Effects of rifampin, itraconazole and esomeprazole on the pharmacokinetics of alisertib, an investigational aurora a kinase inhibitor in patients with advanced malignancies

Xiaofei Zhou, Shubham Pant, John Nemunaitis, Albert Lockhart, Gerald Falchook, Todd M. Bauer, Manish Patel, John Sarantopoulos, Michael Bargfrede, Andreas Muehler, Lakshmi Rangachari, Bin Zhang, Karthik Venkatakrishnan

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Aim Two studies investigated the effect of gastric acid reducing agents and strong inducers/inhibitors of CYP3A4 on the pharmacokinetics of alisertib, an investigational Aurora A kinase inhibitor, in patients with advanced malignancies. Methods In Study 1, patients received single doses of alisertib (50 mg) in the presence and absence of either esomeprazole (40 mg once daily [QD]) or rifampin (600 mg QD). In Study 2, patients received single doses of alisertib (30 mg) in the presence and absence of itraconazole (200 mg QD). Blood samples for alisertib and 2 major metabolites were collected up to 72 h (Study 1) and 96 h (Study 2) postdose. Area under the curve from time zero extrapolated to infinity (AUC0-inf) and maximum concentrations (Cmax) were calculated and compared using analysis of variance to estimate least squares (LS) mean ratios and 90% confidence intervals (CIs). Results The LS mean ratios (90% CIs) for alisertib AUC0-inf and Cmax in the presence compared to the absence of esomeprazole were 1.28 (1.07, 1.53) and 1.14 (0.97, 1.35), respectively. The LS mean ratios (90% CIs) for alisertib AUC0-inf and Cmax in the presence compared to the absence of rifampin were 0.53 (0.41, 0.70) and 1.03 (0.84, 1.26), respectively. The LS mean ratios (90% CIs) for alisertib AUC0-inf and Cmax in the presence compared to the absence of itraconazole were 1.39 (0.99, 1.95) and 0.98 (0.82, 1.19), respectively. Conclusions The use of gastric acid reducing agents, strong CYP3A inhibitors or strong metabolic enzyme inducers should be avoided in patients receiving alisertib.

Original languageEnglish (US)
Pages (from-to)248-258
Number of pages11
JournalInvestigational New Drugs
Volume36
Issue number2
DOIs
StatePublished - Apr 1 2018
Externally publishedYes

Fingerprint

Aurora Kinases
Esomeprazole
Itraconazole
Rifampin
Pharmacokinetics
Least-Squares Analysis
Neoplasms
Confidence Intervals
Gastric Acid
Reducing Agents
Aurora Kinase A
MLN 8237
Area Under Curve
Analysis of Variance

Keywords

  • Alisertib
  • Aurora A kinase
  • CYP3A4
  • Drug-drug interactions
  • Induction
  • Inhibition

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

Cite this

Effects of rifampin, itraconazole and esomeprazole on the pharmacokinetics of alisertib, an investigational aurora a kinase inhibitor in patients with advanced malignancies. / Zhou, Xiaofei; Pant, Shubham; Nemunaitis, John; Lockhart, Albert; Falchook, Gerald; Bauer, Todd M.; Patel, Manish; Sarantopoulos, John; Bargfrede, Michael; Muehler, Andreas; Rangachari, Lakshmi; Zhang, Bin; Venkatakrishnan, Karthik.

In: Investigational New Drugs, Vol. 36, No. 2, 01.04.2018, p. 248-258.

Research output: Contribution to journalArticle

Zhou, X, Pant, S, Nemunaitis, J, Lockhart, A, Falchook, G, Bauer, TM, Patel, M, Sarantopoulos, J, Bargfrede, M, Muehler, A, Rangachari, L, Zhang, B & Venkatakrishnan, K 2018, 'Effects of rifampin, itraconazole and esomeprazole on the pharmacokinetics of alisertib, an investigational aurora a kinase inhibitor in patients with advanced malignancies', Investigational New Drugs, vol. 36, no. 2, pp. 248-258. https://doi.org/10.1007/s10637-017-0499-z
Zhou, Xiaofei ; Pant, Shubham ; Nemunaitis, John ; Lockhart, Albert ; Falchook, Gerald ; Bauer, Todd M. ; Patel, Manish ; Sarantopoulos, John ; Bargfrede, Michael ; Muehler, Andreas ; Rangachari, Lakshmi ; Zhang, Bin ; Venkatakrishnan, Karthik. / Effects of rifampin, itraconazole and esomeprazole on the pharmacokinetics of alisertib, an investigational aurora a kinase inhibitor in patients with advanced malignancies. In: Investigational New Drugs. 2018 ; Vol. 36, No. 2. pp. 248-258.
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abstract = "Aim Two studies investigated the effect of gastric acid reducing agents and strong inducers/inhibitors of CYP3A4 on the pharmacokinetics of alisertib, an investigational Aurora A kinase inhibitor, in patients with advanced malignancies. Methods In Study 1, patients received single doses of alisertib (50 mg) in the presence and absence of either esomeprazole (40 mg once daily [QD]) or rifampin (600 mg QD). In Study 2, patients received single doses of alisertib (30 mg) in the presence and absence of itraconazole (200 mg QD). Blood samples for alisertib and 2 major metabolites were collected up to 72 h (Study 1) and 96 h (Study 2) postdose. Area under the curve from time zero extrapolated to infinity (AUC0-inf) and maximum concentrations (Cmax) were calculated and compared using analysis of variance to estimate least squares (LS) mean ratios and 90{\%} confidence intervals (CIs). Results The LS mean ratios (90{\%} CIs) for alisertib AUC0-inf and Cmax in the presence compared to the absence of esomeprazole were 1.28 (1.07, 1.53) and 1.14 (0.97, 1.35), respectively. The LS mean ratios (90{\%} CIs) for alisertib AUC0-inf and Cmax in the presence compared to the absence of rifampin were 0.53 (0.41, 0.70) and 1.03 (0.84, 1.26), respectively. The LS mean ratios (90{\%} CIs) for alisertib AUC0-inf and Cmax in the presence compared to the absence of itraconazole were 1.39 (0.99, 1.95) and 0.98 (0.82, 1.19), respectively. Conclusions The use of gastric acid reducing agents, strong CYP3A inhibitors or strong metabolic enzyme inducers should be avoided in patients receiving alisertib.",
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T1 - Effects of rifampin, itraconazole and esomeprazole on the pharmacokinetics of alisertib, an investigational aurora a kinase inhibitor in patients with advanced malignancies

AU - Zhou, Xiaofei

AU - Pant, Shubham

AU - Nemunaitis, John

AU - Lockhart, Albert

AU - Falchook, Gerald

AU - Bauer, Todd M.

AU - Patel, Manish

AU - Sarantopoulos, John

AU - Bargfrede, Michael

AU - Muehler, Andreas

AU - Rangachari, Lakshmi

AU - Zhang, Bin

AU - Venkatakrishnan, Karthik

PY - 2018/4/1

Y1 - 2018/4/1

N2 - Aim Two studies investigated the effect of gastric acid reducing agents and strong inducers/inhibitors of CYP3A4 on the pharmacokinetics of alisertib, an investigational Aurora A kinase inhibitor, in patients with advanced malignancies. Methods In Study 1, patients received single doses of alisertib (50 mg) in the presence and absence of either esomeprazole (40 mg once daily [QD]) or rifampin (600 mg QD). In Study 2, patients received single doses of alisertib (30 mg) in the presence and absence of itraconazole (200 mg QD). Blood samples for alisertib and 2 major metabolites were collected up to 72 h (Study 1) and 96 h (Study 2) postdose. Area under the curve from time zero extrapolated to infinity (AUC0-inf) and maximum concentrations (Cmax) were calculated and compared using analysis of variance to estimate least squares (LS) mean ratios and 90% confidence intervals (CIs). Results The LS mean ratios (90% CIs) for alisertib AUC0-inf and Cmax in the presence compared to the absence of esomeprazole were 1.28 (1.07, 1.53) and 1.14 (0.97, 1.35), respectively. The LS mean ratios (90% CIs) for alisertib AUC0-inf and Cmax in the presence compared to the absence of rifampin were 0.53 (0.41, 0.70) and 1.03 (0.84, 1.26), respectively. The LS mean ratios (90% CIs) for alisertib AUC0-inf and Cmax in the presence compared to the absence of itraconazole were 1.39 (0.99, 1.95) and 0.98 (0.82, 1.19), respectively. Conclusions The use of gastric acid reducing agents, strong CYP3A inhibitors or strong metabolic enzyme inducers should be avoided in patients receiving alisertib.

AB - Aim Two studies investigated the effect of gastric acid reducing agents and strong inducers/inhibitors of CYP3A4 on the pharmacokinetics of alisertib, an investigational Aurora A kinase inhibitor, in patients with advanced malignancies. Methods In Study 1, patients received single doses of alisertib (50 mg) in the presence and absence of either esomeprazole (40 mg once daily [QD]) or rifampin (600 mg QD). In Study 2, patients received single doses of alisertib (30 mg) in the presence and absence of itraconazole (200 mg QD). Blood samples for alisertib and 2 major metabolites were collected up to 72 h (Study 1) and 96 h (Study 2) postdose. Area under the curve from time zero extrapolated to infinity (AUC0-inf) and maximum concentrations (Cmax) were calculated and compared using analysis of variance to estimate least squares (LS) mean ratios and 90% confidence intervals (CIs). Results The LS mean ratios (90% CIs) for alisertib AUC0-inf and Cmax in the presence compared to the absence of esomeprazole were 1.28 (1.07, 1.53) and 1.14 (0.97, 1.35), respectively. The LS mean ratios (90% CIs) for alisertib AUC0-inf and Cmax in the presence compared to the absence of rifampin were 0.53 (0.41, 0.70) and 1.03 (0.84, 1.26), respectively. The LS mean ratios (90% CIs) for alisertib AUC0-inf and Cmax in the presence compared to the absence of itraconazole were 1.39 (0.99, 1.95) and 0.98 (0.82, 1.19), respectively. Conclusions The use of gastric acid reducing agents, strong CYP3A inhibitors or strong metabolic enzyme inducers should be avoided in patients receiving alisertib.

KW - Alisertib

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KW - CYP3A4

KW - Drug-drug interactions

KW - Induction

KW - Inhibition

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