Pharmacokinetics and pharmacodynamics of docetaxel with or without ketoconazole modulation in chemonaive breast cancer patients.
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.
Lim
Y-W
YW
Department of Haematology-Oncology, National University Health System.
Goh
B-C
BC
Department of Haematology-Oncology, National University Health System; Experimental Therapeutics Program, Cancer Science Institute.
Wang
L-Z
LZ
Department of Haematology-Oncology, National University Health System.
Tan
S-H
SH
Department of Haematology-Oncology, National University Health System.
Chuah
B Y S
BYS
Department of Haematology-Oncology, National University Health System.
Lim
S-E
SE
Department of Haematology-Oncology, National University Health System.
Iau
P
P
Department of Surgery, National University Health System, Singapore.
Buhari
S A
SA
Department of Surgery, National University Health System, Singapore.
Chan
C-W
CW
Department of Surgery, National University Health System, Singapore.
Sukri
N B
NB
Department of Haematology-Oncology, National University Health System.
Cordero
M T
MT
Department of Haematology-Oncology, National University Health System.
Soo
R
R
Department of Haematology-Oncology, National University Health System.
Lee
S-C
SC
Department of Haematology-Oncology, National University Health System; Experimental Therapeutics Program, Cancer Science Institute. Electronic address: Soo_Chin_Lee@nuhs.edu.sg.
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
D043823:Taxoids; D000077143:Docetaxel; D007654:Ketoconazole