Pharmacodynamic Analysis of Bosutinib in Patients with Chronic Myelogenous Leukemia,

Bosutinib (SKI-606) is an orally active, dual competitive inhibitor of the Src and Abl tyrosine kinases. In clinical studies bosutinib has demonstrated efficacy and an acceptable safety profile in patients with Philadelphia chromosome–positive chronic myelogenous leukemia (CML). The current analysis estimated the association of bosutinib pharmacokinetic (PK) exposure at steady-state with safety and efficacy.

Oral bosutinib 500 mg/day was administered to patients with chronic phase (CP), accelerated phase, and blast phase CML who were resistant/intolerant to prior TKI therapy in a phase 2 trial, and to patients with newly diagnosed CP CML in a phase 3 trial. Patients with paired PK and pharmacodynamic data were included in the analysis. Bosutinib exposure metrics (area under the curve [AUC], maximal plasma concentration [C_max], and minimum plasma concentration [C_min]) were derived from a previously developed 2-compartment PK model with first-order absorption and an absorption lag. Evaluated safety metrics (ordinal metrics) included gastrointestinal events (diarrhea, nausea, vomiting), rash, aminotransferase elevations, and hematologic events (thrombocytopenia, neutropenia); safety data were pooled from both studies, and the maximum toxicity for each patient was assigned to a 5-point scale (0–4) based on severity (no event to grade 4 event, respectively). Response rates based on an intent-to-treat analysis were evaluated separately for each study and coded as binary variables, where 0 indicated no response and 1 indicated response.

A total of 749 patients were included in the pooled safety analysis: mean age was 50.2 years (range, 18–91 years); 54% were male. An exposure-response relationship (E_max model) was identified for the incidence of diarrhea (but not severity), with a predicted probability of diarrhea incidence ranging from 0.575 to 0.797 for the lowest and highest bosutinib AUC bins, respectively. There was also a weak exposure-response relationship (log-linear model) for the incidence (but not severity) of rash, with a predicted probability of rash incidence ranging from 0.216 to 0.419. However, there was no evidence to support an exposure-response relationship for the incidence or severity of nausea, vomiting, neutropenia, thrombocytopenia, or elevation of alanine and aspartate aminotransferases. In 266 patients with resistance/intolerance to prior TKI therapy, no exposure-response relationship for major cytogenetic response (MCyR) at 24 weeks was found. Although an exposure-response relationship (linear or log-linear model) was observed for cumulative complete hematologic response (CHR) in patients with prior TKI exposure, the relationship was paradoxical, with higher bosutinib exposure associated with a lower probability of cumulative CHR; the predicted probability of cumulative CHR ranged from 0.926 to 0.743 for the lowest and highest AUC bins, respectively. In 245 newly diagnosed patients with CP CML, exposure-response relationships were observed for complete cytogenetic response (CCyR), major molecular response (MMR), and CHR at 1 year. CCyR at 1 year could be related to AUC and C_min, but not C_max, using a sigmoid E_max model, with a predicted probability of CCyR ranging from 0.476 to 0.650. The exposure-response relationship for MMR at 1 year could be described using an E_max model for AUC and C_max or a log-linear model for C_min, with a predicted probability of MMR ranging from 0.238 to 0.497. The relationship of CHR at 1 year with AUC and C_min, but not C_max, could be described using an E_max model, with a predicted probability of CHR ranging from 0.605 to 0.763.

An exposure-response relationship was identified for incidence of diarrhea and rash, but not for the incidence or severity of other investigated toxicities commonly observed with bosutinib treatment. Additionally, an exposure-response relationship was found for CCyR, MMR, and CHR at 1 year in newly diagnosed patients with CP CML, but the relationship between bosutinib exposure and efficacy was less clear in the pretreated population. The absence of exposure-response relationships for some safety and efficacy metrics may reflect bosutinib concentrations that exceeded the half-maximal inhibitory concentration (IC₅₀) for these metrics and reached a plateau effect.

Amantea:Pfizer Inc: Employment, Equity Ownership. Mould:Projections Research Inc: Employment; Pfizer Inc: Consultancy. Upton:Pfizer Inc: Consultancy. Pearce:Pfizer Inc: Employment. Hsyu:Pfizer Inc: Employment, Equity Ownership.