title: Population pharmacokinetics of Daunorubicin in adult patients with acute myeloid leukemia.
abstract: OBJECTIVE
  Chemotherapy drug resistance and relapse of the disease have been the major factors limiting the success of acute myeloid leukemia (AML) therapy. Several factors, including the pharmacokinetics (PK) of Cytarabine (Ara-C) and Daunorubicin (Dnr), could contribute to difference in treatment outcome in AML.
  
  
  METHODS
  In the present study, we evaluated the plasma PK of Dnr, the influence of genetic polymorphisms of genes involved in transport and metabolism of Dnr on the PK, and also the influence of these factors on clinical outcome. Plasma levels of Dnr and its major metabolite, Daunorubicinol (DOL), were available in 70 adult de novo AML patients. PK parameters (Area under curve (AUC) and clearance (CL)) of Dnr and DOL were calculated using nonlinear mixed-effects modeling analysis performed with Monolix. Genetic variants in ABCB1, ABCG2, CBR1, and CBR3 genes as well as RNA expression of CBR1, ABCB1, and ABCG2 were compared with Dnr PK parameters.
  
  
  RESULTS
  The AUC and CL of Dnr and DOL showed wide inter-individual variation. Patients with an exon1 variant of rs25678 in CBR1 had significantly higher plasma Dnr AUC [p = 0.05] compared to patients with wild type. Patients who achieved complete remission (CR) had significantly lower plasma Dnr AUC, Cmax, and higher CL compared to patients who did not achieve CR.
  
  
  CONCLUSIONS
  Further validation of these findings in a larger cohort of AML patients is warranted before establishing a therapeutic window for plasma Dnr levels and targeted dose adjustment.
authors.affiliation: Department of Haematology, Christian Medical College, Vellore, Tamilnadu, 632004, India.
authors.forename: Savitha
authors.initials: S
authors.lastname: Varatharajan
authors.affiliation: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Panetta
authors.affiliation: Department of Haematology, Christian Medical College, Vellore, Tamilnadu, 632004, India.
authors.forename: Ajay
authors.initials: A
authors.lastname: Abraham
authors.affiliation: Department of Haematology, Christian Medical College, Vellore, Tamilnadu, 632004, India.
authors.forename: Sreeja
authors.initials: S
authors.lastname: Karathedath
authors.affiliation: Department of Haematology, Christian Medical College, Vellore, Tamilnadu, 632004, India.
authors.forename: Ezhilpavai
authors.initials: E
authors.lastname: Mohanan
authors.affiliation: Department of Haematology, Christian Medical College, Vellore, Tamilnadu, 632004, India.
authors.forename: Kavitha M
authors.initials: KM
authors.lastname: Lakshmi
authors.affiliation: Department of Haematology, Christian Medical College, Vellore, Tamilnadu, 632004, India.
authors.forename: Nancy
authors.initials: N
authors.lastname: Arthur
authors.affiliation: Cytogenetics Unit, Christian Medical College, Vellore, Tamilnadu, 632004, India.
authors.forename: Vivi M
authors.initials: VM
authors.lastname: Srivastava
authors.affiliation: Department of Haematology, Christian Medical College, Vellore, Tamilnadu, 632004, India.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Nemani
authors.affiliation: Department of Haematology, Christian Medical College, Vellore, Tamilnadu, 632004, India.
authors.forename: Biju
authors.initials: B
authors.lastname: George
authors.affiliation: Department of Haematology, Christian Medical College, Vellore, Tamilnadu, 632004, India.
authors.forename: Alok
authors.initials: A
authors.lastname: Srivastava
authors.affiliation: Department of Haematology, Christian Medical College, Vellore, Tamilnadu, 632004, India.
authors.forename: Vikram
authors.initials: V
authors.lastname: Mathews
authors.affiliation: Department of Haematology, Christian Medical College, Vellore, Tamilnadu, 632004, India. bpoonkuzhali@cmcvellore.ac.in.
authors.forename: Poonkuzhali
authors.initials: P
authors.lastname: Balasubramanian
mesh_terms: D000293:Adolescent; D000328:Adult; D000429:Alcohol Oxidoreductases / Q000235:genetics; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001711:Biotransformation; D003630:Daunorubicin / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004347:Drug Interactions; D005260:Female; D014644:Genetic Variation; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic / Q000235:genetics; D011446:Prospective Studies; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000903:Antibiotics, Antineoplastic; D000429:Alcohol Oxidoreductases; C531129:CBR1 protein, human; C000847:daunorubicinol; D003630:Daunorubicin
keywords: Acute myeloid leukemia; Daunorubicin; Genetic factors; Pharmacokinetics