CYP3A activity in severe liver cirrhosis correlates with Child-Pugh and model for end-stage liver disease (MELD) scores

Abstract

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 Child-Pugh (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 (CLu ), 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: CLu = 843 ± 346 l h(-1), MELD ≥ 15: CLu = 805 ± 474 l h(-1), controls: CLu = 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.

Keywords: Child-Pugh score; MELD score; cytochrome P450 CYP3A; liver cirrhosis; midazolam; pharmacokinetics.

Figure 1

Correlation between Child–Pugh and model of end-stage liver disease (MELD) scores in patients with liver cirrhosis (small circles and squares; squares indicate two patients with transjugular intrahepatic portosystemic shunts, filled symbols indicate two patients with primary biliary cirrhosis, r² = 0.68, P < 0.01). Control patients without liver disease are indicated by large grey circles

Figure 2

Dose-normalized midazolam (black continuous lines) and 1′-hydroxymidazolam (blue broken lines) plasma concentration–time profiles in patients with liver cirrhosis grouped according to Child–Pugh class and MELD score categories (thin lines) and patients without liver disease (Control, thick lines). Error bars indicate SEMs

Figure 3

Midazolam plasma clearance in patients with liver cirrhosis (small circles and squares; squares indicate two patients with transjugular intrahepatic portosystemic shunts, filled symbols indicate two patients with primary biliary cirrhosis) and control patients without liver disease (large grey circles). All correlations were highly significant (P < 0.01, Table 3)

Figure 4

Unbound midazolam fraction and plasma half-life in patients with liver cirrhosis (small circles and squares; squares indicate two patients with transjugular intrahepatic portosystemic shunts, filled symbols indicate two patients with primary biliary cirrhosis) and control patients without liver disease (large grey circles). Unbound fraction: Spearman ρ = 0.75 (95% CI 0.52, 0.88) for Child–Pugh score and 0.61 (95% CI 0.31, 0.80) for MELD score. Half-life: Spearman ρ = 0.75 (95% CI 0.52, 0.88) for Child–Pugh score and 0.76 (95% CI 0.50, 0.88) for MELD score (all P < 0.01)