Characterization of vancomycin pharmacokinetics in the adult acute myeloid leukemia population.

Current vancomycin dosing guidelines in our acute myeloid leukemia population too often achieve suboptimal initial drug concentrations. Our aim was to assess vancomycin pharmacokinetic parameters in acute myeloid leukemia patients and develop an improved dosing equation to attain more accurate initial therapeutic trough levels. Acute myeloid leukemia patients receiving vancomycin for a presumed or documented gram positive infection were eligible. Patients hospitalized in the intensive care unit, those with creatinine clearance <30 mL/min or with limb amputation were excluded. Three samples were collected at the following post-infusion time ranges: 1 h, 3-8 h, and 8-24 h post-infusion, contingent on the dosing interval. Pharmacokinetic data were then fit using a Bayesian-based population pharmacokinetic model. A total of 25 acute myeloid leukemia patients were studied with a mean volume in the central compartment (Vc; L/65 kg), volume of distribution at steady state (Vss; L/65 kg) and distributional clearance (CLd; L/h/65 kg) of 15, 38.9, and 9.32, respectively. CLslope was 0.59 (mg of vancomycin clearance per unit of creatinine clearance in mL/min); this value is 21.4% lower than the established literature value (0.75). The derived equation, based upon these values, was reasonably precise at achieving the desired trough concentration using a priori dosing. The mean (CV%) of the achieved trough was 94% (29%) with a range of 66-188%; 3/25 at <75% and >125%]. We have established that the derived dosing equation can place ≈ 75% of adult acute myeloid leukemia patients at vancomycin trough levels within 75-125% of the target trough level.

Nilotinib: a new tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemia.

Chronic myelogenous leukemia (CML) is a myeloproliferative disorder arising from a single genetic mutation that leads to an increase in immature myeloid cells in the bone marrow and the accumulation of these cells in the blood. Typically, CML represents 15-20% of all adult leukemias, with 4830 new cases expected in 2008. The cytogenetic hallmark of CML is the Philadelphia chromosome, which is the result of the reciprocal translocation and conjugation of the breakpoint cluster region (BCR) gene, BCR, on chromosome 22 and the Abelson (ABL) kinase gene, ABL, on chromosome 9. Current treatment is aimed at inhibiting BCR and ABL kinase with novel agents, the first being imatinib in 2003, and more recently dasatinib in 2006. Nilotinib is a new small-molecule inhibitor of tyrosine kinase rationally developed from the crystalline structure of the imatinib-ABL complex. It represents an aminopyrimidine derivative of imatinib with approximately 30 times more potency in vitro against imatinib-sensitive BCR-ABL-expressing cell lines and activity against 32 of 33 point mutations conferring resistance to imatinib. Data from phase I and II studies show that nilotinib has activity against all phases of CML in patients who are intolerant or have failed therapy with imatinib or dasatinib. Nilotinib represents a new therapeutic option for patients with CML who are intolerant or have failed therapy with imatinib. Ongoing clinical trials are assessing nilotinib's role in the treatment of patients with newly diagnosed CML and its long-term efficacy and safety.