Phase I clinical trial of the flavonoid quercetin: pharmacokinetics and evidence for in vivo tyrosine kinase inhibition
Abstract
We have performed a Phase I clinical trial with the naturally occurring flavonoid quercetin (3,3',4',5,7-pentahydroxyflavone). Quercetin has antiproliferative activity in vitro and is known to inhibit signal transduction targets including tyrosine kinases, protein kinase C, and phosphatidyl inositol-3 kinase. Quercetin was administered by short i.v. infusion at escalating doses initially at 3-week intervals. The first dose level was 60 mg/m2; at the 10th dose level of 1700 mg/m2, dose-limiting nephrotoxicity was encountered, but no myelosuppression. At the preceding dose level of 1400 mg/m2, five patients were treated at 3-week intervals, and another eight patients were treated on a once-weekly schedule; overall, 2 of 10 evaluable patients had renal toxicity, 1 at grade 2 and 1 at grade 4. We therefore treated other patients at 945 mg/m2 (eight at 3-week intervals and six at weekly intervals); 3 of 14 patients had clinically significant renal toxicity, 2 patients with grade 2 and 1 patient with grade 3. Patients treated on the weekly schedule did not have cumulative renal impairment but did have a fall in the glomerular filtration rate of 19 +/- 8% in the 24 h after drug administration. We recommend 1400 mg/m2 as the bolus dose, which may be given either in 3-week or weekly intervals, for Phase II trials. Quercetin pharmacokinetics were described by a first-order two-compartment model with a median t(1/2)alpha of 6 min and median t(1/2)beta of 43 min. The median estimated…
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Evidence Hub reads this as a clinical trial, done in people. Its evidence level is 3 of 5 (Moderate · trial / cohort / secondary analysis). Trials without a large randomized design, cohorts and secondary analyses give moderate evidence. Reported size: 10 participants or records.
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