugs, two studies were performed in cancer patients. A study of cabazitaxel in patients with moderate RI (GFR: 30-50mL/min/1. 73m2) and severe RI (GFR < 30mL/min/1. 73m2) and a study of trabectedin in patients with HI defined by total bilirubin >1. 5-≤3 upper normal limit and AST/ALT <8 upper normal limit. Both studies included a control group of patients with normal renal and hepatic function. The aim of these studies is to investigate the effect of RI and HI on the pharmacokinetic parameters and safety of cabazitaxel and trabectedin. Twenty-five patients (cohort A [normal renal function]: n=8, cohort B [moderate RI]: n=8, cohort C [severe RI]: n=9) were treated with cabazitaxel. Patients from cohorts A and B received the dose of 25mg/m2 and patients from cohort C, 20mg/m2 at the first cycle (4 patients had dose escalation to 25mg/m2 at cycle 2 and 3, 5 patients did not receive 25mg/m2 at cycle 2 and subsequent cycles due to dose-limiting toxicity [3 patients] and Investigator´s decision [2 patients]). The data analysis included 24 eligible patients (8 patients from each cohort) and the estimated geometric means for CL/BSA in patients with moderate and severe RI versus normal were 0. 90 (90% IC 0. 80-1. 13) and 0,89 (90% IC 0. 61-1. 32) and for AUC/dose 1. 06 (90% IC 0. 88-1. 27) and 1. 14 (90% IC 0. 76-1. 71) respectively. In addition, 15 patients were treated in the trabectedin study, 9 patients with normal hepatic function received trabectedin dose 1. 3mg/m2 and 6 patients with HI received dose of 0. 58mg/m2 (n=3) and 0. 9mg/m2 (n=3). The trabectedin ratios of estimated geometric means for Cmax and AUClast were 1. 40 (90% IC 0. 99-1. 99) and 1. 97 (90% IC 1. 20-3. 22) respectively for HI patients compared to control. The toxicity of cabazitaxel in patients with RI was similar to that in patients with normal renal function. The toxicity of trabectedin was similar in both groups, HI and control groups. Although a higher frequency of adverse events (nausea, vomiting, increased ALT, decreased appetite) was observed at dose of 0. 9mg/m2 compared to dose of 0. 58mg/m2 being hepatoxicity higher in patients with normal hepatic function. In conclusion, RI does not affect the pharmacokinetics and safety of cabazitaxel at dose of 25mg/m2 in patients with moderate and severe RI. In contrast HI affects the pharmacokinetics of trabectedin without changing safety. A dose adjustment of trabectedin at dose of 0. 9mg/m2 is necessary in patients with HI.

Date of Award	28 Jan 2021
Original language	Spanish
Supervisor	Marta Valle Cano (Tutor)