title: High incidence of adverse events in healthy volunteers receiving rifampicin and adjusted doses of lopinavir/ritonavir tablets.
abstract: OBJECTIVE
  Previous research in healthy volunteers has demonstrated that rifampicin and adjusted doses of lopinavir/ritonavir soft-gel capsules resulted in adequate exposure to lopinavir. Our objective was to study the combined use of rifampicin and the newly introduced lopinavir/ritonavir tablets.
  
  
  METHODS
  A total of 40 healthy volunteers were planned to start with 600 mg rifampicin once daily from days 1-5. From days 6-15, volunteers were randomized to receive lopinavir/ritonavir tablets dosed as either 600/150 or 800/200 mg twice daily, both in addition to 600 mg rifampicin once daily. A 12 h pharmacokinetic curve was planned on day 15. Safety assessments were conducted regularly throughout the study period.
  
  
  RESULTS
  Eleven volunteers started as the first group in this study. No major complaints occurred during day 1-5 (rifampicin only). After addition of lopinavir/ritonavir, eight volunteers suffered from both nausea and vomiting, one from nausea only, and one from vomiting only. On day 7, increases in aspartate aminotransferase/alanine aminotransferase (AST/ALT) levels were reported in all volunteers and on day 8, the study was prematurely terminated. The AST/ALT levels continued to rise and peaked (grade 2, n = 2; grade 3, n = 1; grade 4, n = 8) on days 9-10. All values returned to normal within 6 weeks.
  
  
  CONCLUSIONS
  The study showed a high incidence of adverse events when a higher than standard dose of the new lopinavir/ritonavir tablets was combined with rifampicin. In the future, this drug combination should not be given to healthy volunteers. Liver function should be carefully monitored when rifampicin and lopinavir/ritonavir are combined in patients.
authors.affiliation: Department of Clinical Pharmacy, Radboud University Nijmegen Medical Centre, The Netherlands.
authors.forename: Hanneke M J
authors.initials: HM
authors.lastname: Nijland
authors.forename: Rafaëlla F A
authors.initials: RF
authors.lastname: L'homme
authors.forename: Gerard A
authors.initials: GA
authors.lastname: Rongen
authors.forename: Peter
authors.initials: P
authors.lastname: van Uden
authors.forename: Reinout
authors.initials: R
authors.lastname: van Crevel
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Boeree
authors.forename: Rob E
authors.initials: RE
authors.lastname: Aarnoutse
authors.forename: Peter P
authors.initials: PP
authors.lastname: Koopmans
authors.forename: David M
authors.initials: DM
authors.lastname: Burger
mesh_terms: D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D000904:Antibiotics, Antitubercular / Q000009:adverse effects*; D001219:Aspartate Aminotransferases / Q000097:blood; D004334:Drug Administration Schedule; D004338:Drug Combinations; D004347:Drug Interactions; D005260:Female; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D006801:Humans; D061466:Lopinavir; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D011744:Pyrimidinones / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D012293:Rifampin / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D019438:Ritonavir / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D013607:Tablets; D014839:Vomiting / Q000139:chemically induced
chemical_list: D000904:Antibiotics, Antitubercular; D004338:Drug Combinations; D017320:HIV Protease Inhibitors; D011744:Pyrimidinones; D013607:Tablets; D061466:Lopinavir; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D019438:Ritonavir; D012293:Rifampin