CYP3A activity in severe liver cirrhosis correlates with C hild– P ugh and model for end‐stage liver disease ( MELD ) scores

Aims Impaired liver function often necessitates drug dose adjustment to avoid excessive drug accumulation and adverse events, but a marker for the extent of the required adjustment is lacking. The aim of this study was to investigate whether C hild– P ugh ( CP ) and model for end‐stage liver disease ( MELD ) scores correlate with drug clearance. Methods Midazolam was used as a CYP3A probe and its pharmacokinetics were analyzed in 24 patients with mild to severe liver cirrhosis ( n = 4, 10 and 10 with CP class A , B and C , respectively) and six patients without liver disease. Results Both scores correlated well with unbound midazolam clearance ( CL u ), unbound midazolam fraction and half‐life (all P < 0.01), whereas the unbound steady‐state volume of distribution was not significantly changed. In patients with severe liver cirrhosis unbound midazolam clearance was only 14% of controls ( CP C : CL u = 843 ± 346 l h −1 , MELD ≥ 15: CL u = 805 ± 474 l h −1 , controls: CL u = 5815 ± 2649 l h −1 , P < 0.01). Conclusion The correlation with unbound midazolam clearance suggests that either score predicts the metabolic capacity of CYP3A , the most relevant drug metabolizing enzyme subfamily in humans.