title: Pharmacokinetic interactions between lersivirine and zidovudine, tenofovir disoproxil fumarate/emtricitabine and abacavir/lamivudine.
abstract: BACKGROUND
  To investigate pharmacokinetic interactions associated with coadministration of lersivirine with zidovudine, tenofovir disoproxil fumarate (DF)/emtricitabine (Truvada(®)) or abacavir/lamivudine (Epzicom(®)/Kivexa(®)).
  
  
  METHODS
  Three Phase I, open, crossover studies with two (studies 1 and 3) or three (study 2) treatment periods were conducted in healthy individuals. In study 1, individuals received zidovudine and placebo or zidovudine and lersivirine on days 1-14. In study 2, individuals received lersivirine and tenofovir DF/emtricitabine, lersivirine and placebo or tenofovir DF/emtricitabine and placebo on days 1-10. In study 3, individuals received abacavir/lamivudine only in period 1 (5 days) and abacavir/lamivudine and lersivirine in period 2 (10 days). Blood samples were taken on days 1-14 (study 1) or day of final dose (studies 2 and 3) and analysed using high performance liquid chromatography/dual mass spectrometry. Pharmacokinetic parameters were calculated by standard non-compartmental methods.
  
  
  RESULTS
  When coadministered with lersivirine, zidovudine exposure increased by 35%, and exposure of its metabolite zidovudine-glucuronide decreased by 19%. Following coadministration of lersivirine and tenofovir DF/emtricitabine, tenofovir exposure increased by 30%, and lersivirine exposure decreased by 12%. Coadministration of lersivirine and abacavir/lamivudine increased abacavir exposure by 27% and decreased lamivudine exposure by 8%. Adverse events were predominantly mild in these Phase I studies.
  
  
  CONCLUSIONS
  Coadministration of lersivirine with zidovudine, tenofovir DF/emtricitabine or abacavir/lamivudine influenced the systemic exposure of all nucleoside reverse transcriptase inhibitor agents investigated (except for lamivudine; emtricitabine pharmacokinetics were not assessed). Changes were not considered clinically meaningful for zidovudine and abacavir. The clinical relevance of the effect on tenofovir pharmacokinetics is currently unknown.
authors.affiliation: Pfizer Global Research and Development, New York, NY, USA. manoli.vourvahis@pfizer.com.
authors.forename: Manoli
authors.initials: M
authors.lastname: Vourvahis
authors.forename: John
authors.initials: J
authors.lastname: Davis
authors.forename: Grant
authors.initials: G
authors.lastname: Langdon
authors.forename: Gary
authors.initials: G
authors.lastname: Layton
authors.forename: Juanzhi
authors.initials: J
authors.lastname: Fang
authors.forename: Heng Wee
authors.initials: HW
authors.lastname: Choo
authors.forename: Arne G
authors.initials: AG
authors.lastname: Hansson
authors.forename: Margaret
authors.initials: M
authors.lastname: Tawadrous
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D015224:Dideoxynucleosides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004338:Drug Combinations; D004347:Drug Interactions; D000068679:Emtricitabine; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D064368:Healthy Volunteers; D006801:Humans; D019259:Lamivudine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D009570:Nitriles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D063065:Organophosphonates / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D011720:Pyrazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000068698:Tenofovir; D055815:Young Adult; D015215:Zidovudine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000099227:Abacavir
chemical_list: D000225:Adenine; D019380:Anti-HIV Agents; D003841:Deoxycytidine; D015224:Dideoxynucleosides; D004338:Drug Combinations; D000068679:Emtricitabine; D019259:Lamivudine; D009570:Nitriles; D063065:Organophosphonates; D011720:Pyrazoles; D000068698:Tenofovir; D015215:Zidovudine; C531151:UK 453,061; C492871:abacavir, lamivudine drug combination; D000099227:Abacavir