Yazarlar : Würthwein G, Young C, Lanvers-Kaminsky C, Hempel G, Trame MN, Schwerdtfeger R, Ostermann H, Heinz WJ, Cornely OA, Kolve H, Boos J, Silling G, Groll AH.

Yayın : Antimicrob Agents Chemother.

Pubmed Linki : http://www.ncbi.nlm.nih.gov/pubmed/22083471

Konu : Enfeksiyon

Literatür İçeriği :  

Abstract

Liposomal amphotericin B (LAMB) and caspofungin (CAS) are important antifungal agents in allogeneic hematopoietic stem cell transplant (aHSCT) recipients. Little is known, however, about the pharmacokinetics (PK) of both agents and their combination in this population.The PK of LAMB and CAS and the potential for PK interactions between both agents were investigated within a risk-stratified, randomized phase II clinical trial in 53 adult aHSCT recipients with granulocytopenia and refractory fever. Patients received either LAMB (n=17; 3 mg/kg once a day (QD), CAS (n=19; 50 mg QD; day 1: 70 mg) or the combination of both (CASLAMB; n=17) for a median duration of 10 to 13 days (range, 4 - 28) until defervescence and granulocyte recovery. PK sampling was performed on days 1 and 4. Drug concentrations in plasma (LAMB: 405, CAS: 458 samples) were quantified by HPLC and were analyzed using population pharmacokinetic modeling.CAS concentration data fitted best to a two-compartment model with proportional error model and interindividual variability (IIV) on clearance (CL) and central volume of distribution (V1) (CL: 0.462 L/h ± 25 %, V1: 8.33 L ± 29 %, intercompartmental clearance (Q): 1.25 L/h, peripheral volume of distribution (V2): 3.59 L). Concentration data of LAMB fitted best to a two-compartment model with proportional error model and IIV on all parameters (CL: 1.22 L/h ± 64 %, V1: 19.2 L ± 38 %, Q: 2.18 L/h ± 47 %, V2: 52.8 L ± 84 %). Internal model validation showed predictability and robustness of both models. None of the covariates tested (LAMB- or CAS- comedication, respectively, gender, body weight, age, body surface area, serum bilirubin, creatinine clearance) further improved the models.In summary, the disposition of LAMB and CAS were best described by two compartment models. Drugs exposures in aHSCT patients were comparable to those in other populations, and no PK interactions were observed between the two compounds.

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