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11.12.2018 | Original Article | Ausgabe 3/2019

Cancer Chemotherapy and Pharmacology 3/2019

Evaluation of the effects of an oral notch inhibitor, crenigacestat (LY3039478), on QT interval, and bioavailability studies conducted in healthy subjects

Zeitschrift:
Cancer Chemotherapy and Pharmacology > Ausgabe 3/2019
Autoren:
Eunice Yuen, Maria Posada, Claire Smith, Katharine Thorn, Dale Greenwood, Michelle Burgess, Karim A. Benhadji, Demetrio Ortega, Louise Chinchen, Jeffrey Suico
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1007/​s00280-018-3750-1) contains supplementary material, which is available to authorized users.

Abstract

Purpose

Crenigacestat (LY3039478) is a Notch inhibitor currently being investigated in advanced cancer patients. Conducting clinical pharmacology studies in healthy subjects avoids nonbeneficial drug exposures in cancer patients and mitigates confounding effects of disease state and concomitant medications.

Methods

Three studies were conducted in healthy subjects, assessing safety, pharmacokinetics, effect on QT interval, and relative and absolute bioavailability of crenigacestat. Crenigacestat was administered as single 25, 50, or 75 mg oral doses or as an intravenous dose of 350 µg 13C15N2H-crenigacestat. Electrocardiogram measurements, and plasma and urine samples were collected up to 48 h postdose, and safety assessments were conducted up to 14 days postdose.

Results and conclusions

Exposures were dose proportional in the 25 to 75 mg dose range and mean elimination half-life was approximately 5–6 h. The exposure achieved from the new formulated capsule was approximately 30% and 20% higher for area under the plasma concentration time curve from time zero to infinity [AUC(0–∞)] and maximum plasma concentration (Cmax), respectively, compared to the reference drug in capsule formulation. The geometric least-squares mean [90% confidence interval (CI)] absolute bioavailability of crenigacestat was 0.572 (0.532, 0.615). The regression slope (90% CI) of placebo-adjusted QTcF against crenigacestat plasma concentration was − 0.001 (− 0.006, 0.003), suggesting no significant linear association. Thirty-nine subjects completed the studies and the majority of adverse events were mild. Single oral doses of 25 to 75 mg crenigacestat and an IV dose of 350 µg 13C15N2H-crenigacestat were well tolerated in healthy subjects.

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Zusatzmaterial
Supplementary material 1 (DOCX 174 KB)
280_2018_3750_MOESM1_ESM.docx
Literatur
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