title: Pharmacokinetics and pharmacodynamics of docetaxel with or without ketoconazole modulation in chemonaive breast cancer patients.
abstract: BACKGROUND
  We previously found 70 mg flat-dose docetaxel coadministered with ketoconazole to modulate CYP3A4 to be the maximum tolerated dose that resulted in comparable docetaxel area under the plasma concentration-time curve (AUC) as 75-100 mg/m² docetaxel.
  
  
  METHODS
  We compared cycle 1 docetaxel pharmacokinetics and pharmacodynamics between ketoconazole-modulated (70 mg flat-dose docetaxel, n = 31) and conventional-dosed docetaxel (75 mg/m², n = 51) in chemonaive breast cancer patients in two sequential phase II studies.
  
  
  RESULTS
  Ketoconazole-modulated docetaxel resulted in reduced docetaxel clearance (22.05 ± 8.29 versus 36.52 ± 13.39 l/h, P < 0.001), similar docetaxel AUC (3.93 ± 2.77 versus 3.77 ± 2.70 mg/l·h, P = 0.794) and tumor efficacy (cycle 1 responder 52% versus 55%) and less day 8 neutrophil suppression (1.24 ± 1.02 × 10⁹/l versus 0.47 ± 0.56 × 10⁹/l, P < 0.001), grade 4 neutropenia (32.3% versus 72.0%, P < 0.001) and febrile neutropenia (3.2 versus 23.5%, P = 0.015), compared with conventional-dosed docetaxel. Chinese had the lowest docetaxel clearance, highest AUC and most myelosuppression, followed by Malays and Indians, in response to ketoconazole-modulated docetaxel, while no significant interethnic differences were observed with conventional-dosed docetaxel.
  
  
  CONCLUSIONS
  Ketoconazole-modulated docetaxel achieved similar docetaxel AUC and tumor efficacy but reduced neutrophil suppression and febrile neutropenia at ∼40% reduced dose, representing a feasible alternative to conventional-dosed docetaxel. Interethnic differences in CYP3A4 inhibition by ketoconazole exist and are important when evaluating the impact of concomitant medications.
authors.affiliation: Department of Haematology-Oncology, National University Health System.
authors.forename: Y-W
authors.initials: YW
authors.lastname: Lim
authors.affiliation: Department of Haematology-Oncology, National University Health System; Experimental Therapeutics Program, Cancer Science Institute.
authors.forename: B-C
authors.initials: BC
authors.lastname: Goh
authors.affiliation: Department of Haematology-Oncology, National University Health System.
authors.forename: L-Z
authors.initials: LZ
authors.lastname: Wang
authors.affiliation: Department of Haematology-Oncology, National University Health System.
authors.forename: S-H
authors.initials: SH
authors.lastname: Tan
authors.affiliation: Department of Haematology-Oncology, National University Health System.
authors.forename: B Y S
authors.initials: BYS
authors.lastname: Chuah
authors.affiliation: Department of Haematology-Oncology, National University Health System.
authors.forename: S-E
authors.initials: SE
authors.lastname: Lim
authors.affiliation: Department of Surgery, National University Health System, Singapore.
authors.forename: P
authors.initials: P
authors.lastname: Iau
authors.affiliation: Department of Surgery, National University Health System, Singapore.
authors.forename: S A
authors.initials: SA
authors.lastname: Buhari
authors.affiliation: Department of Surgery, National University Health System, Singapore.
authors.forename: C-W
authors.initials: CW
authors.lastname: Chan
authors.affiliation: Department of Haematology-Oncology, National University Health System.
authors.forename: N B
authors.initials: NB
authors.lastname: Sukri
authors.affiliation: Department of Haematology-Oncology, National University Health System.
authors.forename: M T
authors.initials: MT
authors.lastname: Cordero
authors.affiliation: Department of Haematology-Oncology, National University Health System.
authors.forename: R
authors.initials: R
authors.lastname: Soo
authors.affiliation: Department of Haematology-Oncology, National University Health System; Experimental Therapeutics Program, Cancer Science Institute. Electronic address: Soo_Chin_Lee@nuhs.edu.sg.
authors.forename: S-C
authors.initials: SC
authors.lastname: Lee
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D000077143:Docetaxel; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage; D020714:Maximum Tolerated Dose; D009367:Neoplasm Staging; D015996:Survival Rate; D043823:Taxoids / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D043823:Taxoids; D000077143:Docetaxel; D007654:Ketoconazole