title: The pharmacokinetics of lersivirine (UK-453,061) and HIV-1 protease inhibitor coadministration in healthy subjects.
abstract: OBJECTIVE
  Lersivirine (UK-453,061) is a next-generation nonnucleoside reverse transcriptase inhibitor, active against wild-type HIV-1 and several nonnucleoside reverse transcriptase inhibitor-resistant strains. Four studies evaluated the pharmacokinetic (PK) interactions between lersivirine and various HIV-1 protease inhibitors.
  
  
  METHODS
  Four phase I trials were conducted to assess the PK of lersivirine when coadministered with lopinavir/ritonavir, darunavir/ritonavir, or atazanavir with/without ritonavir, and to examine the effects of lersivirine on the PK of atazanavir with/without ritonavir. PK data included the area under the plasma concentration-time profile from time zero to the end of the dosing interval (AUC24), maximum plasma concentration (Cmax), minimum plasma concentration (Cmin, C24, or Ctrough), and time to Cmax (Tmax). Safety was assessed by recording adverse events, vital signs, and laboratory data.
  
  
  RESULTS
  Coadministration of lersivirine with lopinavir/ritonavir, darunavir/ritonavir, or atazanavir/ritonavir decreased mean plasma lersivirine AUC24 by 43%, 22%, and 19%, respectively. Atazanavir had no effect on lersivirine exposure, except for a 16% decrease in lersivirine C24. Lersivirine had no effect on atazanavir AUC24 or Cmax, although Ctrough was reduced by 18% in the absence of ritonavir.
  
  
  CONCLUSIONS
  Lersivirine exposure was reduced when coadministered with ritonavir-boosted protease inhibitors; a dose adjustment may be warranted. Unboosted atazanavir had no effect on lersivirine exposure, except for a small decrease in lersivirine C24. Lersivirine had no effect on atazanavir (with/without ritonavir) exposure, except for a decrease in Ctrough. Caution should be applied when unboosted atazanavir is coadministered with lersivirine. Coadministration of lersivirine with lopinavir/ritonavir, darunavir/ritonavir, or atazanavir with/without ritonavir seems to be generally well tolerated.
authors.affiliation: Department of Clinical Pharmacology, Pfizer Global Research and Development, New York, NY, USA. manoli.vourvahis@pfizer.com
authors.forename: Manoli
authors.initials: M
authors.lastname: Vourvahis
authors.forename: Grant
authors.initials: G
authors.lastname: Langdon
authors.forename: Gary
authors.initials: G
authors.lastname: Layton
authors.forename: Robert R
authors.initials: RR
authors.lastname: Labadie
authors.forename: Heng Wee
authors.initials: HW
authors.lastname: Choo
authors.forename: Marie-Noella
authors.initials: MN
authors.lastname: Ndongo
authors.forename: John
authors.initials: J
authors.lastname: Davis
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects / Q000379:methods*; D005260:Female; D017320:HIV Protease Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009570:Nitriles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D010949:Plasma / Q000737:chemistry; D011720:Pyrazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D009570:Nitriles; D011720:Pyrazoles; C531151:UK 453,061