Population Dose-Response-Time Analysis of Itch Reduction and Patient-Reported Tolerability Supports Phase III Dose Selection for Linerixibat.

Autor: Carreño F; UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.; GSK, Collegeville, Pennsylvania, USA., Karatza E; UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.; GSK, Durham, North Carolina, USA., Mehta R; GSK, Durham, North Carolina, USA., Collins J; GSK, Durham, North Carolina, USA., Austin D; GSK, Brentford, Middlesex, UK., Swift B; GSK, Durham, North Carolina, USA.
Jazyk: angličtina
Zdroj: Clinical pharmacology and therapeutics [Clin Pharmacol Ther] 2024 Feb; Vol. 115 (2), pp. 288-298. Date of Electronic Publication: 2023 Dec 03.
DOI: 10.1002/cpt.3103
Abstrakt: Increase in serum bile acids (BAs) in patients with primary biliary cholangitis (PBC) may play a causal role in cholestatic pruritus (itch). Linerixibat is a selective small molecule inhibitor of the ileal bile acid transporter, which blocks re-absorption of BAs in the gastrointestinal tract thereby lowering BAs in the systemic circulation and reducing itch. One consequence is excess BAs in the colon, leading to diarrhea and abdominal pain. GLIMMER (NCT02966834) was a placebo-controlled phase IIb dose-ranging trial of linerixibat once (q.d.) or twice daily (b.i.d.) in adults with moderate to severe pruritus and PBC. To determine the optimal dose for maximum itch reduction while minimizing diarrhea, a kinetic-pharmacodynamic (k-PD) model was developed using data from GLIMMER. The PD end point modeled was worst daily itch, derived from itch score reported by patients b.i.d. A proportional odds model was developed post hoc to indicate the probability of diarrhea occurrence, a patient-reported outcome (GI-5) recorded weekly. The final k-PD model successfully described the effects of linerixibat and placebo on itch. Model simulations were consistent with the observed dose-dependent increase in the average number of itch responders (patients with a ≥ 2-point improvement in itch). This was paralleled by a dose-dependent increase in the probability of higher diarrhea frequency scores. The b.i.d. dosing regimens led to a modest increase in the number of itch responders as compared with q.d. dosing. This quantitative framework highlights the trade-off between benefit and tolerability and supported the selection of 40 mg b.i.d. in the phase III GLISTEN trial (NCT04950127).
(© 2023 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
Databáze: MEDLINE
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