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Jun 21, 2018

MASCC/ISOO Annual Meeting on Supportive Care in Cancer

09 / EFFECTS OF STRONG CYTOCHROME P450 (CYP)3A4 AND CYP2D6 INDUCERS AND INHIBITORS ON THE PHARMACOKINETIC (PK) PROFILE OF ANAMORELIN IN HEALTHY VOLUNTEERS

;

Bernareggi, A.;

Matson, M.A.;

Duus, E.

Abstract

Abstract

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Keywords

Abstract

EFFECTS OF STRONG CYTOCHROME P450 (CYP)3A4 AND CYP2D6 INDUCERS AND INHIBITORS ON THE PHARMACOKINETIC (PK) PROFILE OF ANAMORELIN IN HEALTHY VOLUNTEERS Authors: Alberto Bernareggi1, Mark Matson2, Elizabeth Duus3 1Helsinn Healthcare SA, Lugano, Switzerland 2Prism Clinical Research, St. Paul, MN, USA 3Helsinn Therapeutics (US), Inc., Iselin, NJ, USA Abstract Submission Deadline: Feb 9th, 2018 Title word count: 21 of 25 words maximum (required in uppercase) Abstract word count: 221 of 250 (excluding title; excluding authors and affiliations) Tables/Images: 1 of 3 (maximum size 500 KB) Topic: Palliative care and end-stage disease Keywords (minimally 1, maximally 6 key words): anamorelin, CYP3A4, CYP2D6, drug-drug interactions Introduction The oral selective ghrelin receptor agonist anamorelin, which is currently in development, improved body weight, body composition parameters, and symptom burden in patients with advanced non-small cell lung cancer and anorexia/cachexia (ROMANA studies; Temel J. Lancet Oncol. 2016; Currow D. Ann Oncol. 2017). Anamorelin is metabolized by the liver, predominantly by CYP3A4 and marginally by CYP2D6. Strong CYP3A4/CYP2D6 inducers and inhibitors might alter its PK profile. Objectives The effects of the CYP3A4 inhibitor ketoconazole, the CYP3A4 inducer rifampin, and the CYP2D6 inhibitor paroxetine on the PK profile of anamorelin were evaluated in two phase I clinical trials in healthy volunteers. Methods Healthy volunteers received anamorelin orally, alone or in combination with oral ketoconazole, rifampin, or paroxetine (Table). Serial blood samples were collected in both studies to assess the PK parameters of anamorelin. Results Concomitant ketoconazole administration significantly increased anamorelin maximum plasma concentration (Cmax) 3.1-fold and exposure (AUC0-) 3.2-fold (Table). Concomitant rifampin administration significantly decreased anamorelin Cmax 2.2-fold and AUC0- 3.1-fold (Table). Concomitant paroxetine administration significantly increased anamorelin Cmax by 28%, while anamorelin AUC0- was 15% lower post-paroxetine, but this unexpected decrease was not significant (Table). Conclusions Concomitant administration of anamorelin should be approached with caution with strong CYP3A4 inhibitors and inducers because it may affect the PK profile of anamorelin. No restrictions regarding concomitant use of CYP2D6 inhibitors are needed. PK parameter (anamorelin) CYP3A4 CYP2D6 CYP3A4 inhibitor (ketoconazole) CYP3A4 inducer (rifampin) CYP2D6 inhibitor (paroxetine) Study 1 (N=12) (ANAM 25 mg alone or with ketoconazole 200 mg every 12 hours for 3 doses) Study 2 (N=16) (ANAM 100 mg alone or with rifampin 600 mg QD for 7 days or paroxetine 20 mg QD for 11 days) Mean Cmax (SD), ng/mL 118 (114) vs 368 (120) (p≤0.001) 1006 (340) vs 454 (209) (p<0.001) 796 (353) vs 1017 (514) (p=0.003) Mean tmax (SD), hours 1.53 (0.70) vs 0.64 (0.22) (p≤0.01) 1.02 (0.71) vs 0.86 (0.50) (p=0.663) 0.83 (0.62) vs 0.72 (0.43) (p=0.400) Mean AUC0- (SD), ng*hr/mL 261 (127) vs 840 (193) (p≤0.001) 2391 (1019) vs 779.0 (435) (p<0.001) 2087 (1271) vs 1780 (1033) (p=0.072) ANAM, anamorelin; AUC0-, area under the plasma concentration-time curve from time 0 to infinity; Cmax, maximum drug plasma concentration; CYP, cytochrome P450; PK, pharmacokinetic; QD, once daily; tmax, time necessary to reach Cmax; SD, standard deviation. Disclosures: E. Duus: employee of Helsinn Therapeutics (US), Inc. M. A. Matson: employee of Prism Research LLC. A. Bernareggi: employee of Helsinn Healthcare SA.

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All rights reserved.