In vitrometabolism of the specific endothelin-A receptor antagonist ZD4054 and clinical drug interactions between ZD4054 and rifampicin or itraconazole in healthy male volunteers

Abstract

ZD4054 is an oral specific endothelin-A receptor antagonist in development for the treatment of hormone-resistant prostate cancer. Both renal and metabolic processes contribute to its overall clearance. Two preclinical in vitro studies investigated the metabolism of ZD4054 using human liver microsomes, individual cytochrome P450 (CYP) isozymes, and flavin-containing monooxygenase isoforms. Two Phase I open-label crossover volunteer studies subsequently investigated in vivo drug interactions between ZD4054 and the CYP450 inducer rifampicin or CYP3A4 inhibitor itraconazole. The most abundant metabolite produced in in vitro incubations accounted for 12.8% of radioactivity after ZD4054 was incubated with CYP3A4. No significant flavin-containing monooxygenase metabolism of ZD4054 was observed. In the in vivo studies, rifampicin co-administration reduced the area under the concentration-time curve and maximum plasma concentration of ZD4054 by 68% and 29%, respectively, whilst co-administration with itraconazole was associated with an increase in ZD4054 area under the curve of approximately 28%. While co-administration of CYP450 inducers might be associated with reduced efficacy of ZD4054, dose reduction is unlikely to be required with concomitant administration of CYP3A4 inhibitors.

Pharmacokinetics and tolerability of zibotentan (ZD4054) in subjects with hepatic or renal impairment: two open-label comparative studies

“…Zibotentan plasma and plasma ultrafiltrate concentrations were determined as described previously [17]. An additional calibration curve ranging from 5 to 5000 ng/mL which used an internal standard concentration of 10,000 ng/mL in water (rather than the 100 ng/mL solution previously reported for the 0.5 to 500 ng/mL calibration range) was used for plasma samples in the renal study and for plasma ultrafiltrate samples.…”

“…A 25 μL portion of each sample was aliquoted into a 2 mL square well plate and internal standard (900 μL, 1400 ng/mL) was added to each sample, except appropriate blanks, to which mobile phase (900 μL) was added. The plate was vortex mixed and centrifuged (3 minutes, 2500 rpm, 20°C), prior to being submitted for HPLC-MS-MS analysis as previously described [17]. The CV of the assay was ≤7.2% and the accuracy typically ranged from 101 to 107%.…”

“…The drug and its metabolites are predominantly eliminated in urine with ~58% of parent compound being eliminated by renal clearance. Metabolism of zibotentan is known to be mediated by the CYP3A4 isozyme [16,17]. When zibotentan was administered in combination with the potent inhibitor of CYP3A4, itraconazole, exposure evaluated by the area under the plasma concentration time curve from time zero to infinity (AUC) was increased by 28% [17].…”

“…Metabolism of zibotentan is known to be mediated by the CYP3A4 isozyme [16,17]. When zibotentan was administered in combination with the potent inhibitor of CYP3A4, itraconazole, exposure evaluated by the area under the plasma concentration time curve from time zero to infinity (AUC) was increased by 28% [17]. Therefore, patients with hepatic or renal impairment may have reduced drug clearance which could potentially lead to a greater exposure to zibotentan than in patients with normal organ function.…”

Single- and multiple-dose pharmacokinetics, safety and tolerability of zibotentan (ZD4054) in Chinese men with advanced solid tumors

“…During the multiple-dose phase, samples were taken predose on Day 8 and on Day 10, 11 or 12; predose and at 1, 2, 3, 4, 6, 8, 12 and 16 h following the dose on Day 15; and a final sample was taken at 24 h on Day 16. Zibotentan plasma concentrations were determined by high-performance liquid chromatography with tandem mass spectrometry, as described previously [13].…”