title: Pharmacokinetics of lopinavir/ritonavir crushed versus whole tablets in children.
abstract: OBJECTIVE
  Lopinavir/ritonavir (Kaletra) is first-line therapy for pediatric HIV infection. In clinical practice, Kaletra tablets are occasionally crushed for pediatric administration. This study compared lopinavir/ritonavir exposure between whole and crushed tablets in HIV-infected children.
  
  
  METHODS
  This was a randomized, open-label, cross-over study of pediatric patients taking lopinavir/ritonavir as part of their antiretroviral regimen. Each subject had 2 separate (within 30 days) steady-state 12-hour pharmacokinetic (PK) studies with crushed and whole 200/50 mg lopinavir/ritonavir tablets.
  
  
  METHODS
  PK blood samples were drawn at 0 (predose), 1, 2, 4, 6, 8, and 12 hours postdose. Lopinavir and ritonavir plasma concentrations measured by high-performance liquid chromatography were used to calculate non-compartmental area under the concentration versus time curve (AUC) and clearance. Wilcoxon signed-rank tests compared PK values between crushed and whole tablets.
  
  
  RESULTS
  Twelve children, median age of 13 years (10-16 years), took 550/138 mg·m(-2) per day lopinavir/ritonavir divided every 12 hours. The median lopinavir AUC after crushed and whole tablets were 92 mg·hr·L(-1) and 144 mg·hr·L(-1), respectively, with an AUC ratio of 0.55 (P = 0.003). Median ritonavir AUC of crushed and whole tablets were 7 mg·hr·L(-1) and 13.3 mg·hr·L(-1), respectively, with an AUC ratio of 0.53 (P = 0.006).
  
  
  CONCLUSIONS
  Administration of crushed 200/50 mg lopinavir/ritonavir tablets to children significantly reduced lopinavir and ritonavir exposure with a decrease in AUC by 45% and 47%, respectively. The administration of crushed tablets would require higher doses and therapeutic drug monitoring to ensure adequate lopinavir exposure in patients requiring this practice. The use of crushed lopinavir/ritonavir tablets should be avoided, if possible.
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093-0719, USA. brookie@ucsd.edu
authors.forename: Brookie M
authors.initials: BM
authors.lastname: Best
authors.forename: Edmund V
authors.initials: EV
authors.lastname: Capparelli
authors.forename: Huy
authors.initials: H
authors.lastname: Diep
authors.forename: Steven S
authors.initials: SS
authors.lastname: Rossi
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Farrell
authors.forename: Elaine
authors.initials: E
authors.lastname: Williams
authors.forename: Grace
authors.initials: G
authors.lastname: Lee
authors.forename: John N
authors.initials: JN
authors.lastname: van den Anker
authors.forename: Natella
authors.initials: N
authors.lastname: Rakhmanina
mesh_terms: D000293:Adolescent; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002648:Child; D018592:Cross-Over Studies; D004338:Drug Combinations; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D061466:Lopinavir / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D019438:Ritonavir / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013607:Tablets; D016896:Treatment Outcome
chemical_list: D019380:Anti-HIV Agents; D004338:Drug Combinations; D013607:Tablets; C558899:lopinavir-ritonavir drug combination; D061466:Lopinavir; D019438:Ritonavir