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

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.

Development and validation of a HPLC method for the assay of dapivirine in cell-based and tissue permeability experiments

“…Dapivirine presented P app values (mean ± SD) of 3.70 × 10 −6 ± 0.36 × 10 −6 and 4.44 × 10 −6 ± 0.26 × 10 −6 cm s −1 for CaSki and Caco-2 cell monolayers, respectively, when dapivirine-loaded nanoparticles were used; in the case of the free drug, these results increased to 4.84 × 10 −6 ± 0.28 × 10 −6 and 5.26 × 10 −6 ± 0.38 × 10 −6 cm s −1 for CaSki and Caco-2 cell monolayers, respectively. Even if higher, the values found in this study are in order with those previously reported for free dapivirine in Caco-2 cell monolayers (2.14 × 10 −6 ± 0.81 × 10 −6 cm s −1 ) [35].…”

Vaginal Microbicide Gel for Delivery of IQP-0528, a Pyrimidinedione Analog with a Dual Mechanism of Action against HIV-1

“…Typically, drugs with Log P values in the range of 2 to 3 show optimal permeability across the stratum cornea (SC), as well as moderate partitioning out of the SC. On the contrary, drugs with a Log P of Ͼ3 are expected to exhibit high partitioning into the SC but poor partitioning into the systemic circulation (22). It is known that lipophilic compounds have higher tissue residence times and therefore lower systemic exposure (10).…”

In Search of a Novel Anti-HIV Drug: Multidisciplinary Coordination in the Discovery of 4-[[4-[[4-[(1E)-2-Cyanoethenyl]-2,6-dimethylphenyl]amino]-2- pyrimidinyl]amino]benzonitrile (R278474, Rilpivirine)

“…It thus appears that there is a minimum threshold on the number of molecules that are required to inhibit virus reproduction in an infected cell. 42,43 It is known that lipophilic compounds (such as TMC120 and R278474) can form aggregates. 44 Formation of aggregates is common, and it may be the cause of nonspecific binding to proteins that has been observed in high-throughput screening (HTS) tests.…”