Venetoclax pharmacokinetics with triazole prophylaxis in patients with Acute Myeloid Leukemia in India: Pilot study Free

Venetoclax (VEN) combined with a hypomethylating agent is standard induction therapy for patients with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy. Triazole antifungal prophylaxis—routinely used in this setting—significantly alters venetoclax pharmacokinetics: FDA data show that posaconazole 300 mg increases VEN Cmax by 61–86% and AUC24 by 90–144% at reduced VEN doses (www.accessdat.fda.gov). Although Asian patients may exhibit higher VEN exposure—likely due to bioavailability differences—standard non-Asian dosing is generally maintained ( Salem HA et al. Clin Transl Sci. 2024). In India, where VEN has only recently become commercially available, clinicians often combine azoles with reduced VEN doses to optimize exposure and cost, but real-world pharmacokinetic data in our population in India are lacking

Identifying with this goal, we undertook a pilot ultra-performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) study in adults with acute myeloid leukemia (AML) receiving hypomethylating agent (HMA)–venetoclax induction. Patients received HMA–venetoclax therapy (100 mg VEN) along with either posaconazole 300 mg once daily or voriconazole 200 mg twice daily as prophylaxis.Calibration standards (0.03–7.0 mg/L) were prepared by spiking plasma with serial dilutions of a methanolic stock, and samples underwent liquid–liquid extraction, nitrogen drying, and reconstitution in 80:20 methanol/0.1% formic acid–water. Chromatographic separation on a Waters CORTECS octylsilane (C8) column (2.1×50 mm, 2.7 µm) at 40 °C with a 0.4 milliliters per minute (mL/min) gradient of 0.1% formic acid in water and methanol was followed by positive-ion multiple-reaction monitoring (MRM) quantification. The m/z transitions quantified were 350 → 224, 701.34 → 127.05 and 353.11 → 130.07 for voriconazole, posaconazole and voriconazole-D3 respectively. Samples were analyzed at post-dose 6-hour (C6) sampling at a median 6.03 hours (range 6.0–6.3 h), consistent with expected time-to-maximum concentration (Tmax).

Ten plasma samples from eight AML patients on HMA–venetoclax induction were analysed: seven on posaconazole prophylaxis and three on voriconazole. Median age was 73 years (range 62–81), and 62.5% were female. Overall, the median VEN trough was 0.639 mg/L (range 0.244–3.683), and the median C6 was 1.873 mg/L (range 0.411–4.938). By antifungal, under posaconazole the median venetoclax trough was 0.455 mg/L (range 0.244–1.504), while under voriconazole it was 1.935 mg/L (range 1.229–3.683). For C6 (~6 h), median venetoclax concentrations were 1.596 mg/L (posaconazole; 0.411–2.394) and 2.431 mg/L (voriconazole; 1.507–4.938). In our cohort, six posaconazole troughs were measurable, with a median of 0.2405 mg/L (range 0.09–0.455 mg/L). Voriconazole trough measured in a single patient was 1.83 mg/L. When analyzed by antifungal prophylaxis received, patients on posaconazole had lower VEN exposure than those on voriconazole: median trough 0.455 mg/L and median C6 1.596 mg/L with posaconazole (trough range 0.244–1.504, C6 0.411–2.394) versus median trough 1.935 mg/L and median C6 2.431 mg/L with voriconazole (trough 1.229–3.683, C6 1.507–4.938). In this pilot, voriconazole showed approximately 4.3-fold higher trough and 1.5-fold higher C6 concentrations than posaconazole.

In conclusion, in our real-world pilot, co-administration of posaconazole with reduced-dose venetoclax achieved standard target exposures . Our analyses did not yield the 60–80% maximum concentration (Cmax) increase reported in formal drug–drug interaction (DDI) studies with posaconazole; instead, 100 mg venetoclax exposures remained comparable to the 400-mg reference. Measured posaconazole troughs were low—median 0.2405 milligrams per liter (mg/L) (range 0.09–0.455 mg/L)—falling below the usual prophylactic target of 0.5–0.7 mg/L. However, voriconazole co-administration was associated with higher venetoclax levels, suggesting a potential need for even more conservative dosing. Limitations include the small sample size and incomplete recording of venetoclax dose and meal status (precluding dose-normalized analysis). Even so, these early data offer actionable guidance on venetoclax use in India: posaconazole-enabled dose reduction may safely achieve target exposures, while voriconazole may require additional dose adjustments.