thiohydantoins and Body-Weight

Therapeutic strategies for prostate cancer are currently undergoing a paradigm shift due to the advent of next-generation androgen receptor inhibitors. Among these inhibitors, apalutamide is regarded as a key drug because of its effectiveness. However, risk factors for and the timing of the onset of apalutamide-related cutaneous adverse events remain unclear. Therefore, the present study investigated key risk factors for and timing of the onset of apalutamide-related cutaneous adverse events.. Sixty-two Japanese patients with non-metastatic castration-resistant prostate cancer treated with 240 mg/day of apalutamide were enrolled in the present study.. Twenty-four patients (38.7%) developed cutaneous adverse events. Multivariable logistic regression analysis of age, height, and body weight identified body weight as a significant predictive factor for the incidence of cutaneous adverse events (p=0.019). When the mean body weight of patients (63.80 kg) was set as the cut-off value, the Kaplan-Meier analysis revealed that the risk of cutaneous adverse events was significantly increased in those with a body weight <63.8 kg (p=0.003, the log-rank test). The analysis also showed that cutaneous adverse events developed within the first 6 months regardless of body weight.. A lower body weight is a significant risk factor for apalutamide-related cutaneous adverse events and their onset is within 6 months of initiation of therapy.

Topics: Body Weight; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Risk Factors; Thiohydantoins

Apalutamide is a next-generation androgen receptor inhibitor approved for treatment of subjects with high-risk, non-metastatic, castration-resistant prostate cancer (NM-CRPC).. The objective of this study was to characterize the population pharmacokinetics of apalutamide and its metabolite N-desmethyl-apalutamide in healthy male and castration-resistant prostate cancer subjects.. Plasma concentration data for apalutamide and N-desmethyl-apalutamide from 1092 subjects (seven clinical studies) receiving oral apalutamide (30-480 mg) once daily were pooled for a population pharmacokinetic analysis using a non-linear mixed-effect modelling approach. The impact of clinically relevant covariates was also assessed.. Apalutamide absorption was rapid, and the apparent steady-state volume of distribution was large (276 L), reflecting a wide body distribution. Apalutamide was eliminated slowly, with its apparent clearance increasing from 1.31 L/h after the first dose to 2.04 L/h at steady state. No evidence of time-dependent disposition was observed for N-desmethyl-apalutamide, which was also widely distributed and slowly cleared (1.5 L/h). After 4 weeks of treatment, more than 95% of steady-state exposure of apalutamide and N-desmethyl-apalutamide was reached. At a dose of apalutamide 240 mg/day, apalutamide and N-desmethyl-apalutamide exposure exhibited 5.3- and 85.2-fold accumulation in plasma, respectively. Inter-individual variability in apalutamide apparent clearance is low (< 20%). Among the covariates evaluated, apalutamide and N-desmethyl-apalutamide exposure were statistically associated only with health status, body weight, and albumin concentration, and the effect was low (< 25%).. A population pharmacokinetic modelling approach was successfully applied to describe the pharmacokinetics of apalutamide and N-desmethyl-apalutamide. No clinically relevant covariates were identified as predictors of apalutamide and N-desmethyl-apalutamide pharmacokinetics.

Topics: Adult; Aged; Aged, 80 and over; Albumins; Androgen Receptor Antagonists; Biological Variation, Population; Body Weight; Case-Control Studies; Health Status; Healthy Volunteers; Humans; Male; Middle Aged; Models, Theoretical; Predictive Value of Tests; Prostatic Neoplasms, Castration-Resistant; Thiohydantoins