Phase I trial of bortezomib in combination with docetaxel in patients with advanced solid tumors.

PURPOSE: Bortezomib (PS-341), a first-in-class proteasome inhibitor, is metabolized by deboronation involving cytochrome P4503A (CYP3A), which also metabolizes docetaxel. Preclinical studies have shown synergy between bortezomib and taxanes. We conducted a phase I study combining bortezomib and docetaxel in refractory solid tumor patients. EXPERIMENTAL DESIGN: Patients received escalating doses of weekly docetaxel (days 1 and 8) and twice weekly bortezomib (days 2, 5, 9, and 12) in 3-week cycles. Two subjects were enrolled at each dose level, with cohort expansion to six for dose-limiting toxicity (DLT). Dose levels 1, 2, and 3 consisted of docetaxel/bortezomib 25/0.8, 25/1.0, and 30/1.0 mg/m(2), respectively. CYP3A activity and docetaxel pharmacokinetic studies were conducted, and proteasome inhibition was assessed. RESULTS: Fourteen patients received a total of 34 cycles of treatment. Dose level 2 was expanded for DLT that occurred in two of six patients consisting of febrile neutropenia in one patient and grade 3 thrombocytopenia in one patient. One patient received two cycles at dose level 3 with dose reduction to dose level 2, where grade 3 thrombocytopenia occurred at cycle 3. Both episodes of grade 3 thrombocytopenia were transient (<7 days). Dose level 1 was then expanded to six patients where no DLTs occurred. CYP3A activity and docetaxel clearance did not change between weeks 1 and 5. CONCLUSIONS: The maximum tolerated dose was docetaxel 25 mg/m(2) (days 1 and 8) with bortezomib 0.8 mg/m(2) (days 2, 5, 9, and 12) given every 21 days. Bortezomib treatment did not alter CYP3A activity and docetaxel clearance.

Expansion of inpatient clinical pharmacy services through reallocation of pharmacists.

PURPOSE: The redesign of an inpatient pharmacy practice model through reallocation of pharmacy resources in order to expand clinical services is described. METHODS: A pharmacy practice model change was implemented at a nonprofit academic medical center to meet the increasing demand for direct patient care services. In order to accomplish this change, the following steps were completed: reevaluation of daily tasks and responsibilities, reallocation of remaining tasks to the most appropriate pharmacy staff member, determination of the ideal number of positions needed to complete each task, and reorganization of the model into a collection of teams. Data were collected in both the preimplementation and postimplementation periods to assess the impact of the model change on operational workflow and clinical service expansion. RESULTS: The mean ± S.D. times to order verification were 17 ± 52 minutes during the preimplementation period and 21 ± 70 minutes in the postimplementation period (p < 0.001). During the 3 months before and after implementation of the model change, the mean number of medication reconciliations performed increased from 114 to 144. After implementation of the model change, total interventions increased 194%. Notably, there was a 736% increase in the number of interventions focused on facilitating safe discharge. CONCLUSION: A pharmacy practice model change was successfully implemented by reallocating existing pharmacist and technician roles and increasing incorporation of pharmacy residents and students. This change led to an expansion of direct patient care coordination services without negatively affecting the operational responsibilities of the pharmacy or the need to hire additional staff.