Rate of onset of inhibition of gut-wall and hepatic CYP3A by clarithromycin.

AIMS: To determine the extent and time-course of hepatic and intestinal cytochrome P450 3A (CYP3A) inactivation due to the mechanism-based inhibitor clarithromycin. METHODS: Intestinal and hepatic CYP3A inhibition was examined in 12 healthy volunteers following the administration of single and multiple doses of oral clarithromycin (500 mg). Intestinal biopsies were obtained under intravenous midazolam sedation at baseline and after the first dose, on days 2-4, and on days 6-8 of the clarithromycin treatment. The formation of 1'-hydroxymidazolam in biopsy tissue and the serum 1'-hydroxymidazolam:midazolam ratio were indicators of intestinal and hepatic CYP3A activity, respectively. RESULTS: Intestinal CYP3A activity decreased by 64 % (p = 0.0029) following the first dose of clarithromycin, but hepatic CYP3A activity did not significantly decrease. Repeated dosing of clarithromycin caused a significant decrease in hepatic CYP3A activity (p = 0.005), while intestinal activity showed little further decline. The CYP3A5 or CYP3A4*1B genotype were unable to account for inter-individual variability in CYP3A activity. CONCLUSIONS: Following the administration of clarithromycin, the onset of hepatic CYP3A inactivation is delayed compared to that of intestinal CYP3A. The time-course of drug-drug interactions due to clarithromycin will vary with the relative contribution of intestinal and hepatic CYP3A to the clearance and bioavailability of a victim substrate.

A phase I dose escalation and pharmacokinetic study of vatalanib (PTK787/ZK 222584) in combination with paclitaxel in patients with advanced solid tumors.

PURPOSE: To define the maximum-tolerated dose (MTD) for weekly paclitaxel administered in combination with daily vatalanib (PTK787/ZK 222584, PTK/ZK) and assess for a drug-drug interaction. METHODS: Patients were treated with escalating doses of weekly paclitaxel (75-85 mg/m(2)), and daily PTK/ZK (250-1,000 mg). During the first cycle only, paclitaxel was given on days 1 and 15, and PTK/ZK on days 3-28. Pharmacokinetic studies were conducted on cycle 1 days 1 and 15 for paclitaxel, and on cycle 1 day 15 for PTK/ZK. Therapy was given until disease progression. RESULTS: Twenty-seven patients were accrued to four dose levels. Two of five patients treated with paclitaxel 85 mg/m(2) and PTK/ZK 1,000 mg had Grade 3 transaminase elevation as dose-limiting toxicity. Paired PK analyses demonstrated a significant increase in paclitaxel clearance on day 15 (p = 0.006). Activity included one partial response and 11 patients with stable disease > or =4 months, including patients previously treated with paclitaxel. CONCLUSIONS: The MTD for weekly paclitaxel plus daily PTK/ZK is 75 mg/m(2) and 750 mg. PK analysis revealed a significant drug-drug interaction, with an increase in paclitaxel clearance. This combination was well tolerated with evidence of anti-cancer activity and provides guidance for phase 2 planning.

Increased risk of cholestatic hepatitis C in recipients of grafts from living versus cadaveric liver donors.

Histologic injury caused by recurrent hepatitis C virus (HCV) has been reported in up to 90% of HCV-infected patients who undergo liver transplantation with a cadaveric graft. However, the natural history of HCV after living donor liver transplantation (LDLT) is not well described. We performed a retrospective analysis of 68 consecutive HCV-infected adult patients: 45 recipients of cadaveric grafts (CAD) were compared with 23 LDLT patients. Elevated serum transaminases, positive HCV RNA, and liver biopsy consistent with histologic evidence of HCV defined recurrence. When comparing CAD with LDLT, both the incidence of HCV recurrence and time to recurrence were not different. The overall incidence of severe sequelae of HCV recurrence, either cholestatic hepatitis, grade III-IV inflammation, and/or HCV-induced graft failure requiring retransplantation, was also not different when comparing CAD with LDLT. However, when comparing CAD versus LDLT, no CAD patient developed cholestatic hepatitis C, compared with 17% of LDLT who developed this complication (P =.001). Thus, in this patient population, the timing and incidence of HCV recurrence were not different when comparing CAD versus LDLT, but the incidence of cholestatic hepatitis was significantly greater in patients with HCV who underwent LDLT.