Effect of aprepitant on the pharmacokinetics of the cyclin-dependent kinase inhibitor dinaciclib in patients with advanced malignancies.
OBJECTIVE
Dinaciclib, a selective inhibitor of cyclin-dependent kinase (CDK) 1, CDK2, CDK5, and CDK9, is metabolized via CYP3A4. Aprepitant, a neurokinin-1 receptor antagonist for the prevention of chemotherapy-induced nausea and vomiting, is an inhibitor and inducer of CYP3A4. We conducted a randomized, crossover study to investigate the effects of single oral doses of aprepitant when coadministered with dinaciclib.


METHODS
As part of a phase 1 dose-escalation trial, subjects with advanced malignancies were randomized into a 2-period, multi-cycle, crossover study to investigate the effect of single doses of oral aprepitant on the pharmacokinetics of 29.6 mg/m(2) dinaciclib administered by 2-h intravenous infusion. During cycle 1 and cycle 2, subjects received dinaciclib with aprepitant in one cycle and dinaciclib without aprepitant in the other cycle; aprepitant was administered at a dose of 125 mg orally on day 1 and 80 mg orally on days 2 and 3, along with standard dosing regimens of ondansetron and dexamethasone.


RESULTS
Twelve patients completed the study; T (max) occurred approximately 2 h after the initiation of the infusion. The percent geometric mean ratio (dinaciclib + aprepitant vs. dinaciclib alone) was 106 % (90 % confidence interval [CI] 89-126 %) and 111 % (90 % CI 93-132 %) for dinaciclib C(max) and AUC([I]), respectively. The half-life and clearance of dinaciclib were similar, with or without aprepitant.


CONCLUSIONS
Coadministration of dinaciclib with aprepitant resulted in no clinically significant effect on the pharmacokinetics and did not alter the safety profile of dinaciclib in patients with advanced malignancies.
Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA.
Da
D
Zhang
Monica
M
Mita
Geoffrey I
GI
Shapiro
Jennifer
J
Poon
Karen
K
Small
Anjela
A
Tzontcheva
Bhavna
B
Kantesaria
Yali
Y
Zhu
Rajat
R
Bannerji
Paul
P
Statkevich
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000932:Antiemetics / Q000008:administration & dosage / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000077608:Aprepitant; D019540:Area Under Curve; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D003497:Cyclic N-Oxides; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D003907:Dexamethasone / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005260:Female; D006207:Half-Life; D006801:Humans; D007212:Indolizines; D007262:Infusions, Intravenous; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology*; D009325:Nausea / Q000139:chemically induced / Q000517:prevention & control*; D009369:Neoplasms / Q000188:drug therapy*; D017294:Ondansetron / Q000008:administration & dosage; D011726:Pyridinium Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D017211:Treatment Failure; D014839:Vomiting / Q000139:chemically induced / Q000517:prevention & control*
D000932:Antiemetics; D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003497:Cyclic N-Oxides; D007212:Indolizines; D009025:Morpholines; D011726:Pyridinium Compounds; D000077608:Aprepitant; D017294:Ondansetron; C553669:dinaciclib; D003907:Dexamethasone; D018844:Cyclin-Dependent Kinases