Abstract
Background Venetoclax (VNX), an orally bioavailable BCL-2 inhibitor, is now a gold standard treatment for newly diagnosed AML patients who were ineligible for intensive chemotherapy, in association with hypomethylating agent (HMA) or low-dose cytarabine (LDAC). Even if VNX pharmacokinetics (PK) have been well characterized and are described in the literature, only one clinical trials-based PK study has been conducted in AML patients. For example, bioavailability (F) and clearance (Cl) are largely influenced by food intake and CYP3A inhibitors (such as posaconazole PCZ), as shown by the 32% (F) and 44% (Cl) inter-individual variability for F and Cl, respectively. For such oral targeted therapies, real-world data highlighted a larger PK inter-variability (IIV) than expected. The most commonly reported toxicity under VNX treatment is neutropenia, frequently resulting in dose reduction and/or treatment discontinuation. In this study, we reported our local experience of VNX use with measure of PK exposure.
Material and Methods We retrospectively evaluated patients treated by VNX + azacitidine (AZA) for AML with available PK blood sample. Briefly, VNX was administered at a dose of 400mg (or 70mg if co-medication with PCZ) once daily, and PK was mainly performed from C1D4 to C1D7 (T0, T4, T8) during hospitalization. In order to estimate individual PK parameters in our cohort, we integrated a published PK population (PKpop) model2 into the Bayesian software program Tucuxi®. For each patient, model was used to fit the VNX dataset, which basically computes the individual Bayesian posterior parameter values based on the prior information. Goodness-of-fit was assessed by computing bias and imprecision of individual model predicted concentrations. Then, individual area under the concentration-time curves (AUC) and PK parameters were computed. In parallel, the following outcomes have been collected in order to evaluate any potential PK-PD relationships. All informed consents have been obtained according to the reference methodology MR-004.
Results Twenty patients (H/F = 12/8, mean age = 66 years [min 38 max 77]) were included in this study, they all received in average 4 courses of VNX-AZA (Table 1). After a median follow-up of 152 days [27-642], 65% of patients were in CR + CRi. All patients who did not achieve CR, received VNX-AZA in second line after failure of previous chemotherapy. Minimal residual disease (MRD) assessed by flow cytometry was negative in 40% of patients. At the last follow up, 11 patients (55%) were alive in CR and 1 patient (5%) in relapse. Eight patients (40%) died from progression in 6 patients and toxic death in 2 patients. All patients experienced at least one hematological toxicity grade ≥ 3. Between November 2021 and June 2022, 93 PK blood sampling were analyzed (80% in course 1). Nine patients had a second day of supplementary PK. Seven patients received concomitant PZC and 3 did not take VNX with food. PKpop model applied to our cohort showed a satisfactory goodness-of-fit (Figure 1, R²=0.83, bias of 2.8% and imprecision of 26.5%). Mean individual daily AUC was 35.8 mg.h/L with high IIV (CV=47%) and no difference according to PCZ use or food intake (p=NS). No PK-PD relationships (efficacy and toxicity) has been highlighted.
Conclusion This work described exposure and PK variability in real-world setting. Even if some covariates have been highlighted as sources of variability, it seems difficult to control exposure with a "one size fits all" dosing. PK variability could be an explanation for PD variability (both efficacy and toxicity). VNX seems to be a good candidate for therapeutic drug monitoring but some PK-PD relationships studies need to be conducted to find precise PK target.
Disclosures
No relevant conflicts of interest to declare.
