Population Pharmacokinetics of Liposomal Amphotericin B, Caspofungin and the Combination of Both in Allogeneic Hematopoietic Stem Cell Recipients
G. Würthwein(1), C. Young (1), C. Lanvers-Kaminsky(2), G. Silling(3), G. Hempel(2,4), J. Boos(2), A. H. Groll(2)
(1)Centre for clinical trials, University Hospital Münster, Münster, Germany; (2)Department of Paediatric Haematology and Oncology, University Hospital Münster, Münster, Germany; (3) Dept. of Internal Medicine A, Hematology and Oncology, University Hospital Muenster, Muenster, Germany; (4)Department of Pharmaceutical and Medical Chemistry, Clinical Pharmacy, University of Münster, Münster, Germany
Objectives: Caspofungin (CAS), liposomal amphotericin B (LAMB) and the combination of both (CASLAMB) are used for management of invasive fungal infections in allogeneic hematopoietic stem cell (aHSCT) recipients. Little is known, however, about the disposition of both agents and their combination in this special population.
Methods: The population pharmacokinetics and interactions of CAS and LAMB were investigated within a risk-stratified, randomized, multicenter phase II trial in 53 adult, cyclosporine-immunosuppressed aHSCT patients in the setting of granulocytopenia and refractory fever. Patients received either CAS (50 mg QD; d 1:70 mg), LAMB (3 mg/kg QD) or the combination of both until defervescence and granulocyte recovery. Pharmacokinetic sampling was mainly performed on days 1 and 4. Drug concentrations in plasma (LAMB: 405, CAS: 458 samples) were quantified by HPLC.
Results: CAS concentration data fitted best to a two-compartment model with proportional error model and interindividual variability (IIV) on clearance (CL) and central volume (V1) (CL: 0.426 L/h ± 24 %, V1: 9.25 L ± 29 %, intercompartimental clearance (Q): 0.823 L/h, peripheral volume (V2): 3.06 L). Concentration data of LAMB fitted best to a two-compartment model with combined error model and IIV on all parameters (CL: 0.786 L/h ± 69 %, V1: 18.6 L ± 42 %, Q: 2.86 L/h ± 56 %, V2: 81.7 L ± 60 %). Internal validation showed that both models adequately described the observed data. None of the covariates tested (LAMB- or CAS- comedication, respectively, sex, weight, age, bilirubin, creatinine clearance) further improved the models.
Conclusions: The disposition of LAMB and CAS was best described by two compartment models. Drugs exposures in aHSCT patients were comparable to those in other populations, and no pharmacokinetic interactions were observed between the two compounds.
