A Dual-Administration Microtracer Technique to Characterize the Absorption, Distribution, Metabolism, and Excretion of [14C]Seletalisib (UCB5857) in Healthy Subjects.

Autor:	Helmer, Eric, Nicolas, Jean‐Marie, Long, Jeff, Roffel, Ad F., Jones, Emma, Chanteux, Hugues, Diaz, Nieves, Garratt, Holly, Bosje, Tjerk
Předmět:	ANTI-inflammatory agents BIOAVAILABILITY BIOTRANSFORMATION (Metabolism) CONFIDENCE intervals CROSSOVER trials DOSE-effect relationship in pharmacology FECES HEALTH status indicators INFLAMMATION INTRAVENOUS therapy MEDICAL technology ORAL drug administration PATIENT safety PHOSPHOTRANSFERASES RADIOISOTOPES STATISTICAL sampling RANDOMIZED controlled trials DESCRIPTIVE statistics CHEMICAL inhibitors
Zdroj:	Journal of Clinical Pharmacology; Dec2017, Vol. 57 Issue 12, p1582-1590, 9p
Abstrakt:	Phosphoinositide 3 kinases are targets for development of small-molecule inhibitors to disrupt progression of immune-inflammatory diseases. This phase 1 open-label study (Eudract 2014-005353-39) evaluated the safety and relative bioavailability of 2 new seletalisib (UCB5857) formulations (A and B) compared with a reference formulation. Absolute bioavailability (period 1a, n = 6) and disposition and metabolism (period 1b, n = 6) of the reference formulation were evaluated: healthy subjects received 30 mg orally plus ~20 μg of a 14C-labeled microtracer (intravenously in 1a, orally in 1b). New formulations were evaluated: subjects from periods 1a and 1b were pooled and randomly distributed to receive a single oral dose (30 mg) of formulation A (n = 6) or B (n = 6) in periods 2 and 3, using a crossover design. Absolute oral bioavailability of seletalisib was 97% (90% confidence interval 87, 107). Unchanged [14C]seletalisib was the predominant radioactive component in plasma (94.8%). After oral dosing, the radioactive dose was primarily recovered in feces (74.6%, geometric coefficient of variation [GeoCV] 18.1%), mostly as metabolites. Seletalisib demonstrated a 24-hour terminal half-life, volume of distribution of 60.9 L (GeoCV 23.8%), and a total plasma clearance of 1.7 L/h (GeoCV 35.4%). Formulations A and B displayed similar or even higher exposure compared with reference seletalisib (areas under the concentration-time curves 19-337 [GeoCV 30.8%], 20-380 [GeoCV 37.7%], and 15-932 [GeoCV 36.4%] h·ng/mL, respectively). New formulations A and B were bioequivalent with each other, and all 3 formulations showed acceptable safety profiles. This radiolabeled microtracer approach successfully informed on the absorption, distribution, metabolism, and excretion of seletalisib and further guided the mechanistic pharmacokinetic modeling. [ABSTRACT FROM AUTHOR]
Databáze:	Complementary Index
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