Novel Population Pharmacokinetic Modeling of Arabinosyl Cytosine Triphosphate: Insights On Potential Preferential Formation of Ara-CTP Directly From Elacytarabine As Well As From Ara-C

Elacytarabine (CP-4055) is an elaidic acid ester of arabinosyl cytosine (Ara-C), administered as a liposomal formulation, that is being developed to treat hematologic malignancies. CP-4055 is metabolized to Ara-C, which is transformed intracellularly to active arabinosyl cytosine triphosphate (Ara-CTP) and inactive deaminated metabolite arabinosyl uracil (Ara-U). The present analysis aimed to elucidate the pharmacokinetics (PK) of Ara-CTP and identify its relationship with CP-4055, Ara-C, Ara-U and various blood parameters measured in the target patient population.

Patients suffering from hematologic malignancies, including refractory/relapsing acute myeloid leukemia (AML), who participated in Phase I or II CP-4055 trials, were included in this analysis. CP-4055 monotherapy was given as an intravenous infusion over 2 h/day for 5 days, 4 h/day for 5 days or continuously over 120 hours at doses ranging from 200 to 2500 mg/m²/day. Blood samples were collected at various time-points (until 168 hours post-dose) and plasma was assayed for CP-4055, Ara-C, and Ara-U using a validated LC-MS/MS method. Ara-CTP was measured by HPLC in isolated leukemic blast cells from AML patients. Cholesterol levels were also measured. Population PK analyses were conducted using the iterative two-stage method in ADAPT 5®. First, a model was determined for cholesterol, which was incorporated into a PK model for CP-4055, Ara-C and Ara-U. Individual PK parameters from this model were fixed and then used for the analysis of Ara-CTP. For Ara-CTP modeling, 1-compartment (cpt) models were tested with various routes of formation. For all models, model discrimination was performed using standard criteria (residual variability, quality of fit graphs, Akaike information criterion test).

In the cholesterol analysis, 13 patients (57 concentrations) were included while 43 patients (around 27 concentrations per patient) were included in the modeling of CP-4055, Ara-C and Ara-U. A subset of 17 patients (46 concentrations) was part of the Ara-CTP analysis. Cholesterol was described by an indirect model with a rate of elimination and a rate of formation that was increased by phospholipids infused along with CP-4055. CP-4055 PK was best described by a 2-cpt model, where the central cpt was partitioned into 2 sub-cpts. The first sub-cpt represented a lipid depot cpt where liposomal-bound CP-4055 was infused, and which transferred CP-4055 into the other sub-cpt, which represented CP-4055 released from liposomes. The transfer of CP-4055 from the liposomes was unidirectional and saturable, and cholesterol level influenced the size of the second sub-cpt. Ara-CTP appeared to be formed from unbound CP-4055, presumably within cancer cells, and was also formed as expected from Ara-C which was best described by a 2-cpt model, while Ara-U followed a 1-cpt model with an elimination that was dependent upon creatinine clearance. The proposed model is depicted below.

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Based on the model, terminal elimination half-life values for CP-4055, Ara-C, Ara-U and Ara-CTP were around 9, 68, 5 and 3 hours, respectively, and were independent of dose and infusion time. Residual variabilities for cholesterol, CP-4055, Ara-C, Ara-U and Ara-CTP were 21.0%, 34.0%, 39.4%, 12.5% and 29.2%, respectively.

For the first time, a population PK approach was used to describe the PK of a triphosphate metabolite in relation to a parent drug as well as other metabolites. Indeed, the novel multi-cpt model developed herein simultaneously described and explained the PK of cholesterol, elacytarabine, Ara-C, Ara-U and Ara-CTP. The inclusion of cholesterol levels in the model improved the overall quality of fit, especially for administered liposomal-elacytarabine. The proposed PK model describing Ara-CTP disposition suggests that Ara-CTP is formed not only from Ara-C but also from elacytarabine, presumably within cancer cells, although the exact mechanism is unknown.

Seng Yue:Learn and Confirm: Employment; Clavis Pharma: Consultancy. Gandhi:Clavis Pharma: Research Funding. O'Brien:Clavis Pharma: Research Funding. Ravandi:Clavis Pharma: Research Funding. Jacobsen:Clavis Pharma: Employment, Equity Ownership. Dirven:Clavis Pharma: Employment. Hagen:Clavis Pharma: Employment, Equity Ownership. Hals:Clavis Pharma: Employment. Ducharme:Learn and Confirm: Employment, Equity Ownership; Clavis Pharma: Consultancy.