PMID- 36469250 OWN - NLM STAT- MEDLINE DCOM- 20230110 LR - 20230111 IS - 2107-0180 (Electronic) IS - 0378-7966 (Linking) VI - 48 IP - 1 DP - 2023 Jan TI - Preclinical and Clinical Pharmacokinetics and Bioavailability in Healthy Volunteers of a Novel Formulation of the Selective P2X3 Receptor Antagonist Eliapixant. PG - 75-87 LID - 10.1007/s13318-022-00805-5 [doi] AB - BACKGROUND AND OBJECTIVES: The potent, selective P2X3 receptor antagonist eliapixant (BAY 1817080) is under development for conditions characterized by neuronal hypersensitization. As prominent food effects and limited bioavailability in the fasted state were observed with immediate-release eliapixant tablets, a novel formulation was needed. Accordingly, several novel eliapixant formulations were assessed by in vitro and animal studies in a structured way. The most promising of the formulations was then investigated in a phase I study designed to assess its pharmacokinetics, food effect, and bioavailability in healthy volunteers. METHODS: In vitro non-sink dissolution tests were performed with two amorphous solid dispersion (ASD) granule prototypes compared with pure crystalline eliapixant as a surrogate for the immediate-release formulation. Subsequently, the drug exposure of novel eliapixant formulations under fed and fasted conditions in rats and dogs was assessed to confirm improvements in bioavailability versus the suspension-based formulation. A novel Kollidon VA64(R)-based eliapixant formulation was identified from the preclinical studies and compared with the original tablet formulation in an open-label, partially randomized, threefold, crossover phase I study, in which healthy males received single oral doses (25-400 mg, fasted/fed). Pharmacokinetic parameters, absolute bioavailability (using an intravenous [(13)C(7)(15)N]-eliapixant microdose), relative bioavailability (novel versus original formulation), effect of food, and adverse events (AEs) were evaluated. RESULTS: The non-sink dissolution test demonstrated that the two ASD formulations had an improved dissolution rate compared with pure crystalline eliapixant, with a Kollidon VA64-based prototype having the highest dissolution rate. Further testing of this prototype in animal studies confirmed an approximately twofold higher bioavailability compared with the suspension-based formulation. In the phase I study, 30 subjects were randomized. With the novel Kollidon VA64(R) formulation (400 mg; fasted), area under the concentration-time curve (AUC) and maximum plasma concentration (C(max)) were up to 3.1-fold and 1.7-fold higher, respectively, than with the original formulation (fed). AUC increased dose proportionally between 25 and 100 mg, and less than dose proportionally from 100 to 400 mg. Food had no clinically relevant effect on the novel formulation, with AUC increasing 1.3-fold and C(max) 2.1-2.4-fold (time to maximum concentration was delayed by 1.5-2.25 h). Absolute bioavailability with the novel formulation (100 mg) was 50%. AEs occurred in 57% of patients; most were mild in severity. CONCLUSIONS: The novel eliapixant formulation substantially improved bioavailability compared with immediate-release eliapixant and may be administered with/without food. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov: NCT03773068 (initial registration: 12 December 2018). CI - (c) 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG. FAU - Francke, Klaus AU - Francke K AD - Bayer AG Research and Development, Pharmaceuticals, Clinical Pharmacology 1, Building M004, Muellerstrasse 178, 13353, Berlin, Germany. FAU - Chattopadhyay, Niladri AU - Chattopadhyay N AD - Bayer AG Research and Development, Pharmaceuticals, Clinical Pharmacology 1, Building M004, Muellerstrasse 178, 13353, Berlin, Germany. FAU - Klein, Stefan AU - Klein S AD - Bayer AG Research and Development, Pharmaceuticals, Clinical Pharmacology 1, Building M004, Muellerstrasse 178, 13353, Berlin, Germany. FAU - Rottmann, Antje AU - Rottmann A AD - Bayer AG Research and Development, Pharmaceuticals, Clinical Pharmacology 1, Building M004, Muellerstrasse 178, 13353, Berlin, Germany. FAU - Krickau, Dennis AU - Krickau D AD - Bayer AG Research and Development, Pharmaceuticals, Clinical Pharmacology 1, Building M004, Muellerstrasse 178, 13353, Berlin, Germany. FAU - van de Wetering, Jeroen AU - van de Wetering J AD - PRA Health Sciences, Van Swietenlaan 6, 9728 NZ, Groningen, The Netherlands. FAU - Friedrich, Christian AU - Friedrich C AUID- ORCID: 0000-0001-8955-4808 AD - Bayer AG Research and Development, Pharmaceuticals, Clinical Pharmacology 1, Building M004, Muellerstrasse 178, 13353, Berlin, Germany. christian.friedrich@bayer.com. LA - eng SI - ClinicalTrials.gov/NCT03773068 PT - Clinical Trial, Phase I PT - Journal Article PT - Randomized Controlled Trial DEP - 20221205 PL - France TA - Eur J Drug Metab Pharmacokinet JT - European journal of drug metabolism and pharmacokinetics JID - 7608491 RN - 0 (poly(vinylpyrrolidone-co-vinyl-acetate)) RN - 0 (Purinergic P2X Receptor Antagonists) RN - 0 (Tablets) SB - IM MH - Male MH - Animals MH - Dogs MH - Rats MH - Humans MH - Biological Availability MH - *Purinergic P2X Receptor Antagonists MH - Healthy Volunteers MH - Area Under Curve MH - Therapeutic Equivalency MH - Cross-Over Studies MH - Administration, Oral MH - Tablets EDAT- 2022/12/06 06:00 MHDA- 2023/01/11 06:00 CRDT- 2022/12/05 11:22 PHST- 2022/10/25 00:00 [accepted] PHST- 2022/12/06 06:00 [pubmed] PHST- 2023/01/11 06:00 [medline] PHST- 2022/12/05 11:22 [entrez] AID - 10.1007/s13318-022-00805-5 [pii] AID - 10.1007/s13318-022-00805-5 [doi] PST - ppublish SO - Eur J Drug Metab Pharmacokinet. 2023 Jan;48(1):75-87. doi: 10.1007/s13318-022-00805-5. Epub 2022 Dec 5.