PURPOSE: This study evaluated the effects of varying degrees of hepatic impairment on the pharmacokinetics and safety of valdecoxib following single and multiple dosing. METHODS: This was an open-label, randomised, parallel group study in 12 subjects with mild hepatic impairment (Child-Pugh Class A) and in 13 with moderate hepatic impairment (Child-Pugh Class B) matched for age, weight, sex, and smoking status; there were two control groups of 12 healthy volunteers, one for each study group. All subjects received a single dose of valdecoxib 20 mg on day 1 and valdecoxib 20 mg twice daily on days 4-7, followed by a single morning dose on day 8. Plasma concentrations of free (unbound) and total valdecoxib and its active hydroxylated metabolite (SC-66905) were measured following single and multiple dosing (day 1 and day 8). Additionally, all subjects received a single intravenous dose of lidocaine 60 mg during the pretreatment period to determine plasma concentrations of monoethylglycinexylidide (MEGX) as a marker of hepatic CYP3A4 activity. RESULTS: The mean apparent oral clearance of free valdecoxib in plasma at steady state decreased by 22-25% in those with mild to moderate impairment (corresponding to a 28-33% increase in the AUC of free valdecoxib and a 19-23% decrease in the AUC of total SC-66905). The mean free fraction of valdecoxib in plasma increased by 9-38%, resulting in a mean decrease in apparent oral clearance of total valdecoxib in plasma of 0-15% (corresponding to a 0-17% increase in the AUC of total valdecoxib). Individual AUCs for free valdecoxib and total SC-66905 did not correlate well with AUCs for MEGX, indicating that decreases in intrinsic clearance of valdecoxib in those with hepatic impairment could not solely be explained by decreased CYP3A4 expression in hepatic impairment. CONCLUSIONS: In our small study sample, mild and moderate hepatic impairment appeared to have only a modest effect on valdecoxib and SC-66905 pharmacokinetics. The adjustment of valdecoxib dose or dosing regimen does not appear mandatory in subjects with mild or moderate hepatic impairment, although caution is necessary during treatment of these patients with valdecoxib.
RCT Entities:
PURPOSE: This study evaluated the effects of varying degrees of hepatic impairment on the pharmacokinetics and safety of valdecoxib following single and multiple dosing. METHODS: This was an open-label, randomised, parallel group study in 12 subjects with mild hepatic impairment (Child-Pugh Class A) and in 13 with moderate hepatic impairment (Child-Pugh Class B) matched for age, weight, sex, and smoking status; there were two control groups of 12 healthy volunteers, one for each study group. All subjects received a single dose of valdecoxib 20 mg on day 1 and valdecoxib 20 mg twice daily on days 4-7, followed by a single morning dose on day 8. Plasma concentrations of free (unbound) and total valdecoxib and its active hydroxylated metabolite (SC-66905) were measured following single and multiple dosing (day 1 and day 8). Additionally, all subjects received a single intravenous dose of lidocaine 60 mg during the pretreatment period to determine plasma concentrations of monoethylglycinexylidide (MEGX) as a marker of hepatic CYP3A4 activity. RESULTS: The mean apparent oral clearance of free valdecoxib in plasma at steady state decreased by 22-25% in those with mild to moderate impairment (corresponding to a 28-33% increase in the AUC of free valdecoxib and a 19-23% decrease in the AUC of total SC-66905). The mean free fraction of valdecoxib in plasma increased by 9-38%, resulting in a mean decrease in apparent oral clearance of total valdecoxib in plasma of 0-15% (corresponding to a 0-17% increase in the AUC of total valdecoxib). Individual AUCs for free valdecoxib and total SC-66905 did not correlate well with AUCs for MEGX, indicating that decreases in intrinsic clearance of valdecoxib in those with hepatic impairment could not solely be explained by decreased CYP3A4 expression in hepatic impairment. CONCLUSIONS: In our small study sample, mild and moderate hepatic impairment appeared to have only a modest effect on valdecoxib and SC-66905 pharmacokinetics. The adjustment of valdecoxib dose or dosing regimen does not appear mandatory in subjects with mild or moderate hepatic impairment, although caution is necessary during treatment of these patients with valdecoxib.
Authors: Nancy G B Agrawal; Mark J Rose; Catherine Z Matthews; Eric J Woolf; Arturo G Porras; Leslie A Geer; Patrick J Larson; Josee Cote; Stacy C Dilzer; Kenneth C Lasseter; Imtiaz Alam; Kevin J Petty; Keith M Gottesdiener Journal: J Clin Pharmacol Date: 2003-10 Impact factor: 3.126