title: Cell disposition of raltegravir and newer antiretrovirals in HIV-infected patients: high inter-individual variability in raltegravir cellular penetration.
abstract: OBJECTIVE
  The site of pharmacological activity of raltegravir is intracellular. Our aim was to determine the extent of raltegravir cellular penetration and whether raltegravir total plasma concentration (C(tot)) predicts cellular concentration (C(cell)).
  
  
  METHODS
  Open-label, prospective, pharmacokinetic study on HIV-infected patients on a stable raltegravir-containing regimen. Plasma and peripheral blood mononuclear cells were simultaneously collected during a 12 h dosing interval after drug intake. C(tot) and C(cell) of raltegravir, darunavir, etravirine, maraviroc and ritonavir were measured by liquid chromatography coupled to tandem mass spectrometry after protein precipitation. Longitudinal mixed effects analysis was applied to the C(cell)/C(tot) ratio.
  
  
  RESULTS
  Ten HIV-infected patients were included. The geometric mean (GM) raltegravir total plasma maximum concentration (C(max)), minimum concentration (C(min)) and area under the time-concentration curve from 0-12 h (AUC(0-12)) were 1068 ng/mL, 51.1 ng/mL and 4171 ng·h/mL, respectively. GM raltegravir cellular C(max), C(min) and AUC(0-12) were 27.5 ng/mL, 2.9 ng/mL and 165 ng·h/mL, respectively. Raltegravir C(cell) corresponded to 5.3% of C(tot) measured simultaneously. Both concentrations fluctuate in parallel, with C(cell)/C(tot) ratios remaining fairly constant for each patient without a significant time-related trend over the dosing interval. The AUC(cell)/AUC(tot) GM ratios for raltegravir, darunavir and etravirine were 0.039, 0.14 and 1.55, respectively.
  
  
  CONCLUSIONS
  Raltegravir C(cell) correlated with C(tot) (r = 0.86). Raltegravir penetration into cells is low overall (∼5% of plasma levels), with distinct raltegravir cellular penetration varying by as much as 15-fold between patients. The importance of this finding in the context of development of resistance to integrase inhibitors needs to be further investigated.
authors.affiliation: Division of Clinical Pharmacology and Toxicology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Fayet Mello
authors.forename: Thierry
authors.initials: T
authors.lastname: Buclin
authors.forename: Claudia
authors.initials: C
authors.lastname: Franc
authors.forename: Sara
authors.initials: S
authors.lastname: Colombo
authors.forename: Sandra
authors.initials: S
authors.lastname: Cruchon
authors.forename: Nicole
authors.initials: N
authors.lastname: Guignard
authors.forename: Jérôme
authors.initials: J
authors.lastname: Biollaz
authors.forename: Amalio
authors.initials: A
authors.lastname: Telenti
authors.forename: Laurent A
authors.initials: LA
authors.lastname: Decosterd
authors.forename: Matthias
authors.initials: M
authors.lastname: Cavassini
mesh_terms: D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002853:Chromatography, Liquid; D003593:Cytoplasm / Q000737:chemistry; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000737:chemistry*; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D010949:Plasma / Q000737:chemistry*; D011446:Prospective Studies; D011760:Pyrrolidinones / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000068898:Raltegravir Potassium
chemical_list: D019380:Anti-HIV Agents; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium