Pharmacokinetics and Safety of Multiple-Dose Alpelisib in Participants with Moderate or Severe Hepatic Impairment: A Phase 1, Open-Label, Parallel Group Study.

The pharmacokinetics (PK) and safety of single-dose alpelisib (300 mg) were assessed in participants with moderate to severe hepatic impairment (n = 6 each) compared with their matching healthy controls (n = 11). Blood samples were collected upto 144 hours post-dose and evaluated by liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. The primary PK parameters (maximum plasma concentration [Cmax], area under the curve [AUC]inf and AUClast) and secondary PK parameters (AUC0-t, apparent total body clearance [CL/F], apparent volume of distribution [Vz/F], time of maximum observed concentration [Tmax], and half-life [T1/2]) of oral alpelisib 300 mg were determined from individual plasma concentration-time profiles using non­compartmental analysis. Cmax of alpelisib decreased by approximately 17% in the moderate hepatic impairment group vs. the healthy control group (geometric mean ratio; GMR [90% confidence interval; CI], 0.833 [0.530, 1.31]). Cmax in the severe hepatic impairment group was comparable to that of the healthy control group (GMR [90% CI], 1.00 [0.636, 1.58]). AUClast for alpelisib decreased by approximately 27% in the moderate hepatic impairment group vs. the healthy control group (GMR [90% CI], 0.726 [0.487, 1.08]). AUClast was 26% higher in the severe hepatic impairment group compared with the healthy control group (GMR [90% CI], 1.26 [0.845, 1.87]). Overall, 3 participants (13.0%) experienced at least 1 adverse event which were either grade 1 or 2. Adverse events did not lead to study drug discontinuation. No grade 3 or 4 adverse events, serious adverse events or deaths were reported. The results indicate that a single dose of alpelisib was well tolerated in this study population. There was no significant impact of moderate or severe hepatic impairment on the exposure of alpelisib.

Genome-wide response of the human Hep3B hepatoma cell to proinflammatory cytokines, from transcription to translation.

Given the unknown timing of the onset of an acute systemic inflammation in humans, the fine tuning of cascades and pathways involved in the associated hepatocyte response cannot be appraised in vivo. Therefore, the authors used a genome-wide and kinetic analysis in the human Hep3B hepatoma cell line challenged with a conditioned medium from bacterial lipopolysaccharide-stimulated macrophages. A complete coverage of the liver transcriptome disclosed 648 mRNAs whose change in abundance allowed for their clustering in mRNA subsets with an early, intermediate, or late regulation. The contribution of transcription, stability, or translation was appraised with genome-wide studies of the changes in nuclear primary transcripts, mRNA decay, or polysome-associated mRNAs. A predominance of mRNAs with decreased stability and the fact that translation alone controls a significant number of acute phase-associated proteins are prominent findings. Transcription and stability act independently or, more rarely, cooperate or even counteract in a gene-by-gene manner, which results in a unidirectional change in mRNA abundance. Waves of mRNAs for groups of functionally related proteins are up- or downregulated in an ordered fashion. This includes an early regulation of transcription-associated proteins, an intermediate repression of detoxication and metabolism proteins, and finally an enhanced translation and transport of a number of membranous or secreted proteins along with an enhanced protein degradation. In conclusion, this study provides a comprehensive and simultaneous overview of events in the human hepatocyte during the inflammatory acute phase.