A phase I trial of ispinesib, a kinesin spindle protein inhibitor, with docetaxel in patients with advanced solid tumours.

The aim of this study is to define the maximum tolerated dose (MTD), safety, pharmacokinetics (PKs) and efficacy of ispinesib (SB-715992) in combination with docetaxel. Patients with advanced solid tumours were treated with ispinesib (6-12 mg m(-2)) and docetaxel (50-75 mg m(-2)). Docetaxel was administered over 1 h followed by a 1-h infusion of ispinesib on day 1 of a 21-day schedule. At least three patients were treated at each dose level. Blood samples were collected during cycle 1 for PK analysis. Clinical response assessments were performed every two cycles using RECIST guidelines. Twenty-four patients were treated at four dose levels. Prolonged neutropaenia and febrile neutropaenia were dose limiting in six and two patients, respectively. The MTD was ispinesib 10 mg m(-2) with docetaxel 60 mg m(-2). Pharmacokinetic assessment demonstrated concentrations of ispinesib and docetaxel, consistent with published data from single agent studies of the drugs. Seven patients (six hormone refractory prostate cancer (HRPC), one renal cancer) had a best response of stable disease (>or=18 weeks). One patient with HRPC had a confirmed >50% prostatic-specific antigen decrease. The MTD for ispinesib and docetaxel was defined and the combination demonstrated an acceptable toxicity profile. Preliminary PK data suggest no interaction between ispinesib and docetaxel.

In vitro-in vivo correlation of hepatobiliary drug clearance in humans.

The biliary clearance (Cl(biliary)) of three compounds was estimated using sandwich-cultured human hepatocytes (SCHH) and compared with Cl(biliary) values measured in vivo. Tc-99m sestamibi (MIBI) Cl(biliary) was determined in seven healthy volunteers using an oroenteric catheter to aspirate duodenal secretions, and gamma scintigraphy to determine gallbladder contraction; this technique was used previously to determine Tc-99m mebrofenin (MEB) and piperacillin (PIP) in vivo Cl(biliary). In vitro Cl(biliary) of MEB, MIBI, and PIP was quantified in SCHH as the ratio of mass excreted into bile canaliculi and area under the blood concentration-time curve (AUC) in medium. MIBI Cl(biliary) in vivo was 5.5+/-1.2 mL/min/kg (mean+/-SD). The rank order of Cl(biliary) predicted from SCHH corresponded well with the in vivo Cl(biliary) values in mL/min/kg for MEB (7.44 vs 16.1), MIBI (1.20 vs 5.51), and PIP (0.028 vs 0.032). In conclusion, the methods developed allowed for reproducible quantification of Cl(biliary) of drugs in healthy humans and prediction of Cl(biliary) from in vitro data.