The effect of ketoconazole on the pharmacokinetics and pharmacodynamics of ixabepilone: a first in class epothilone B analogue in late-phase clinical development.
OBJECTIVE
To determine if ixabepilone is a substrate for cytochrome P450 3A4 (CYP3A4) and if its metabolism by this cytochrome is clinically important, we did a clinical drug interaction study in humans using ketoconazole as an inhibitor of CYP3A4.


METHODS
Human microsomes were used to determine the cytochrome P450 enzyme(s) involved in the metabolism of ixabepilone. Computational docking (CYP3A4) studies were done for epothilone B and ixabepilone. A follow-up clinical study was done in patients with cancer to determine if 400 mg/d ketoconazole (inhibitor of CYP3A4) altered the pharmacokinetics, drug-target interactions, and pharmacodynamics of ixabepilone.


RESULTS
Molecular modeling and human microsomal studies predicted ixabepilone to be a good substrate for CYP3A4. In patients, ketoconazole coadministration resulted in a maximum ixabepilone dose administration to 25 mg/m(2) when compared with single-agent therapy of 40 mg/m(2). Coadministration of ketoconazole with ixabepilone resulted in a 79% increase in AUC(0-infinity). The relationship of microtubule bundle formation in peripheral blood mononuclear cells to plasma ixabepilone concentration was well described by the Hill equation. Microtubule bundle formation in peripheral blood mononuclear cells correlated with neutropenia.


CONCLUSIONS
Ixabepilone is a good CYP3A4 substrate in vitro; however, in humans, it is likely to be cleared by multiple mechanisms. Furthermore, our results provide evidence that there is a direct relationship between ixabepilone pharmacokinetics, neutrophil counts, and microtubule bundle formation in PBMCs. Strong inhibitors of CYP3A4 should be used cautiously in the context of ixabepilone dosing.
Goel
Sanjay
S
Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Cohen
Marvin
M
Cömezoglu
S Nilgün
SN
Perrin
Lionel
L
André
François
F
Jayabalan
David
D
Iacono
Lisa
L
Comprelli
Adriana
A
Ly
Van T
VT
Zhang
Donglu
D
Xu
Carrie
C
Humphreys
W Griffith
WG
McDaid
Hayley
H
Goldberg
Gary
G
Horwitz
Susan B
SB
Mani
Sridhar
S
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D019295:Computational Biology; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors; D034261:Epothilones / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D005260:Female; D005833:Genital Neoplasms, Female / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D050257:Tubulin Modulators / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology
D000970:Antineoplastic Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D034261:Epothilones; D050257:Tubulin Modulators; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C430592:ixabepilone; D007654:Ketoconazole