Population pharmacokinetics and site of action exposures of veliparib with topotecan plus carboplatin in patients with haematological malignancies.
Veliparib is a potent inhibitor of poly(ADP-ribose) polymerase (PARP) enzyme. The objectives of the analysis were to evaluate the effect of baseline covariates and co-administration of topotecan plus carboplatin (T + C) on pharmacokinetics of veliparib in patients with refractory acute leukaemia, and compare veliparib concentration in various biological matrices.



A population pharmacokinetic model was developed and effect of age, body size indices, sex, creatinine clearance (CrCL) and co-administration of T + C on the pharmacokinetics of veliparib were evaluated. The final model was qualified using bootstrap and quantitative predictive check. Linear regression was conducted to correlate concentrations of veliparib in various biological matrices.



A two compartment model with first-order absorption with Tlagdescribed veliparib pharmacokinetics. The apparent clearance (CL/F) and volume (Vc/F) were 16.5 l h-1and 122.7 l, respectively. The concomitant administration of T + C was not found to affect veliparib CL/F. CrCL and lean body mass (LBM) were significant covariates on CL/F and Vc/F, respectively. While a strong positive relationship was observed between veliparib concentrations in plasma and bone marrow supernatant, no correlation was observed between plasma and peripheral blood or bone marrow blasts.



Consistent with veliparib's physiochemical properties and its elimination mechanism, LBM and CrCL were found to affect pharmacokinetics of veliparib while concomitant administration of T + C did not affect veliparib's CL/F. Plasma concentrations were found to be a reasonable surrogate for veliparib concentrations in peripheral blood and bone marrow supernatant but not blasts. The current model will be utilized to conduct exposure-response analysis to support dosing recommendations.
Center for Translational Medicine, University of Maryland, Baltimore, Maryland.
Shailly
S
Mehrotra
Center for Translational Medicine, University of Maryland, Baltimore, Maryland.
Mathangi
M
Gopalakrishnan
Center for Translational Medicine, University of Maryland, Baltimore, Maryland.
Jogarao
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.
Richard
R
Piekarz
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.|Department of Oncology, Johns Hopkins University, Baltimore, Maryland.
Keith
K
Pratz
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.|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 / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001562:Benzimidazoles / Q000032:analysis / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016190:Carboplatin / Q000493:pharmacokinetics / Q000627:therapeutic use; D054796:Drug Dosage Calculations; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007938:Leukemia / Q000097:blood / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D008954:Models, Biological; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000032:analysis / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019772:Topotecan / Q000493:pharmacokinetics / Q000627:therapeutic use; D055815:Young Adult
D001562:Benzimidazoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib; D019772:Topotecan; D016190:Carboplatin
bone marrow blast; carboplatin; population pharmacokinetics; topotecan; veliparib