PKモデリングが肝障害患者への投与戦略をサポート
原発性胆汁性胆管炎（PBC）は、肝臓からの胆汁の流れを阻害し、その結果、胆汁酸濃度が上昇し、細胞障害を引き起こす慢性疾患です。PBCを未治療のままにしておくと、肝不全になり死に至ることもあります。このプロジェクトがスタートした時点では、PBCに対して唯一承認されている治療法は、すべての患者に対して有効ではありませんでした。
Intercept Pharmaceuticals was developing obeticholic acid (OCA) as an alternative treatment for PBC. OCA activates farnesoid X receptors (FXR) in the liver to decrease bile acid concentration.
As liver damage occurs as PBC progresses, Intercept needed to develop an OCA dosing strategy for patients both with and without hepatic impairment. A clinical hepatic impairment study revealed that while systemic OCA concentrations increased as hepatic impairment worsened, the level of FXR activation in the liver remained similar across all groups. Plasma OCA concentration proved to be a poor surrogate for liver OCA concentration.
Therefore, Phoenix NLME was used to create a physiologic PK model to explore the relationship further. The model was validated by comparing its predicted OCA-plasma exposures to those observed in both the patients and volunteers.
Both the Phoenix model and clinical data demonstrated a significant increase in systemic exposure to OCA in patients with hepatic impairment. But liver exposure to OCA increased only modestly in patients with hepatic impairment compared to healthy volunteers. These results supported the safety and efficacy of OCA and the need to reduce dosing only for PBC patients with moderate and severe hepatic impairment.
When the FDA approved Ocaliva (OCA) in May 2016, it was the first new drug approved for PBC in almost 20 years.
Headquartered in New York, Intercept Pharmaceuticals is a biopharmaceutical company focused on the development and commercialization of novel therapeutics to treat progressive non-viral liver diseases, including PBC and nonalcoholic steatohepatitis (NASH). Founded in 2002, Intercept has operations in the United States, Europe, and Canada.
