title: Effects of enzyme inducers efavirenz and tipranavir/ritonavir on the pharmacokinetics of the HIV integrase inhibitor dolutegravir.
abstract: OBJECTIVE
  Dolutegravir (DTG) is an unboosted, integrase inhibitor for the treatment of HIV infection. Two studies evaluated the effects of efavirenz (EFV) and tipranavir/ritonavir (TPV/r) on DTG pharmacokinetics (PK) in healthy subjects.
  
  
  METHODS
  The first study was an open-label crossover where 12 subjects received DTG 50 mg every 24 hours (q24h) for 5 days, followed by DTG 50 mg and EFV 600 mg q24h for 14 days. The second study was an open-label crossover where 18 subjects received DTG 50 mg q24h for 5 days followed by TPV/r 500/200 mg every 12 hours (q12h) for 7 days and then DTG 50 mg q24h and TPV/r 500/200 mg q12h for a further 5 days. Safety assessments and serial PK samples were collected. Non-compartmental PK analysis and geometric mean ratios and 90% confidence intervals were generated.
  
  
  RESULTS
  The combination of DTG with EFV or TPV/r was generally well tolerated. Four subjects discontinued the TPV/r study due to increases in alanine aminotransferase that were considered related to TPV/r. Co-administration with EFV resulted in decreases of 57, 39 and 75% in DTG AUC(0-τ), Cmax and Cτ, respectively. Co-administration with TPV/r resulted in decreases of 59, 46 and 76% in DTG AUC(0-τ), Cmax and Cτ, respectively.
  
  
  CONCLUSIONS
  Given the reductions in exposure and PK/pharmacodynamic relationships in phase II/III trials, DTG should be given at an increased dose of 50 mg twice daily when co-administered with EFV or TPV/r, and alternative regimens without inducers should be considered in integrase inhibitor-resistant patients.
authors.affiliation: GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, Durham, NC, 27709, USA, ivy.h.song@gsk.com.
authors.forename: Ivy
authors.initials: I
authors.lastname: Song
authors.forename: Julie
authors.initials: J
authors.lastname: Borland
authors.forename: Shuguang
authors.initials: S
authors.lastname: Chen
authors.forename: Phyllis
authors.initials: P
authors.lastname: Guta
authors.forename: Yu
authors.initials: Y
authors.lastname: Lou
authors.forename: David
authors.initials: D
authors.lastname: Wilfret
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Wajima
authors.forename: Paul
authors.initials: P
authors.lastname: Savina
authors.forename: Amanda
authors.initials: A
authors.lastname: Peppercorn
authors.forename: Stephen
authors.initials: S
authors.lastname: Castellino
authors.forename: David
authors.initials: D
authors.lastname: Wagner
authors.forename: Louise
authors.initials: L
authors.lastname: Hosking
authors.forename: Michael
authors.initials: M
authors.lastname: Mosteller
authors.forename: Justin P
authors.initials: JP
authors.lastname: Rubio
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Piscitelli
mesh_terms: D000328:Adult; D000368:Aged; D000480:Alkynes; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D019540:Area Under Curve; D048588:Benzoxazines / Q000009:adverse effects / Q000494:pharmacology*; D018592:Cross-Over Studies; D003521:Cyclopropanes; D004338:Drug Combinations; D004347:Drug Interactions; D005260:Female; D019428:HIV Integrase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics; D006575:Heterocyclic Compounds, 3-Ring / Q000009:adverse effects / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010078:Oxazines; D010879:Piperazines; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D011728:Pyridones; D011753:Pyrones / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D019438:Ritonavir / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D013449:Sulfonamides; D055815:Young Adult; D000099226:Dolutegravir
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D004338:Drug Combinations; D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011725:Pyridines; D011728:Pyridones; D011753:Pyrones; D019438:Ritonavir; D013449:Sulfonamides; D000099226:Dolutegravir; C098320:efavirenz; C107201:tipranavir