Exposure-Response Analysis of Alvocidib (Flavopiridol) Treatment by Bolus or Hybrid Administration in Newly Diagnosed or Relapsed/Refractory Acute Leukemia Patients.
Purpose:To elucidate any differences in the exposure-response of alvocidib (flavopiridol) given by 1-hour bolus or a hybrid schedule (30-minute bolus followed by a 4-hour infusion) using a flavopiridol/cytosine arabinoside/mitoxantrone sequential protocol (FLAM) in patients with acute leukemia. The hybrid schedule was devised to be pharmacologically superior in chronic leukemia based on unbound exposure.Experimental Design:Data from 129 patients in three FLAM studies were used for pharmacokinetic/pharmacodynamic modeling. Newly diagnosed (62%) or relapsed/refractory (38%) patients were treated by bolus (43%) or hybrid schedule (57%). Total and unbound flavopiridol concentrations were fit using nonlinear mixed-effect population pharmacokinetic methodologies. Exposure-response relationships using unbound flavopiridol AUC were explored using recursive partitioning.Results:Flavopiridol pharmacokinetic parameters were estimated using a two-compartment model. No pharmacokinetic covariates were identified. Flavopiridol fraction unbound was 10.9% and not different between schedules. Partitioning found no association between dosing schedule and clinical response. Clinical response was associated with AUC ≥ 780 h*ng/mL for newly diagnosed patients and AUC ≥ 1,690 h*ng/mL for relapsed/refractory patients. Higher exposures were not associated with increases in severe adverse events (≥ grade 3).Conclusions:Pharmacokinetic modeling showed no difference in flavopiridol plasma protein binding for bolus versus hybrid dosing. Further trials in newly diagnosed patients with acute leukemia should utilize the bolus FLAM regimen at the MTD of 50 mg/m2/day. Trials in relapsed/refractory patients should use the hybrid dosing schedule at the MTD (30/60 mg/m2/day) to achieve the higher exposures required for maximal efficacy in this population.Clin Cancer Res; 23(14); 3592-600. ©2017 AACR.
Center for Translational Medicine, University of Maryland, Baltimore, Maryland.
Carl
C
LaCerte
Center for Translational Medicine, University of Maryland, Baltimore, Maryland. mrudek2@jhmi.edu vivaturi@rx.umaryland.edu.
Vijay
V
Ivaturi
Center for Translational Medicine, University of Maryland, Baltimore, Maryland.
Joga
J
Gobburu
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.
Jacqueline M
JM
Greer
Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland.
L Austin
LA
Doyle
Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland.
John J
JJ
Wright
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.|Department of Oncology, Johns Hopkins University, Baltimore, Maryland.
Judith E
JE
Karp
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland. mrudek2@jhmi.edu vivaturi@rx.umaryland.edu.|Department of Oncology, Johns Hopkins University, Baltimore, Maryland.|Department of Medicine, Division of Clinical Pharmacology, Johns Hopkins University, Baltimore, Maryland.
Michelle A
MA
Rudek
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D054316:Biomarkers, Pharmacological / Q000097:blood; D003561:Cytarabine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D005260:Female; D005419:Flavonoids / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D008942:Mitoxantrone / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D010880:Piperidines / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics
D054316:Biomarkers, Pharmacological; D005419:Flavonoids; D010880:Piperidines; D003561:Cytarabine; C077990:alvocidib; D008942:Mitoxantrone; D014740:Vidarabine