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  13th International Workshop on Clinical Pharmacology of HIV Therapy
Barcelona, Spain
April 16-18, 2012
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Drug Interactions With Integrase Inhibitor Dolutegravir Identified
  13th International Workshop on Clinical Pharmacology of HIV Therapy, April 16-18, 2012, Barcelona
Mark Mascolini
Most antiretrovirals and other drugs often prescribed for people with HIV (and assessed so far) do not have clinically relevant interactions with dolutegravir, the once-daily, unboosted experimental integrase inhibitor, according to results of multiple studies [1]. The nonnucleoside etravirine cut dolutegravir trough concentrations by 88%, and the antacid Maalox lowered dolutegravir exposure more than 70%.
Dolutegravir is being tested in integrase inhibitor-naive and experienced people. A phase 2b dose-ranging study in 205 antiretroviral-naive people found similar 48-week virologic response rates with dolutegravir and efavirenz [2]. Taken twice daily, dolutegravir controlled replication of raltegravir-resistant virus in a phase 2 trial, including virus bearing Q148 resistance mutations [3].
The new analysis detailed results of in vitro experiments, a human mass balance study in 6 healthy volunteers to measure dolutegravir recovery in urine and feces, 14 phase 1 studies in healthy volunteers, and phase 2b dose-ranging trials [1].
In vitro, dolutegravir at clinically relevant concentrations did not induce CYP metabolizing enzymes, and it did not inhibit CYP enzymes, UGT metabolizing enzymes, or major transporters, except for OCT2. Drugs that may interact with OCT2 inhibitors include metformin, pindolol, procainamide, ranitidine, and varenicline. But ViiV researchers working on dolutegravir do not expect this antiretroviral to interact with OCT2 substrates, except for those with a narrow therapeutic range, such as dofetilide (Tikosyn), which is used to treat irregular heartbeats.
Dolutegravir is primarily metabolized via UGT1A1, while only 10% to 15% of the integrase inhibitor is metabolized via CYP3A enzymes. Less than 1% of the administered dolutegravir dose is excreted by the kidney. In humans dolutegravir had no impact on concentrations of tenofovir, methadone, or midazolam, a drug routinely used to test the impact of other agents on CYP3A-metabolizing enzymes. Lopinavir/ritonavir, prednisone, and omeprazole (an inhibitor of CYP2C19 and CYP2C9) had no significant impact on dolutegravir exposure.
The UGT1A1 inhibitor atazanavir, and atazanavir/ritonavir, raised dolutegravir area under the concentration-time curve (AUC) 69% to 91% and raised maximum concentrations 33% to 49%. UGT and CYP3A inducers, such as darunavir, tipranavir, fosamprenavir, efavirenz, and rifabutin, lowered dolutegravir exposure from 30% to 76%. The investigators believe these changes in dolutegravir levels are not clinically relevant because dolutegravir exposures remained above those that proved effective in phase 2 dose-ranging trials. Study results indicated that dolutegravir should be dosed at 50 mg twice daily instead of once daily when given with rifampin, a CYP3A4 inducer, in integrase inhibitor-naive people.
Etravirine, a strong CYP3A inducer, lowered dolutegravir trough concentrations by 88%, though that drop was eased by coadministration of CYP3A inhibitors lopinavir/ritonavir or darunavir/ritonavir. The ViiV team believes dolutegravir may be prescribed with etravirine without dose adjustment in people also taking boosted lopinavir or darunavir, but it should not be administered with 200 mg of etravirine twice daily in people not taking a boosted PI.
The antacid Maalox cut dolutegravir exposure more than 70% when the drugs were taken together, not because of a pH effect but because of metal cation chelation. Separating administration of Maalox and dolutegravir by 2 hours attenuated this interaction. ViiV is proposing administering dolutegravir 2 hours before or 6 hours after an antacid.
For drugs that lower dolutegravir exposure, ViiV investigators believe that a 75% reduction in dolutegravir trough concentration should not be clinically relevant. But workshop attendees cautioned that this conclusion still rests on limited data and may not apply when two drugs that may lower dolutegravir levels are given simultaneously with the integrase inhibitor.
On the basis of long-term data in phase 2b dose-ranging studies, the investigators proposed that a 50-mg once-daily dose of dolutegravir "in the face of modest drug interactions is anticipated to achieve adequate drug exposure to maintain good tolerability and antiviral activity in integrase inhibitor-naive subjects." For people with integrase inhibitor-resistant virus, the dose being studied is 50 mg twice daily.
1. Song I, Borland J, Chen S, et al. Metabolism and drug-drug interaction profile of dolutegravir (DTG, S/GSK1349572). 13th International Workshop on Clinical Pharmacology of HIV Therapy, April 16-18, 2012, Barcelona. Abstract O_07.
2. van Lunzen J, Maggiolo F, Arribas JR, et al. 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. Lancet Infect Dis. 2012;12:111-118.
3. Eron J, Kumar P, Lazzarin A, et al. DTG in subjects with HIV exhibiting RAL resistance: functional monotherapy results of VIKING study cohort II. 18th Conference on Retroviruses and Opportunistic Infections. February 27-March 2, 2011. Boston. Abstract 151LB. http://www.natap.org/2011/CROI/croi_33.htm.