Pharmacokinetics/pharmacodynamics of Liposomal Cytarabine (VYXEOS) in AML Patients: Influence of Cytidine Deaminase Genetic Polymorphisms.

e19517 Background: Vyxeos is a liposomal formulation of daunorubicin and cytarabine recently approved for treating adults with newly-diagnosed sAML subtypes therapy-related (t-AML) or AML with myelodysplasia-related changes (AML-MRC). The objective of this pilot study was to evaluate the influence of cytidine deaminase, the enzyme responsible for cytarabine detoxification step in the liver, on drug exposition and clinical outcome. Methods: In this proof-of-concept study, 9 adult patients were treated with Vyxeos. CDA status (i.e., determination of Poor Metabolizer or Extensive Metabolizer phenotypes) was evaluated before treatment by measuring residual CDA activity in serum. Pharmacokinetic sampling was performed 90min before infusion stops, then from T4H to T168H after the end of the infusion. Total cytarabine, encapsulated cytarabine and released cytarabine were discriminated and assayed using a validated LC-MS/MS method. Results: Nine Vyxeos patients (3M, 6F, 66 ±13 years) were included in this pilot study. Aplasia duration was significantly longer in AML-MRC patients than in AML-t (38 ±5.5 days VS. 28 ±3 days, respectively (p < 0.05)). All AML-t had complete response after induction phase (VS. 60% in AML-MRC, p > 0.05). Similar cytarabine exposure was measured in both population. Surprisingly, 8 out of 9 patients (i.e., 88%) were identified as CDA PM (CDA < 2UI/mg). Marked differences in pharmacokinetics were observed between PM and EM patients. Total, encapsulated and released cytarabine AUC’s were 2.77, 1.42, and1.46 mg/ml*h in PM patients. In EM patient, total, encapsulated and released cytarabine AUC’s were 0.97, 0.76 and 0.17 mg/ml*h. When available, microscopy analysis confirmed the presence of liposomes in patients bone marrow. Conclusions: Differences in clinical outcome between AML-t and AML-MRC patient are not supported by differences in exposure levels upon Vyxeos administration. Surprisingly, we found that CDA status has a strong impact on cytarabine pharmacokinetics since PM patients treated with Vyxeos present a +185% increase in cytarabine levels as compared with EM patient. This suggests that upfront CDA testing could help to predict clinical outcome.