Conclusion
The applicant’s model was informed by plasma concentrations of OCA and conjugates
observed in subjects with varying degrees of hepatic impairment (relatively rich model
development dataset) and was able to generally capture OCA exposure observed in subjects
with normal hepatic function and with hepatic impairment (verification datasets). The applicant
also predicted plasma and liver exposures of CDCA in subjects with normal hepatic function
and in subjects with severe hepatic impairment (cholestasis and non-cholestasis). Despite
several limitations recognized for modeling of both OCA and CDCA and the lack of
predictability of PBPK for hepatic impairment [13], the applicant’s prediction of liver OCA
exposures using PBPK is considered useful in supporting dosing recommendations of OCA in
patients with hepatic impairment.
Although the magnitude of elevation in liver OCA concentrations in subjects with severe
hepatic impairment was predicted to be less than that in plasma concentrations, there were
significantly higher plasma OCA exposures in subjects with moderate and severe hepatic
impairment compared to patients with normal liver function. With the evidence of doseresponse
relationship for pruritus (and related discontinuations, see main text of Question Based
Review) and unknown relationship of plasma/liver exposures to pruritus, a conservative
approach of adjustment of starting dose in subjects with severe hepatic impairment to match
plasma exposures to those subjects with normal hepatic function, followed by subsequent uptitrations
of dose and dosing frequency, appears reasonable.
