Clinical Pharmacokinetic Characteristics of Cebranopadol, a Novel First-in-Class Analgesic

• Published in: Clinical pharmacokinetics 2018-01, Vol.57 (1), p.31-50
• Main Authors: Kleideiter, Elke, Piana, Chiara, Wang, Shaonan, Nemeth, Robert, Gautrois, Michael
• Format: Article
• Language: English
• Subjects: Administration, Oral; Analgesics; Analgesics, Opioid - administration & dosage; Analgesics, Opioid - pharmacokinetics; Bioavailability; Clinical medicine; Clinical trials; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug dosages; Half-Life; Humans; Indoles - administration & dosage; Indoles - pharmacokinetics; Internal Medicine; Mass spectrometry; Medicine; Medicine & Public Health; Models, Biological; Narcotics; Original; Original Research Article; Pain; Peptides; Pharmacokinetics; Pharmacology/Toxicology; Pharmacotherapy; Population; Scientific imaging; Spiro Compounds - administration & dosage; Spiro Compounds - pharmacokinetics
• ISSN: 0312-5963; 1179-1926
• DOI: 10.1007/s40262-017-0545-1

Background and Objectives Cebranopadol is a novel first-in-class analgesic acting as a nociceptin/orphanin FQ peptide and opioid peptide receptor agonist with central analgesic activity. It is currently in clinical development for the treatment of chronic pain conditions. This trial focuses on the clinical pharmacokinetic (PK) properties of cebranopadol after oral single- and multiple-dose administration. Methods The basic PK properties of cebranopadol were assessed by means of noncompartmental methods in six phase I clinical trials in healthy subjects and patients. A population PK analysis included two further phase I and six phase II clinical trials. Results After oral administration of the immediate-release (IR) formulation, cebranopadol is characterized by a late time to reach maximum plasma concentration [ C max ] (4–6 h), a long half-value duration [HVD] (14–15 h), and a terminal phase half-life in the range of 62–96 h. After multiple once-daily dosing in patients, an operational half-life (the dosing interval resulting in an accumulation factor [AF] of 2) of 24 h was found to be the relevant factor to describe the multiple-dose PKs of cebranopadol. The time to reach steady state was approximately 2 weeks, the AF was approximately 2, and peak-trough fluctuation (PTF) was low (70–80%). Dose proportionality at steady state was shown for a broad dose range of cebranopadol 200–1600 µg. A two-compartment disposition model with two lagged transition compartments and a first-order elimination process best describes cebranopadol data in healthy subjects and patients after single- and multiple-dose administration. Conclusions Cebranopadol formulated as an IR product can be used as a once-daily formulation; it reaches C max after only 4–6 h, and has a long HVD and a low PTF. Therefore, from a PK perspective, cebranopadol is an attractive treatment option for patients with chronic pain.