Once daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial

Lunzen, Jan van; Maggiolo, Franco; Arribas, José Ramón; Rakhmanova, Aza; Yéni, Patrick; Young, Benjamin; Rockstroh, Jürgen K.; Almond, Steve; Song, Ivy; Min, Sherene

doi:10.1016/s1473-3099(11)70290-0

Cited by 268 publications

(278 citation statements)

References 14 publications

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“…As this value is 4-fold lower than the C max of DTG ([I 1,total ]/IC 50 = 4.2), a potential interaction exists for compounds that undergo renal secretion via OCT2, such as circulating serum creatinine (a product of muscle turnover) and the anti-arrhythmic drug dofetilide. The in vitro OCT2 inhibition data are consistent with the mild 10-14% decreases in serum creatinine clearance observed in patients administered DTG (Koteff et al, 2011;van Lunzen et al, 2012). These mild, reversible changes are similar to other clinical observations with OCT/MATE inhibitors such as dronedarone, AZD0837, and DX-619 (Sarapa et al, 2007;Tschuppert et al, 2007;Schutzer et al, 2010;Imamura et al, 2011).…”

Section: Discussionsupporting

confidence: 83%

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

et al. 2012

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Dolutegravir (DTG; S/GSK1349572) is a potent HIV-1 integrase inhibitor with a distinct resistance profile and a once-daily dose regimen that does not require pharmacokinetic boosting. This work investigated the in vitro drug transport and metabolism of DTG and assessed the potential for clinical drug-drug interactions. DTG is a substrate for the efflux transporters P-glycoprotein (Pgp) and human breast cancer resistance protein (BCRP). Its high intrinsic membrane permeability limits the impact these transporters have on DTG's intestinal absorption. UDP-glucuronosyltransferase (UGT) 1A1 is the main enzyme responsible for the metabolism of DTG in vivo, with cytochrome P450 (P450) 3A4 being a notable pathway and UGT1A3 and UGT1A9 being only minor pathways. DTG demonstrated little or no inhibition (IC 50 values > 30 mM) in vitro of the transporters Pgp, BCRP, multidrug resistance protein 2, organic anion transporting polypeptide 1B1/3, organic cation transporter (OCT) 1, or the drug metabolizing enzymes CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, UGT1A1, or 2B7. Further, DTG did not induce CYP1A2, 2B6, or 3A4 mRNA in vitro using human hepatocytes. DTG does inhibit the renal OCT2 (IC 50 = 1.9 mM) transporter, which provides a mechanistic basis for the mild increases in serum creatinine observed in clinical studies. These in vitro studies demonstrate a low propensity for DTG to be a perpetrator of clinical drug interactions and provide a basis for predicting when other drugs could result in a drug interaction with DTG.

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Section: Discussionsupporting

confidence: 83%

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

et al. 2012

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“…However, DTG exposure was not reduced with prednisone, suggesting that the effect of enzyme induction by prednisone on DTG PK is minimal. Even if other glucocorticoids did have an effect on DTG exposure similar to those of the drugs noted above (ϳ10% to 41% reductions in AUC), such modest decreases in the DTG AUC would not result in a dosage change with DTG given the efficacy data from a DTG dose-ranging study demonstrating that doses as low as 10 mg were safe and efficacious in treatmentnaive subjects (2).…”

Section: Discussionmentioning

confidence: 96%

“…argeting HIV integration of viral DNA into the human genome has yielded a new class of antiretroviral agents, the HIV integrase inhibitors, which have been used successfully in combination with other antivirals to suppress HIV replication (1)(2)(3). Dolutegravir (DTG; ViiV Healthcare, Research Triangle Park, NC) is a once-daily HIV integrase inhibitor with effective antiviral activity and a favorable safety profile.…”

mentioning

confidence: 99%

Effect of Prednisone on the Pharmacokinetics of the Integrase Inhibitor Dolutegravir

Song

Borland

Chen

et al. 2013

Antimicrob Agents Chemother

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Prednisone, a corticosteroid frequently used to treat common AIDS-related illnesses and comorbidities, has been shown to induce drug metabolism. This study was performed to determine whether prednisone coadministration affected the pharmacokinetics of dolutegravir (DTG). In this open-label, repeat-dose study, 12 healthy subjects were administered DTG at 50 mg daily alone for 5 days and then with concomitant prednisone for 10 days (prednisone at 60 mg daily for 5 days, followed by a 5-day taper). Serial blood sampling and safety assessments were performed during the trial. Pharmacokinetic parameters were determined using noncompartmental methods and geometric least-square mean ratios, and 90% confidence intervals were generated. Coadministration of DTG and 5-day high-dose prednisone with a 5-day taper had a modest effect on DTG exposure. The area under the DTG plasma concentration-time curve, maximum observed DTG concentration, and 24-hour postdose DTG concentration were increased by 11%, 6%, and 17%, respectively, on day 10 of the combination. Similar results were observed after 5 days of DTG and prednisone. Dolutegravir and prednisone coadministration was well tolerated. The changes in plasma exposures of DTG in healthy individuals as a result of prednisone dosing were not clinically significant. No dose adjustment is required for DTG coadministered with prednisone. (This study has been registered at ClinicalTrials.gov under registration no. NCT01425099.)T argeting HIV integration of viral DNA into the human genome has yielded a new class of antiretroviral agents, the HIV integrase inhibitors, which have been used successfully in combination with other antivirals to suppress HIV replication (1-3). Dolutegravir (DTG; ViiV Healthcare, Research Triangle Park, NC) is a once-daily HIV integrase inhibitor with effective antiviral activity and a favorable safety profile. Dolutegravir is metabolized primarily by UDP-glucuronosyltransferase (UGT), with CYP3A4 playing a minor role (4). Dolutegravir has a favorable drug interaction profile, with few dose adjustments required, although potent enzyme inducers can reduce DTG exposure (5).Prednisone is used to treat a number of AIDS-related illnesses, such as immune reconstitution inflammatory syndrome, Pneumocystis jirovecii pneumonia, AIDS-related lymphoma, and concomitant diseases such as asthma, chronic obstructive pulmonary disease, autoimmune/rheumatologic disease, inflammatory bowel disease, and cancers (6-10).Some corticosteroids have been shown to decrease the exposure of UGT and CYP3A4 substrates (11, 12), depending on the choice of steroids, dose, and duration. Daily prednisone treatment of 40 mg/m 2 for 28 days increased etoposide clearance by 62% compared with placebo (13). Six-day treatment with low-dose prednisone (10 mg twice daily) modestly decreased metronidazole exposure, by 31% (14). Treatment with another corticosteroid, dexamethasone, at 1.5 mg for 4 days reduced oral triazolam AUC by 19% (15), whereas 2-day dexamethasone treatment at 24 mg per day decre...

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“…Since therapy continues for the life of the patient, there are serious safety concerns about the long term toxicity of anti retrovirals. The anti retrovirals commonly used in HAART can have adverse effects and there have been incidences where the side effects have been life threatening [11][12][13][14][15] . The problems patients encounter with the development of resistance and toxicity underlie the need to develop new drugs that effectively block the replication of the common drug resistant strains of the virus with little or no long term toxicity.…”

Section: Introductionmentioning

confidence: 99%

Rapid Screening of HIV Reverse Transcriptase and Integrase Inhibitors

Smith

Hughes

2014

JoVE

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Although a number of anti HIV drugs have been approved, there are still problems with toxicity and drug resistance. This demonstrates a need to identify new compounds that can inhibit infection by the common drug resistant HIV-1 strains with minimal toxicity. Here we describe an efficient assay that can be used to rapidly determine the cellular cytotoxicity and efficacy of a compound against WT and mutant viral strains.The desired target cell line is seeded in a 96-well plate and, after a 24 hr incubation, serially dilutions of the compounds to be tested are added. No further manipulations are necessary for cellular cytotoxicity assays; for anti HIV assays a predetermined amount of either a WT or drug resistant HIV-1 vector that expresses luciferase is added to the cells. Cytotoxicity is measured by using an ATP dependent luminescence assay and the impact of the compounds on infectivity is measured by determining the amount of luciferase in the presence or the absence of the putative inhibitors.This screening assay takes 4 days to complete and multiple compounds can be screened in parallel. Compounds are screened in triplicate and the data are normalized to the infectivity/ATP levels in absence of target compounds. This technique provides a quick and accurate measurement of the efficacy and toxicity of potential anti HIV compounds.

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Once daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial

Cited by 268 publications

References 14 publications

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

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

Effect of Prednisone on the Pharmacokinetics of the Integrase Inhibitor Dolutegravir

Rapid Screening of HIV Reverse Transcriptase and Integrase Inhibitors

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