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I will try to think like a physician (I am not) tempting to treat one PBC patient with OCALIVA.

FDA told me that I should adapt the dose of OCALIVA depending the hepatic impairment of my patient .. so !

May I use the Child-Pugh score for that ? 

Following the INTERCEPT's CEO conference, I am told that the dosing procedure is clear :

if my patient have : 

  • no hepatic impairment 
  • or a Child-Pugh score A 

the dose start at 5mg/day and can reach 10mg/day  

if my patient have hepatic impairment with: 

  • a Child-Pugh score B
  • or  a Child-Pugh score C

the dose start  at 5mg/week and  can reach 2x10mg/week

So all is clear and i have no risk to be sued for a bad dosage !!

But I am a cautious doctor ! so i took the time to fully read the report published by the FDA to the meeting commitee who granted the OCALIVA agreement in PBC.

And WHAT !!

FDA write : "4.4. What are the limitations of PBPK model for OCA and CDCA?

Hepatic impairment causes multiple physiological changes that directly or indirectly affect the ADME processes of a drug [9,11]. Although many changes have been quantitatively or semi­ quantitatively incorporated into PBPK modeling framework [9,11], predictive performance of these models in prospectively predicting the effect of varying degrees of hepatic impairment on a drug’s pharmacokinetics has not been established [13]. This is further complicated by clinical practice of categorizing hepatic impairment using CP score, which is a composite score of multiple clinical measures. For example, two patients of different liver disease origins may be categorized to have the same CP score. System models for hepatic impairment subjects developed according to CP categorization inherently carry large uncertainty when being used to predict the effect of hepatic impairment on drug exposure. »   

Gloups !! 

So the Child-pugh score is not predictive of the hepatic impairment impact on drug exposure as per the FDA itself ?? 

So what should I use to evaluate the correct dose ? If I am wrong , it seems that my patient can die !!

Maybe i will always use the lightest dose, even if its mean no effect on PBC ? or maybe I will wait one year for a safer  compound !

big dilemma !

G Divry

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