2490 - Gender effect on the pharmacokinetics (PK) and pharmacodynamics (PD) of anamorelin (ANAM) in healthy volunteers and cancer patients with cachexia

Background

ANAM, an oral selective ghrelin receptor agonist, showed benefits for patients with advanced non-small cell lung cancer (NSCLC) and anorexia/cachexia. A clinical trial assessing possible gender effects on ANAM PK/PD in healthy volunteers following a single 25-mg oral ANAM dose reported no significant differences in PK/PD responses (Leese et al, Clin Pharmacol Drug Dev 2015). Given the interest in possible gender effects in cachexia, the effect of gender on ANAM PK/PD in healthy volunteers and NSCLC patients with cachexia receiving the 100-mg ANAM dose intended for therapeutic use was assessed.

Methods

In a phase 1 clinical trial, healthy volunteers received a single ANAM dose and the PK profile was evaluated by non-compartmental methods. Cachectic NSCLC patients from the phase 3 trial ROMANA 1 (NCT01387269) received ANAM once daily up to 12 weeks. Sparse blood samples were collected at steady state from 70 patients consenting to population PK modeling, along with ANAM PK data from phase 1 and 2 studies in healthy subjects and patients. Correlations between gender and predicted individual ANAM PK parameters in patients at steady state were assessed by analysis of variance models. In a separate phase II trial, serum insulin-like growth factor 1 (IGF-1) and insulin-like growth factor-binding protein 3 (IGFBP-3) levels were assessed in NSCLC male and female outpatients receiving ANAM up to 14 weeks.

Results

In healthy volunteers, after dose normalization per body weight, the PK parameters of males and females were similar (Table). In patients with cachexia, no significant correlations were found between gender and predicted ANAM PK parameters at steady state (Table). No gender differences were observed in IGF-1 and IGFBP-3 serum levels.Table:

1784P Gender effect on the main PK parameters of ANAM after single administration in healthy volunteers and at steady state in NSCLC patients with cachexia

ANAM: anamorelin; AUC_0-24,ss: area under the concentration-time curve from time zero to 24 hours at steady state; AUC_inf: area under the concentration-time curve from time zero to infinity; AUC_inf/dose: area under the concentration-time curve from time zero to infinity normalized for the dose-per-kg body weight; CI: confidence interval; CL/F: clearance; C_max: maximum plasma concentration; C_max/dose: maximum plasma concentration normalized for the dose-per-kg body weight; C_max,ss: steady-state maximum plasma concentration; LS: least squares; NSCLC: non-small cell lung cancer; PK: pharmacokinetic; t_1/2,z: elimination half-life; t_max: time to maximum plasma concentration; SD: standard deviation; Vz/F: volume of distribution.

Conclusions

No significant gender effect on ANAM PK/PD was observed in healthy volunteers and NSCLC patients with cachexia at 100 mg ANAM, intended for therapeutic use.

Clinical trial identification

ROMANA 3: NCT01387269.

Editorial acknowledgement

Oana Draghiciu, PhD, CMPP, from Aptitude Health, The Hague, The Netherlands; funded by Helsinn Healthcare SA.

Legal entity responsible for the study

Helsinn Healthcare SA.

Funding

Helsinn Healthcare SA.

Disclosure

S. Kaasa: Shareholder / Stockholder /Stock options: Eir Solution, Research grant / Funding: Nutricia, Research grant / Funding: Recipient, Honoraria: Fresenius Kabi, Honoraria: Nutricia. J.M. Garcia: Research grant / Funding: Helsinn Healthcare SA. A. Bernareggi: Full / Part-time employment: Helsinn Healthcare SA.