In Vitro Investigations into the Roles of Drug Transporters and Metabolizing Enzymes in the Disposition and Drug Interactions of Dolutegravir, a HIV Integrase Inhibitor

2012 ◽  
Vol 41 (2) ◽  
pp. 353-361 ◽  
Author(s):  
Melinda J. Reese ◽  
Paul M. Savina ◽  
Grant T. Generaux ◽  
Helen Tracey ◽  
Joan E. Humphreys ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Drug Transporters ◽  
Integrase Inhibitor ◽  
Hiv Integrase ◽  
Metabolizing Enzymes

scholarly journals In Vitro Evaluation of the Drug Interaction Potential of Doravirine

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Kelly Bleasby ◽  
Kerry L. Fillgrove ◽  
Robert Houle ◽  
Bing Lu ◽  
Jairam Palamanda ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Reversible Inhibitor ◽  
Drug Metabolizing Enzymes ◽  
Cancer Resistance ◽  
Metabolizing Enzymes ◽  
Anion Transporter ◽  
Major Drug

ABSTRACT Doravirine is a novel nonnucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus type 1 infection. In vitro studies were conducted to assess the potential for drug interactions with doravirine via major drug-metabolizing enzymes and transporters. Kinetic studies confirmed that cytochrome P450 3A (CYP3A) plays a major role in the metabolism of doravirine, with ∼20-fold-higher catalytic efficiency for CYP3A4 versus CYP3A5. Doravirine was not a substrate of breast cancer resistance protein (BCRP) and likely not a substrate of organic anion transporting polypeptide 1B1 (OATP1B1) or OATP1B3. Doravirine was not a reversible inhibitor of major CYP enzymes (CYP1A2, -2B6, -2C8, -2C9, -2C19, -2D6, and -3A4) or of UGT1A1, nor was it a time-dependent inhibitor of CYP3A4. No induction of CYP1A2 or -2B6 was observed in cultured human hepatocytes; small increases in CYP3A4 mRNA (≤20%) were reported at doravirine concentrations of ≥10 μM but with no corresponding increase in enzyme activity. In vitro transport studies indicated a low potential for interactions with substrates of BCRP, P-glycoprotein, OATP1B1 and OATP1B3, the bile salt extrusion pump (BSEP), organic anion transporter 1 (OAT1) and OAT3, organic cation transporter 2 (OCT2), and multidrug and toxin extrusion 1 (MATE1) and MATE2K proteins. In summary, these in vitro findings indicate that CYP3A4 and CYP3A5 mediate the metabolism of doravirine, although with different catalytic efficiencies. Clinical trials reported elsewhere confirm that doravirine is subject to drug-drug interactions (DDIs) via CYP3A inhibitors and inducers, but they support the notion that DDIs (either direction) are unlikely via other major drug-metabolizing enzymes and transporters.

scholarly journals Pharmacokinetics and antiviral activity of cabotegravir and rilpivirine in cerebrospinal fluid following long-acting injectable administration in HIV-infected adults

2019 ◽  
Vol 75 (3) ◽  
pp. 648-655 ◽  
Author(s):  
Scott L Letendre ◽  
Anthony Mills ◽  
Debbie Hagins ◽  
Susan Swindells ◽  
Franco Felizarta ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Steady State ◽  
Antiviral Activity ◽  
Plasma Concentrations ◽  
Integrase Inhibitor ◽  
Virological Suppression ◽  
Hiv Integrase ◽  
Long Acting ◽  
Hiv 1

Abstract Background Long-acting (LA) formulations of cabotegravir, an HIV integrase inhibitor, and rilpivirine, an NNRTI, are in development as monthly or 2 monthly intramuscular (IM) injections for maintenance of virological suppression. Objectives To evaluate cabotegravir and rilpivirine CSF distribution and HIV-1 RNA suppression in plasma and CSF in HIV-infected adults participating in a substudy of the Phase 2b LATTE-2 study (NCT02120352). Methods Eighteen participants receiving cabotegravir LA 400 mg + rilpivirine LA 600 mg IM [every 4 weeks (Q4W), n = 3] or cabotegravir LA 600 mg + rilpivirine LA 900 mg IM [every 8 weeks (Q8W), n = 15] with plasma HIV-1 RNA <50 copies/mL enrolled. Paired steady-state CSF and plasma concentrations were evaluable in 16 participants obtained 7 (±3) days after an injection visit. HIV-1 RNA in CSF and plasma were assessed contemporaneously using commercial assays. Results Median total CSF concentrations in Q4W and Q8W groups, respectively, were 0.011 μg/mL and 0.013 μg/mL for cabotegravir (0.30% and 0.34% of the paired plasma concentrations) and 1.84 ng/mL and 1.67 ng/mL for rilpivirine (1.07% and 1.32% of paired plasma concentrations). Cabotegravir and rilpivirine total CSF concentrations exceeded their respective in vitro EC50 for WT HIV-1 (0.10 ng/mL and 0.27 ng/mL, respectively). All 16 participants had HIV-1 RNA <50 copies/mL in plasma and CSF, and 15 of 16 participants had HIV-1 RNA <2 copies/mL in CSF. Conclusions A dual regimen of cabotegravir LA and rilpivirine LA achieved therapeutic concentrations in the CSF resulting in effective virological control in CSF.

scholarly journals Antiviral Characteristics of GSK1265744, an HIV Integrase Inhibitor Dosed Orally or by Long-Acting Injection

2014 ◽  
Vol 59 (1) ◽  
pp. 397-406 ◽  
Author(s):  
Tomokazu Yoshinaga ◽  
Masanori Kobayashi ◽  
Takahiro Seki ◽  
Shigeru Miki ◽  
Chiaki Wakasa-Morimoto ◽  
...  
Keyword(s):  
Synergistic Effects ◽  
Integrase Inhibitor ◽  
Culture Conditions ◽  
Strand Transfer ◽  
Hiv Integrase ◽  
Hiv Replication ◽  
Data Set ◽  
Long Acting ◽  
Anti Hiv

ABSTRACTGSK1265744 is a new HIV integrase strand transfer inhibitor (INSTI) engineered to deliver efficient antiviral activity with a once-daily, low-milligram dose that does not require a pharmacokinetic booster. Thein vitroantiviral profile and mechanism of action of GSK1265744 were established through integrase enzyme assays, resistance passage experiments, and cellular assays with site-directed molecular (SDM) HIV clones resistant to other classes of anti-HIV-1 agents and earlier INSTIs. GSK1265744 inhibited HIV replication with low or subnanomolar efficacy and with a selectivity index of at least 22,000 under the same culture conditions. The protein-adjusted half-maximal inhibitory concentration (PA-EC50) extrapolated to 100% human serum was 102 nM. When the virus was passaged in the presence of GSK1265744, highly resistant mutants with more than a 10-fold change (FC) in EC50relative to that of the wild-type were not observed for up to 112 days of culture. GSK1265744 demonstrated activity against SDM clones containing the raltegravir (RAL)-resistant Y143R, Q148K, N155H, and G140S/Q148H signature variants (FC less than 6.1), while these mutants had a high FC in the EC50for RAL (11 to >130). Either additive or synergistic effects were observed when GSK1265744 was tested in combination with representative anti-HIV agents, and no antagonistic effects were seen. These findings demonstrate that, similar to dolutegravir, GSK1265744 is differentiated as a new INSTI, having a markedly distinct resistance profile compared with earlier INSTIs, RAL, and elvitegravir (EVG). The collective data set supports further clinical development of GSK1265744.

scholarly journals The Antagonism of Folate Receptor by the Integrase Inhibitor Dolutegravir: Developmental Toxicity Reduction by Supplemental Folic Acid

2019 ◽  
Author(s):  
Robert M. Cabrera ◽  
Jaclyn P. Souder ◽  
John W. Steele ◽  
Lythou Yeo ◽  
Gabriel Tukeman ◽  
...  
Keyword(s):  
Folic Acid ◽  
Folate Receptor ◽  
Developmental Toxicity ◽  
Fold Increase ◽  
Integrase Inhibitor ◽  
Hiv Integrase ◽  
Binding Studies ◽  
Childbearing Age ◽  
Vitamin B9

ABSTRACTHuman immunodeficiency virus (HIV) integrase inhibitors are increasingly being used for antiretroviral therapy (ART), and dolutegravir (DTG/Tivicay) has emerged as a leading core agent. In 2018, the Tsepamo study reported a 6- to 9-fold increase for neural tube defect (NTD) risk among the offspring of mothers receiving DTG during early gestation. Maternal folate (vitamin B9) status is the largest known modifier of NTD risk, so we evaluated folate-related mechanisms of action and the critical period for DTG developmental toxicity. Folate receptor (FOLR1) binding studies indicate DTG is a non-competitive FOLR1 antagonist at therapeutic concentrations.In vitrotesting indicates calcium (2mM) increases FOLR1-folate interactions and alters DTG-FOLR1-folate interactions and cytotoxicity. DTG does not inhibit downstream folate metabolism by dihydrofolate reductase (DHFR). Early embryonic exposure to DTG is developmentally toxic in zebrafish, and supplemental folic acid can mitigate DTG developmental toxicity. The results from these studies are expected to inform and guide future animal models and clinical studies of DTG-based ART in women of childbearing age.

scholarly journals Elvitegravir: A New HIV Integrase Inhibitor

2009 ◽  
Vol 20 (2) ◽  
pp. 79-85 ◽  
Author(s):  
Kazuya Shimura ◽  
Eiichi N Kodama
Keyword(s):  
Antiviral Drug ◽  
Integrase Inhibitor ◽  
Phase Iii ◽  
Hiv Integrase ◽  
Integrase Inhibitors ◽  
Resistance Mutations ◽  
Hiv 1

Integration is a distinctive and essential process in the HIV infection cycle and thus represents an attractive antiviral drug target. Integrase inhibitors combined with other classes of drug might contribute to long-lasting suppression of HIV type-1 (HIV-1) replication for many patients. Of the numerous potential integrase inhibitor leads that have been reported, few have reached clinical trials and only one, raltegravir, has been approved (in late 2007) for the treatment of HIV-1-infected patients. Another integrase inhibitor, elvitegravir, is currently showing promise in Phase III clinical studies. Once-daily administration of elvitegravir has a comparable antiviral activity to twice-daily of raltegravir in HIV-1-infected patients. Here, we highlight the salient features of elvitegravir: its chemical structure compared with representative integrase inhibitors, mechanism of action, in vitro and in vivo activity against HIV and other retroviruses, and the effect of integrase polymorphisms and resistance mutations on its anti-HIV activity.

scholarly journals The HIV Integrase Inhibitor Raltegravir Inhibits Felid Alphaherpesvirus 1 Replication by Targeting both DNA Replication and Late Gene Expression

2018 ◽  
Vol 92 (20) ◽  
Author(s):  
Matthew R. Pennington ◽  
Ian E. H. Voorhees ◽  
Heather M. Callaway ◽  
Shannon D. Dehghanpir ◽  
Joel D. Baines ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Replication ◽  
Dna Polymerase ◽  
Drug Application ◽  
Integrase Inhibitor ◽  
Late Gene ◽  
Drug Resistant ◽  
Hiv Integrase ◽  
Late Gene Expression

ABSTRACTAlphaherpesvirus-associated ocular infections in humans caused by human alphaherpesvirus 1 (HHV-1) remain challenging to treat due to the frequency of drug application required and the potential for the selection of drug-resistant viruses. Repurposing on-the-market drugs is a viable strategy to accelerate the pace of drug development. It has been reported that the human immunodeficiency virus (HIV) integrase inhibitor raltegravir inhibits HHV-1 replication by targeting the DNA polymerase accessory factor and limits terminase-mediated genome cleavage of human betaherpesvirus 5 (HHV-5). We have previously shown, bothin vitroandin vivo, that raltegravir can also inhibit the replication of felid alphaherpesvirus 1 (FeHV-1), a common ocular pathogen of cats with a pathogenesis similar to that of HHV-1 ocular disease. In contrast to what was reported for HHV-1, we were unable to select for a raltegravir-resistant FeHV-1 strain in order to define any basis for drug action. A candidate-based approach to explore the mode of action of raltegravir against FeHV-1 showed that raltegravir did not impact FeHV-1 terminase function, as described for HHV-5. Instead, raltegravir inhibited DNA replication, similarly to HHV-1, but by targeting the initiation of viral DNA replication rather than elongation. In addition, we found that raltegravir specifically repressed late gene expression independently of DNA replication, and both activities are consistent with inhibition of ICP8. Taken together, these results suggest that raltegravir could be a valuable therapeutic agent against herpesviruses.IMPORTANCEThe rise of drug-resistant herpesviruses is a longstanding concern, particularly among immunocompromised patients. Therefore, therapies targeting viral proteins other than the DNA polymerase that may be less likely to lead to drug-resistant viruses are urgently needed. Using FeHV-1, an alphaherpesvirus closely related to HHV-1 that similarly causes ocular herpes in its natural host, we found that the HIV integrase inhibitor raltegravir targets different stages of the virus life cycle beyond DNA replication and that it does so without developing drug resistance under the conditions tested. This shows that the drug could provide a viable strategy for the treatment of herpesvirus infections.

scholarly journals Rhinacanthin-C Mediated Herb-Drug Interactions with Drug Transporters and Phase I Drug-Metabolizing Enzymes

2019 ◽  
Vol 47 (10) ◽  
pp. 1040-1049 ◽  
Author(s):  
Wilasinee Dunkoksung ◽  
Nontima Vardhanabhuti ◽  
Pongpun Siripong ◽  
Suree Jianmongkol
Keyword(s):  
Drug Interactions ◽  
Phase I ◽  
Drug Transporters ◽  
Drug Metabolizing Enzymes ◽  
Metabolizing Enzymes
Sign in / Sign up

Export Citation Format

Share Document