title: Determinants of darunavir cerebrospinal fluid concentrations:  impact of once-daily dosing and pharmacogenetics.
abstract: OBJECTIVE
  To compare cerebrospinal fluid (CSF) darunavir and ritonavir concentrations in patients receiving darunavir/ritonavir 800/100 mg once daily or 600/100 mg twice daily. To determine the influence of single-nucleotide polymorphisms in the genes encoding for blood-brain barrier transporters (ABCB1 3435 C>T, ABCB1 1236 C>T, ABCB1 2677 G>T, SLCO1A2 38 A>G, SLCO1A2 516 A>C, ABCC2 -24 G>A) on darunavir and ritonavir penetration into CSF.
  
  
  METHODS
  Comparative pharmacokinetics study in patients.
  
  
  METHODS
  Plasma and CSF darunavir and ritonavir concentrations (2-26 h after drug intake) were determined by a validated HPLC coupled with mass spectrometry method in adults on darunavir-based combination antiretroviral therapy undergoing a lumbar puncture.
  
  
  RESULTS
  HIV-infected patients on once-daily darunavir/ritonavir had significantly lower CSF darunavir trough concentrations and CSF-to-plasma ratios than patients on darunavir/ritonavir twice-daily (10.7 versus 38.2 ng/ml and 0.32 versus 0.90%; P < 0.05). No significant effect of single-nucleotide polymorphisms in the genes encoding for blood-brain barrier transporters was noted apart from slightly higher CSF darunavir penetration in patients carrying OATP1A2 uncommon variants.
  
  
  CONCLUSIONS
  This is the first study to compare darunavir CSF concentrations in patients taking the once-daily or the twice-daily dosage: our data show that darunavir and ritonavir dosing significantly affects not only CSF concentrations but also the extent of drug penetration into the CSF. Furthermore a minority of patients in the once-daily arm presented very low CSF concentration of potential concern for HIV control in the central nervous system. The relative importance of pharmacogenetics in influencing CSF darunavir pharmacokinetics deserves further clinical investigation.
authors.affiliation: Department of Infectious Diseases, University of Torino, Torino, Italy. andrea.calcagno@unito.it
authors.forename: Andrea
authors.initials: A
authors.lastname: Calcagno
authors.forename: Aylin
authors.initials: A
authors.lastname: Yilmaz
authors.forename: Jessica
authors.initials: J
authors.lastname: Cusato
authors.forename: Marco
authors.initials: M
authors.lastname: Simiele
authors.forename: Roberto
authors.initials: R
authors.lastname: Bertucci
authors.forename: Marco
authors.initials: M
authors.lastname: Siccardi
authors.forename: Letizia
authors.initials: L
authors.lastname: Marinaro
authors.forename: Antonio
authors.initials: A
authors.lastname: D'Avolio
authors.forename: Giovanni
authors.initials: G
authors.lastname: Di Perri
authors.forename: Stefano
authors.initials: S
authors.lastname: Bonora
mesh_terms: D000328:Adult; D001812:Blood-Brain Barrier; D002851:Chromatography, High Pressure Liquid; D000069454:Darunavir; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000097:blood / Q000134:cerebrospinal fluid* / Q000188:drug therapy; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D020641:Polymorphism, Single Nucleotide; D019438:Ritonavir / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D013449:Sulfonamides / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*
chemical_list: C000715087:ABCC2 protein, human; D017320:HIV Protease Inhibitors; D000089762:Multidrug Resistance-Associated Protein 2; D013449:Sulfonamides; D019438:Ritonavir; D000069454:Darunavir