Management of Venetoclax-Posaconazole Interaction in Acute Myeloid Leukemia Patients: Evaluation of Dose Adjustments.
The effect of posaconazole, a strong cytochrome P450 3A (CYP3A) inhibitor and commonly used antifungal agent, on the pharmacokinetic properties of venetoclax, a CYP3A substrate, was evaluated in patients with acute myeloid leukemia to determine the dose adjustments needed to manage this potential interaction.



Twelve patients received 20- to 200-mg ramp-up treatment with oral venetoclax and 20 mg/m2of intravenous decitabine on days 1 through 5, followed by 400 mg of venetoclax alone on days 6 through 20. On days 21 through 28, patients received 300 mg of posaconazole plus reduced doses of venetoclax (50 or 100 mg) to account for expected increases in venetoclax plasma concentrations. Blood samples were collected before dosing and up to 24 hours after the venetoclax dose on days 20 and 28.



Compared with a venetoclax dose of 400 mg when administered alone (day 20), coadministration of venetoclax at a 50-mg dose with multiple doses of posaconazole increased mean venetoclax Cmaxand AUC0-24by 53% and 76%, respectively, whereas coadministration of venetoclax at a 100-mg dose with posaconazole increased mean venetoclax Cmaxand AUC0-24by 93% and 155%, respectively. When adjusted for different doses and nonlinearity, posaconazole was estimated to increase venetoclax Cmaxand AUC0-24by 7.1- and 8.8-fold, respectively. Both the 50- and 100-mg venetoclax doses administered with posaconazole were well tolerated.



The results are consistent with inhibition of CYP3A-mediated metabolism of venetoclax. Posaconazole can be used for antifungal prophylaxis in patients with acute myeloid leukemia receiving venetoclax after reducing the venetoclax dose by at least 75%. ClinicalTrials.gov identifier: NCT02203773.
AbbVie Inc, North Chicago, Illinois.
Suresh K
SK
Agarwal
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Courtney D
CD
DiNardo
AbbVie Inc, North Chicago, Illinois.
Jalaja
J
Potluri
AbbVie Inc, North Chicago, Illinois.
Martin
M
Dunbar
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Hagop M
HM
Kantarjian
AbbVie Inc, North Chicago, Illinois.
Rod A
RA
Humerickhouse
AbbVie Inc, North Chicago, Illinois.
Shekman L
SL
Wong
AbbVie Inc, North Chicago, Illinois.
Rajeev M
RM
Menon
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Marina Y
MY
Konopleva
AbbVie Inc, North Chicago, Illinois; Department of Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt. Electronic address: ahmed.salem@abbvie.com.
Ahmed Hamed
AH
Salem
D000284:Administration, Oral; D000328:Adult; D000935:Antifungal Agents / Q000494:pharmacology / Q000627:therapeutic use; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology*
D000935:Antifungal Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D013449:Sulfonamides; D014230:Triazoles; C101425:posaconazole; D051544:Cytochrome P-450 CYP3A; C579720:venetoclax
ABT-199/GDC-0199; BCL-2; CYP3A; pharmacokinetic interaction; posaconazole; venetoclax