Pharmacokinetics and safety of intravenous cidofovir for life-threatening viral infections in pediatric hematopoietic stem cell transplant recipients.
Children undergoing hematopoietic stem cell transplantation (HSCT) are at risk for life-threatening viral infections. Cidofovir is often used as a first-line agent for adenovirus infections, despite the absence of randomized controlled trials with HSCT patients, and as a second-line agent for resistant herpesvirus infections. The frequency and severity of adverse effects, particularly nephrotoxicity, in pediatric HSCT recipients are unclear, and pharmacokinetics (PK) of cidofovir in children have not previously been reported. This study was an open-label, nonrandomized, single-dose pilot study to determine the safety and PK of cidofovir in pediatric HSCT recipients with symptomatic adenovirus, nucleoside-resistant cytomegalovirus (CMV) or herpes simplex virus (HSV), and/or human papovavirus infections. Subsequent dosing and frequency were determined by clinical response and side effects, as assessed by the treating physician. Blood and urine samples were obtained from patients for PK studies and assessment of toxicity and virologic response. Twelve patients were enrolled (median age, 9 years; 33.5 days posttransplantation). Four of seven patients with adenovirus infection were successfully treated and eventually cleared their infections. Four of twelve patients died of disseminated viral disease and multiorgan failure. Two of twelve patients had evidence of acute kidney injury after the first dose, and one of these patients developed chronic kidney disease; two other patients developed late nephrotoxicity. The mean drug half-life was 9.5 h. There was no correlation between nephrotoxicity and plasma maximum concentration, clearance, or half-life. PK were similar to those reported for adults, although the drug half-life was significantly longer than that for adults. Cidofovir was well tolerated in the majority of patients. However, effective therapeutic strategies are urgently needed to support patients until immune reconstitution is achieved.
Section of Hematology, Oncology and Bone Marrow Transplantation, Department of Pediatrics, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado, USA aecbrown@gmail.com.
Amy E
AE
Caruso Brown
Department of Anesthesiology, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado, USA.
Mindy N
MN
Cohen
Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado, USA.
Suhong
S
Tong
Department of Ophthalmology, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado, USA.
Rebecca S
RS
Braverman
Gilead Sciences, Foster City, California, USA.
James F
JF
Rooney
Section of Hematology, Oncology and Bone Marrow Transplantation, Department of Pediatrics, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado, USA.
Roger
R
Giller
Section of Pediatric Infectious Diseases, Department of Pediatrics, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado, USA.
Myron J
MJ
Levin
D058186:Acute Kidney Injury / Q000139:chemically induced; D000258:Adenovirus Infections, Human / Q000188:drug therapy* / Q000401:mortality; D000293:Adolescent; D000998:Antiviral Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D001739:BK Virus / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D000077404:Cidofovir; D003586:Cytomegalovirus Infections / Q000188:drug therapy*; D003596:Cytosine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006566:Herpesviridae Infections / Q000188:drug therapy*; D006801:Humans; D008297:Male; D063065:Organophosphonates / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D010865:Pilot Projects; D027601:Polyomavirus Infections / Q000188:drug therapy*; D014766:Viremia / Q000188:drug therapy / Q000821:virology
D000998:Antiviral Agents; D063065:Organophosphonates; D003596:Cytosine; D000077404:Cidofovir