Real-world pharmacokinetics of venetoclax in patients with acute myeloid leukemia in Japan.

Venetoclax (VEN) combined with azacitidine (AZA) or low-dose cytarabine (LDAC) has significantly improved outcomes for older patients with acute myeloid leukemia (AML). However, severe cytopenia often leads to treatment interruptions. Previous literature has reported that Asian patients tend to have higher plasma VEN concentrations and are more prone to severe neutropenia. We hypothesized that VEN pharmacokinetics (PK) influence these adverse events in the Japanese population. In a prospective observational study (UMIN000047371) involving 76 patients, we monitored VEN PK (trough, maximum plasma concentration, and area under the plasma concentration-time curve from 0 to 12 hours [AUC0-12]). Our analysis of an 81-sample PK data set revealed that samples taken 6 hours after VEN dose offered the best correlation to AUC0-12 (r = 0.945). Importantly, in patients who achieved composite complete remission, a positive correlation was found between the duration of grade 3 neutropenia and VEN AUC0-12 (r = 0.338; P = .028). We further investigated potential factors influencing VEN PK and neutropenia, specifically considering tumor burden and renal function. Samples from patients with pretreatment white blood cell (WBC) counts of <3000/μL and an estimated glomerular filtration rate (eGFR) of <60 mL/min exhibited significantly higher VEN AUC0-12 levels (P = .037) than other groups. These patients also demonstrated a significantly more extended period of grade 3 neutropenia (P = .037). These results suggest that VEN PK could be crucial for predicting neutrophil recovery after VEN-containing regimens in AML. Specifically, patients with low pretreatment WBC counts and low eGFR may represent a risk factor for higher VEN concentrations and, consequently, prolonged neutropenia.