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.
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.
Lewi
Paul
P
Center for Molecular Design (CMD), Janssen Pharmaceutica, Vosselaar, Belgium. plewi@prdbe.jnj.com
Arnold
Eddy
E
Andries
Koen
K
Bohets
Hilde
H
Borghys
Herman
H
Clark
Arthur
A
Daeyaert
Frits
F
Das
Kalyan
K
de Béthune
Marie-Pierre
MP
de Jonge
Marc
M
Heeres
Jan
J
Koymans
Luc
L
Leempoels
Jos
J
Peeters
Jef
J
Timmerman
Philip
P
Van den Broeck
Walter
W
Vanhoutte
Frédéric
F
Van't Klooster
Gerben
G
Vinkers
Maarten
M
Volovik
Yulia
Y
Janssen
Paul A J
PA
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*
D019380:Anti-HIV Agents; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; D014227:Triazines