title: Etravirine in CSF is highly protein bound.
abstract: OBJECTIVE
  Etravirine has high affinity for plasma drug-binding proteins, such as albumin and α1-acid glycoprotein, which limits the amount of unbound etravirine available to enter the CNS. The objective of this study was to compare total and unbound etravirine concentrations in CSF with plasma concentrations and the in vitro median inhibitory concentration (IC50) for wild-type HIV (0.9 ng/mL).
  
  
  METHODS
  Total and bound etravirine concentrations were measured in 17 CSF and plasma pairs by isotope-dilution liquid chromatography tandem mass spectroscopy, radioligand displacement and ultracentrifugation. Unbound etravirine concentrations were calculated from the bound fraction. The dynamic range of the assay was 7.8-2000 (plasma) and 0.78-200 (CSF) ng/mL.
  
  
  RESULTS
  Subjects were mostly middle-aged (median 43 years) white (78%) men (89%). All CSF etravirine concentrations were above the limit of quantification. Total and unbound median etravirine concentrations in CSF were 9.5 (IQR 6.4, 26.4) and 0.13 (IQR 0.08, 0.27) ng/mL, respectively. Etravirine was 96% (IQR 94.5, 97.2) protein bound in plasma and 98.4% (IQR 97.8, 98.8) in CSF. Total etravirine in CSF was 4.3% (IQR 3, 5.9) of total and 101% (IQR 76, 160) of unbound etravirine in plasma. There were no significant correlations between unbound etravirine concentrations and concentrations of albumin in plasma or CSF. Unbound etravirine concentrations in CSF did not reach the wild-type IC50 in any of the specimens.
  
  
  CONCLUSIONS
  Unbound etravirine may not achieve optimal concentrations to inhibit HIV replication in the CNS.
authors: Department of Pediatrics (Rady Children's Hospital), University of California San Diego, 3020 Childrens Way, San Diego, CA 92123, USA.
authors: Anh
authors: A
authors: Nguyen
authors: Steven
authors: S
authors: Rossi
authors: David
authors: D
authors: Croteau
authors: Brookie M
authors: BM
authors: Best
authors: David
authors: D
authors: Clifford
authors: Ann C
authors: AC
authors: Collier
authors: Benjamin
authors: B
authors: Gelman
authors: Christina
authors: C
authors: Marra
authors: Justin
authors: J
authors: McArthur
authors: J Allen
authors: JA
authors: McCutchan
authors: Susan
authors: S
authors: Morgello
authors: David
authors: D
authors: Simpson
authors: Ronald J
authors: RJ
authors: Ellis
authors: Igor
authors: I
authors: Grant
authors: Edmund
authors: E
authors: Capparelli
authors: Scott
authors: S
authors: Letendre
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000032:analysis* / Q000378:metabolism / Q000493:pharmacokinetics*; D002555:Cerebrospinal Fluid / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D015331:Cohort Studies; D005260:Female; D015658:HIV Infections / Q000188:drug therapy; D006801:Humans; D020128:Inhibitory Concentration 50; D007553:Isotope Labeling; D008297:Male; D008875:Middle Aged; D009570:Nitriles; D010949:Plasma / Q000737:chemistry; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D011724:Pyridazines / Q000032:analysis* / Q000378:metabolism / Q000493:pharmacokinetics*; D011743:Pyrimidines; D053719:Tandem Mass Spectrometry; D014461:Ultracentrifugation
chemical_list: D019380:Anti-HIV Agents; D009570:Nitriles; D011506:Proteins; D011724:Pyridazines; D011743:Pyrimidines; C451734:etravirine