title: Safety and pharmacokinetics of ribavirin for the treatment of la crosse encephalitis.
abstract: BACKGROUND
  La Crosse viral encephalitis (LACVE) is associated with residual epilepsy and neurocognitive deficits in survivors. This report summarizes 3 phases of clinical studies of children treated with intravenous (IV) ribavirin (RBV), each one exploring a different phase (I, IIA, IIB) of clinical trial development.
  
  
  METHODS
  In phase I, 7 children with life-threatening LACVE were treated with emergency use RBV using a moderate IV dose (8.33 mg/kg/dose q 8 hours day 1, 5 mg/kg/dose q 8 hours days 2-10). In phase IIA, 12 children with severe LACVE were enrolled: 8 treated with RBV (same dose as phase I) and 4 with placebo. In phase IIB an escalated dose was used (33 mg/kg dose 1, then 16 mg/kg/dose q 6 hours for 4 days, and 8 mg/kg/dose q 8 hours for 3 days).
  
  
  RESULTS
  In a group of 15 children treated in phase I and phase IIA, RBV appeared safe at moderate dose, but based on steady-state RBV levels of 9.3 μM, estimated cerebrospinal fluid levels were less than 20% of the EC50 of RBV for LACVE. At the escalated dose used in phase IIB, adverse events occurred, likely related to RBV, and therefore the trial was discontinued. Nevertheless, valuable pharmacokinetic (PK) and safety data were obtained at moderate dose, with potential treatment implications for other indications.
  
  
  CONCLUSIONS
  Although the results do not support the use of RBV for LACVE, this nevertheless is the largest study of antiviral treatment for LACVE to date and the largest pharmacokinetic analysis of IV RBV in children for any indication.
authors.affiliation: Department of Pediatrics, West Virginia University Health Sciences Center, Charleston Division, Charleston, WV, USA. jmcjunkin@hsc.wvu.edu
authors.forename: James E
authors.initials: JE
authors.lastname: McJunkin
authors.forename: Milap C
authors.initials: MC
authors.lastname: Nahata
authors.forename: Emily C
authors.initials: EC
authors.lastname: De Los Reyes
authors.forename: W Garrett
authors.initials: WG
authors.lastname: Hunt
authors.forename: Manuel
authors.initials: M
authors.lastname: Caceres
authors.forename: Raheel R
authors.initials: RR
authors.lastname: Khan
authors.forename: Mouna G
authors.initials: MG
authors.lastname: Chebib
authors.forename: Sasidharan
authors.initials: S
authors.lastname: Taravath
authors.forename: Linda L
authors.initials: LL
authors.lastname: Minnich
authors.forename: Roxane
authors.initials: R
authors.lastname: Carr
authors.forename: Christine A
authors.initials: CA
authors.lastname: Welch
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Whitley
mesh_terms: D000293:Adolescent; D000998:Antiviral Agents / Q000009:adverse effects* / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D004670:Encephalitis, California / Q000188:drug therapy* / Q000821:virology; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D018062:La Crosse virus / Q000302:isolation & purification; D008297:Male; D012254:Ribavirin / Q000009:adverse effects* / Q000493:pharmacokinetics*
chemical_list: D000998:Antiviral Agents; D012254:Ribavirin