Pharmacokinetics of pantoprazole in patients with moderate and severe hepatic dysfunction

Background: Patients with impaired hepatic function usually require gastric acid-suppressant therapy but are at increased risk for drug interactions a nd may require dosage adjustments. The proton pump inhibitor pantoprazole i s rapidly absorbed and eliminated, primarily by cytochrome P450 (CYP) 2C19 isozymes. Objective: This study sought to determine whether dosage adjustment of pant oprazole is required in patients with moderate or severe hepatic impairment by comparing the pharmacokinetic profile of pantoprazole in such patients with that in healthy slow metabolizers of pantoprazole, in whom no dosage a djustment is required. Methods: Patients with moderate (Child-Pugh class 13) and severe (Child-Pug h class C) hepatic impairment received oral pantoprazole 40 mg once daily o n days 1 through 4 and then on alternate days (days 6 and 8). Serial blood samples were collected on days 4 and 8 for analyses of plasma pantoprazole concentrations. Pharmacokinetic data were compared between the 2 groups wit h hepatic impairment and against historical data from 17 healthy subjects w ho were genetically slow CYP2C19 metabolizers of pantoprazole. Results: Twenty-two patients participated in the study, 13 in the Child-Pug h class B group and 9 in the Child-Pugh class C group. No clinically signif icant differences in pantoprazole pharmacokinetics were noted between the p atients with hepatic impairment and the healthy slow metabolizers of pantop razole on days 4 and 8. Pantoprazole was well tolerated. Four Child-Pugh cl ass B patients and 3 Child-Pugh class C patients reported greater than or e qual to1 adverse event. Adverse events were generally mild or moderate, and were similar to those reported in healthy subjects. Two patients discontin ued the study because of severe events related to their underlying disease. Conclusions: The pharmacokinetics and tolerability of pantoprazole were sim ilar in patients with moderate hepatic impairment, patients with severe hep atic impairment, and healthy slow metabolizers of pantoprazole, in whom no dosage adjustment is required. Thus, no dosage adjustment of pantoprazole i s required in patients with hepatic impairment, regardless of its severity. However, caution should be exercised when giving pantoprazole to patients with severe hepatic impairment.