To evaluate the pharmacokinetics and safety of esomeprazole (Nexium), the S-isomer of omeprazole, after repeated oral dosing in patients with hepatic impairment.
Single-centre, open-label one-way study.
Twelve patients (aged 40–60 years) with mild to severe hepatic impairment received once-daily oral esomeprazole 40 mg for 5 days. Serial blood samples were drawn up to 24 h post-dose on day 5 to determine plasma levels of esomeprazole and its metabolites. Pharmacokinetic parameters were compared with an historical control group of 36 gastro-oesophageal reflux disease (GORD) patients (aged 29–58 years) with normal hepatic function.
Esomeprazole was absorbed rapidly (mean maximum plasma concentration (Cmax) 6.1 μmol/l, mean time to Cmax (tmax) 1.9 h) and eliminated rapidly (mean plasma elimination half-life (t1/2) 2.1 h). Elimination of its pharmacologically inactive sulphone and hydroxy metabolites was more gradual. Patients with mild hepatic impairment had area under the plasma concentration–time curve during the dosage interval (AUCτ) and t1/2 values largely within the range of the control group. In patients with moderate hepatic impairment, t1/2 values were similar and AUCτ was slightly higher than in controls, whereas both parameters were increased in patients with severe hepatic impairment. The mean ratios of esomeprazole AUCτ, Cmax and t1/2 values in patients with and without hepatic impairment were 1.8, 1.3 and 1.3, respectively.
The steady-state pharmacokinetics of esomeprazole were not altered substantially by mild or moderate hepatic impairment; however, plasma levels of esomeprazole were elevated in severe cases. Thus, dose adjustment appears unwarranted in mild or moderate hepatic impairment, but may be required in some severely impaired patients. Esomeprazole was tolerated well across the spectrum of hepatic impairment.
aSahlgrenska University Hospital, Göteborg, and bAstraZeneca R&D Mölndal, Mölndal, Sweden
Correspondence to Henrik Sjövall, Department of Internal Medicine, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden Fax: +46 31 822152; e-mail: firstname.lastname@example.org
Sponsor: AstraZeneca R&D Mölndal, Mölndal, Sweden.
Received 28 March 2001
Revised 2 August 2001
Accepted 16 January 2002