Lack of effect of casopitant on the pharmacokinetics of docetaxel in patients with cancer.
OBJECTIVE
The neurokinin-1 receptor antagonist, casopitant, is a weak-to-moderate inhibitor of cytochrome P450 isoenzyme 3A4 (CYP3A) and has the potential to inhibit the metabolism of CYP3A substrates such as docetaxel.


METHODS
Fourteen cancer patients were enrolled in this phase 1, open-label, randomized, two-period crossover study. Intravenous (i.v.) docetaxel was coadministered with oral ondansetron and dexamethasone with (Regimen B) or without (Regimen A) 150 mg single-dose oral casopitant.


RESULTS
The geometric least-squares mean Regimen B: Regimen A ratios (90% confidence interval) for docetaxel maximum plasma concentration and area under the concentration-time curve from time 0 extrapolated to infinity were 0.97 (0.83, 1.12) and 1.06 (0.94, 1.19), respectively. Coadministration of casopitant and docetaxel was well tolerated, with adverse event profiles and absolute neutrophil count nadirs similar for both treatments.


CONCLUSIONS
C(max) and AUC of docetaxel were similar when given as monotherapy or when given in combination with casopitant. Likewise, absolute neutrophil count nadirs were similar for docetaxel alone or docetaxel with casopitant.
Dandamudi
Uday B
UB
Dartmouth Medical School and The Norris Cotton Cancer Center, Lebanon, NH, USA.
Adams
Laurel M
LM
Johnson
Brendan
B
Bauman
John
J
Morris
Shannon
S
Murray
Sharon
S
Webb
R Timothy
RT
Gartner
Elaina
E
Hohl
Raymond
R
Lewis
Lionel D
LD
D000368:Aged; D000369:Aged, 80 and over; D000932:Antiemetics / Q000009:adverse effects / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D003907:Dexamethasone / Q000494:pharmacology; D000077143:Docetaxel; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D016018:Least-Squares Analysis; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D064729:Neurokinin-1 Receptor Antagonists; D009504:Neutrophils / Q000378:metabolism; D017294:Ondansetron / Q000494:pharmacology; D010879:Piperazines / Q000009:adverse effects / Q000494:pharmacology*; D010880:Piperidines / Q000009:adverse effects / Q000494:pharmacology*; D043823:Taxoids / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014508:Urea
D000932:Antiemetics; D000970:Antineoplastic Agents; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D003907:Dexamethasone; D000077143:Docetaxel; D004791:Enzyme Inhibitors; D064729:Neurokinin-1 Receptor Antagonists; D017294:Ondansetron; D010879:Piperazines; D010880:Piperidines; D043823:Taxoids; C531951:casopitant; D014508:Urea; C510163:CYP3A4 protein, human