title: Randomized comparison of safety and pharmacokinetics of caspofungin, liposomal amphotericin B, and the combination of both in allogeneic hematopoietic stem cell recipients.
abstract: The combination of liposomal amphotericin B (LAMB) and caspofungin (CAS) holds promise to improve the outcome of opportunistic invasive mycoses with poor prognosis. Little is known, however, about the safety and pharmacokinetics of the combination in patients at high risk for these infections. The safety and pharmacokinetics of the combination of LAMB and CAS were investigated in a risk-stratified, randomized, multicenter phase II clinical trial in 55 adult allogeneic hematopoietic stem cell recipients (aHSCT) with granulocytopenia and refractory fever. The patients received either CAS (50 mg/day; day 1, 70 mg), LAMB (3 mg/kg of body weight/day), or the combination of both (CASLAMB) until defervescence and granulocyte recovery. Safety, development of invasive fungal infections, and survival were assessed through day 14 after the end of therapy. Pharmacokinetic sampling and analysis were performed on days 1 and 4. All three regimens were well tolerated. Premature study drug discontinuations due to grade III/IV adverse events occurred in 1/18, 2/20, and 0/17 patients randomized to CAS, LAMB, and CASLAMB, respectively. Adverse events not leading to study drug discontinuation were frequent but similar across cohorts, except for a higher frequency of hypokalemia with CASLAMB (P < 0.05). Drug exposures were similar for patients receiving combination therapy and those randomized to monotherapy. There was no apparent difference in the occurrence of proven/probable invasive fungal infections and survival through day 14 after the end of therapy. CASLAMB combination therapy in immunocompromised aHSCT patients was as safe as monotherapy with CAS or LAMB and had similar plasma pharmacokinetics, lending support to further investigations of the combination in the management of patients with invasive opportunistic mycoses.
authors.affiliation: Infectious Disease Research Program, Center for Bone Marrow Transplantation and Department of Pediatric Hematology/Oncology, University Children’s Hospital Muenster, Muenster, Germany. grollan@ukmuenster.de
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Groll
authors.forename: Gerda
authors.initials: G
authors.lastname: Silling
authors.forename: Charlotte
authors.initials: C
authors.lastname: Young
authors.forename: Rainer
authors.initials: R
authors.lastname: Schwerdtfeger
authors.forename: Helmut
authors.initials: H
authors.lastname: Ostermann
authors.forename: Werner J
authors.initials: WJ
authors.lastname: Heinz
authors.forename: Joachim
authors.initials: J
authors.lastname: Gerss
authors.forename: Hedwig
authors.initials: H
authors.lastname: Kolve
authors.forename: Claudia
authors.initials: C
authors.lastname: Lanvers-Kaminsky
authors.forename: João Paulo
authors.initials: JP
authors.lastname: Vieira Pinheiro
authors.forename: Sibylle
authors.initials: S
authors.lastname: Gammelin
authors.forename: Oliver A
authors.initials: OA
authors.lastname: Cornely
authors.forename: Gudrun
authors.initials: G
authors.lastname: Wuerthwein
mesh_terms: D000293:Adolescent; D000328:Adult; D000380:Agranulocytosis / Q000188:drug therapy / Q000628:therapy; D000666:Amphotericin B / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D000935:Antifungal Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000077336:Caspofungin; D002648:Child; D002675:Child, Preschool; D004359:Drug Therapy, Combination; D054714:Echinocandins / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D055666:Lipopeptides; D008297:Male; D008875:Middle Aged; D009181:Mycoses / Q000188:drug therapy / Q000628:therapy; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; C068538:liposomal amphotericin B; D000666:Amphotericin B; D000077336:Caspofungin