title: Correlations between factors determining the pharmacokinetics and antiviral activity of HIV-1 non-nucleoside reverse transcriptase inhibitors of the diaryltriazine and diarylpyrimidine classes of compounds.
abstract: OBJECTIVE
  To investigate the important factors that determine the bioavailability and the antiviral activity of the diaryltriazine (DATA) and diarylpyrimidine (DAPY) non-nucleoside reverse transcriptase inhibitors (NNRTIs) of HIV-1 in animal species and humans using cell-based assays, physicochemical and computed parameters.
  
  
  METHODS
  This naturalistic study included 15 parameters ranging from molecular mechanics calculations to phase I clinical trials. The calculated parameters were solvent-accessible surface area (SASA), polar surface area and Gibbs free energy of solvation. Physicochemical parameters comprised lipophilicity (octanol/water partition coefficient [cLogP]), ionisation constant (pKa), solubility and aggregate radius. Cell-based assays included human colonic adenocarcinoma cell (Caco-2) permeability (transepithelial transport), drug metabolism and antiviral activity (negative logarithm of the molar effective concentration inhibiting viral replication by 50% [pEC50]). Exposure was tested in rats, dogs and human volunteers.
  
  
  RESULTS
  Of the 15 parameters, eight correlated consistently among one another. Exposure (area under the plasma concentration-time curve [AUC]) in humans correlated positively with that in rats (r = 1.00), with transepithelial transport (r = 0.83), lipophilicity (r = 0.60), ionisability (r = 0.89), hydrodynamic radius of aggregates (r = 0.66) and with antiviral activity (r = 0.61). Exposure in humans was also seen to correlate negatively with SASA (r = -0.89). No consistent correlation was found between exposure in dogs and the eight parameters. Of the 14 DATA/DAPY molecules, 11 form aggregates with radii between 34 and 100 nm.
  
  
  CONCLUSIONS
  We observed correlations between exposure in humans with exposure in rats, transepithelial transport (Caco-2 cells), ionisability, lipophilicity, aggregate radius and SASA in the class of DATA/DAPY NNRTI compounds. The lipophilic DATA/DAPY compounds form aggregates. It can be assumed that absorption in the intestinal tract and endocytosis in infected cells of these lipophilic compounds are governed by the common phenomenon of aggregate formation. As the lymphatic system offers a pathway for intestinal uptake of aggregates, this may offer a therapeutic advantage in the treatment of HIV-1 infection. Although it was not the objective of the study, we found that the rat was a better in vivo model than the dog for the prediction of systemic exposure in this particular set of compounds.
authors.affiliation: Center for Molecular Design (CMD), Janssen Pharmaceutica, Vosselaar, Belgium. plewi@prdbe.jnj.com
authors.forename: Paul
authors.initials: P
authors.lastname: Lewi
authors.forename: Eddy
authors.initials: E
authors.lastname: Arnold
authors.forename: Koen
authors.initials: K
authors.lastname: Andries
authors.forename: Hilde
authors.initials: H
authors.lastname: Bohets
authors.forename: Herman
authors.initials: H
authors.lastname: Borghys
authors.forename: Arthur
authors.initials: A
authors.lastname: Clark
authors.forename: Frits
authors.initials: F
authors.lastname: Daeyaert
authors.forename: Kalyan
authors.initials: K
authors.lastname: Das
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: de Béthune
authors.forename: Marc
authors.initials: M
authors.lastname: de Jonge
authors.forename: Jan
authors.initials: J
authors.lastname: Heeres
authors.forename: Luc
authors.initials: L
authors.lastname: Koymans
authors.forename: Jos
authors.initials: J
authors.lastname: Leempoels
authors.forename: Jef
authors.initials: J
authors.lastname: Peeters
authors.forename: Philip
authors.initials: P
authors.lastname: Timmerman
authors.forename: Walter
authors.initials: W
authors.lastname: Van den Broeck
authors.forename: Frédéric
authors.initials: F
authors.lastname: Vanhoutte
authors.forename: Gerben
authors.initials: G
authors.lastname: Van't Klooster
authors.forename: Maarten
authors.initials: M
authors.lastname: Vinkers
authors.forename: Yulia
authors.initials: Y
authors.lastname: Volovik
authors.forename: Paul A J
authors.initials: PA
authors.lastname: Janssen
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D018938:Caco-2 Cells; D004285:Dogs; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D007408:Intestinal Absorption; D008196:Lymph / Q000378:metabolism; D008958:Models, Molecular; D011743:Pyrimidines / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics*; D013329:Structure-Activity Relationship; D014227:Triazines / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: D019380:Anti-HIV Agents; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; D014227:Triazines