Pharmacokinetics of Tipifarnib After Oral and Intravenous Administration in Subjects With Advanced Cancer

Abstract

The primary objective of this study was to identify intravenous regimens of tipifarnib that would mimic the systemic exposure obtained after the current twice-daily oral administration of tipifarnib. After determination of an intravenous dose that 6 subjects with advanced cancer could tolerate, another 26 subjects were randomly assigned to receive 3 consecutive 4-day regimens of tipifarnib with different treatment sequences: a 100-mg 2-hour intravenous infusion, 200-mg oral administration twice daily, and a 200-mg/d continuous intravenous infusion. The systemic exposure to tipifarnib was comparable among these 3 regimens. The plasma concentration-time profile of 2-hour intravenous infusion more closely resembled the oral administration than did the continuous infusion. Glucuronidation is a metabolic pathway for tipifarnib with concentrations of the glucuronide conjugate greatly exceeding the parent compound after oral and intravenous administration. Analysis of plasma metabolites indicated that tipifarnib also undergoes dealkylation and loss of the imidazole group.

Comprehensive Review in Current Developments of Imidazole-Based Medicinal Chemistry

“…The structures for imidazoles as farnesyltransferase inhibitors are shown in Figure . Tipifarnib ( 4 ) is an excellent imidazole‐based FTase inhibitor in clinical trials to treat blood cancers, its success has provoked an increasing effort to investigate the potentiality of imidazole derivatives as anticancer agents …”

A phase 1 trial dose-escalation study of tipifarnib on a week-on, week-off schedule in relapsed, refractory or high-risk myeloid leukemia

“…Blood was centrifuged for 10 minutes at 1000 × g within 2 hours after collection for separation of plasma, and the resulting plasma samples were stored frozen at < -20°C until batch analysis. Plasma concentrations of tipifarnib were determined using a previously described validated LCMS/MS assay (10). …”

A phase I clinical and pharmacokinetic study of tipifarnib in combination with docetaxel in patients with advanced solid malignancies

“…Tipifarnib and the internal standard were detected by UV absorption at a wavelength of 240 nm. The standard curve range was 2-5000 ng/mL for a 1.0-mL sample 22 . Plasma samples for docetaxel were analyzed as follows: 200-µL aliquots of plasma were spiked with internal standard (paclitaxel), and 3 mL of 0.1 M phosphate buffer ( pH 7) were added.…”