Doravirine and the Potential for CYP3A-Mediated Drug-Drug Interactions.

Identifying and understanding potential drug-drug interactions (DDIs) are vital for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. This article discusses DDIs between doravirine, a nonnucleoside reverse transcriptase inhibitor (NNRTI), and cytochrome P450 3A (CYP3A) substrates and drugs that modulate CYP3A activity. Consistent with previously published in vitro data and DDI trials with the CYP3A substrates midazolam and atorvastatin, doravirine did not have any meaningful impact on the pharmacokinetics of the CYP3A substrates ethinyl estradiol and levonorgestrel. Coadministration of doravirine with CYP3A inhibitors (ritonavir or ketoconazole) increased doravirine exposure approximately 3-fold. However, these increases were not considered clinically meaningful. Conversely, previously published trials showed that coadministered CYP3A inducers (rifampin and rifabutin) decreased doravirine exposure by 88% and 50%, respectively (K. L. Yee, S. G. Khalilieh, R. I. Sanchez, R. Liu, et al., Clin Drug Investig 37:659-667, 2017 [https://doi.org/10.1007/s40261-017-0513-4]; S. G. Khalilieh, K. L. Yee, R. I. Sanchez, R. Liu, et al., J Clin Pharmacol 58:1044-1052, 2018 [https://doi.org/10.1002/jcph.1103]), while doravirine exposure following prior efavirenz administration led to an initial reduction in doravirine exposure of 62%, but the reduction became less pronounced with time (K. L. Yee, R. I. Sanchez, P. Auger, R. Liu, et al., Antimicrob Agents Chemother 61:e01757-16, 2017 [https://doi.org/10.1128/AAC.01757-16]). Overall, the coadministration of doravirine with CYP3A inhibitors and substrates is, therefore, supported by these data together with efficacy and safety data from clinical trials, while coadministration with strong CYP3A inducers, such as rifampin, cannot be recommended. Concomitant dosing with rifabutin (a CYP3A inducer less potent than rifampin) is acceptable if doravirine dosing is adjusted from once to twice daily; however, the effect of other moderate inducers on doravirine pharmacokinetics is unknown.

Inhibition of cell proliferation by potential peroxisome proliferator-activated receptor (PPAR) gamma agonists and antagonists.

This study was initiated to determine if potential PPAR gamma antagonists could block the inhibition of cell proliferation caused by 4-phenylbutyrate. The action of 4-phenylbutyrate differed from other PPAR gamma ligands examined in that it induces histone acetylation. Proliferation of DS19 mouse erythroleukemia cells was inhibited by PPAR gamma agonists (4-phenylbutyrate, rosiglitazone, ciglitazone and GW1929) and by potential PPAR gamma antagonists: BADGE (Biphenol A diglycidyl ether), GW9662, PD068235 and diclofenac. Combined incubations tended to exhibit additive inhibitory effects. Potential PPAR gamma agonists and antagonists inhibited the incorporation of thymidine into DNA of human prostate (PC3), colon (Caco-2) and breast (T47D) cancer cells but also affected NIH3T3 cells that have little or no expression of PPAR gamma. Lipid accumulation in T47D cells was seen after incubation with 4-phenylbutyrate and both potential PPAR gamma agonists and antagonists. The extent to which the effects of 4-phenylbutyrate on cell proliferation are mediated through PPAR gamma or induction of histone acetylation remains an open question. We conclude that potential PPAR gamma antagonists may fail to reverse the growth inhibitory effect of PPAR gamma ligands and may themselves act as growth inhibitory agents.

Induction of histone acetylation and inhibition of growth by phenyl alkanoic acids and structurally related molecules.

PURPOSE: A structure-activity study was undertaken to determine the influence of side chain length of phenyl alkanoic acids and the degree of unsaturation of phenyl alkenoic acids on the induction of histone acetylation and inhibition of cancer cell proliferation. MATERIALS AND METHODS: Studies on cell proliferation were performed with DS19 mouse erythroleukemic cells, PC-3 human prostate cancer cells and Caco-2 human colon cancer cells. Actions on histone deacetylase and the induction of histone acetylation were compared for 4-phenylbutyrate and structurally related molecules. RESULTS: Increasing inhibition of cell proliferation by phenyl alkanoic acids together with a decrease in cells in S phase and an increase in apoptotic cells was observed with increased chain length between four and ten carbons. Introduction of double bonds into the side chain was associated with increased growth inhibition. In contrast, 4-phenylbutyrate was a more potent inhibitor of histone deacetylase and inducer of histone acetylation than the other phenyl alkanoic acids examined. CONCLUSIONS: In comparison with the action of 4-phenylbutyrate, actions other than inhibition of histone deacetylase appear to be more important for growth inhibition by longer chain phenyl alkanoic and phenyl alkenoic acids.