Dolutegravir approved in the US

1 October 2013. Related: Antiretrovirals.

Simon Collins, HIV i-Base

dolutegravir
50 mg

On 12 August 2013, the FDA approved dolutegravir (50 mg tablets), a new integrase inhibitor to be used in combination with other antiretroviral drugs. [1, 2]

The indication is for use in adults and children aged 12 years and older weighing at least 40 kg (approx. 88 lbs). Approval is based on results from four phase 3 studies whose results have already been reported in HIV Treatment Bulletin (HTB). [3]

• SPRING-2: dolutegravir (once-daily) vs raltegravir (twice-daily) with investigator chosen dual NRTIs (abacavir/3TC or tenofovir/FTC)
• SINGLE: dolutegravir plus abacavir/3TC vs efavirenz/tenofovir/FTC (Atripla) in treatment naïve patients
• SAILING: dolutegravir (once-daily) vs raltegravir (twice-daily) with investigator chosen background regimen in treatment-experienced but integrase-naive patients on currently failing combinations; and
• VIKING-3: dolutegravir (once-daily) with investigator chosen background regimen in treatment-experienced patients with resistance to raltegravir or elvitegravir.

The indication for children older than 12 years is based on a 24-week open-label label study in integrase-naïve patients.

Dolutegravir is dosed 50 mg once-daily for naïve and integrase-naïve patients and at 50 mg twice-daily for patients who are integrase-experienced. Twice-daily dosing is also required for naïve and experienced patients when coadministered with efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, or rifampin to overcome UGT1A/CYP3A inducing by these drugs.

Dolutegravir should be taken 2 hours before or 6 hours after taking cation-containing antacids or laxatives, sucralfate, oral iron supplements, oral calcium supplements, or buffered medications.

Side effects include hypersensitivity reactions and worsening liver enzymes in patients with HIV and hepatitis B and/or hepatitis C coinfection.

Dolutegravir can be taken with or without food.

For prescribing details see the full product information. [4]

Dolutegravir is marketed by ViiV Healthcare and has the tradename Tivicay.

Comment

US approval of this long-awaited new integrase inhibitor is welcomed and it is clearly supported by good efficacy and tolerability results. At a low milligram dose it also has the potential to be coformulated with other ARVs and a Fixed Dose Combination (FDC) with abacavir/3TC is already underway.

Although dolutegravir is active against HIV that is resistant to raltegravir or elvitegravir, even using twice-daily dose it is not able to overcome extensive integrase inhibitor resistance. The prescribing information notes that poor virologic response was observed in subjects treated with 50 mg twice daily with Q148 mutations plus two or more additional integrase-associated mutations including L74I/M, E138A/D/K/T, G140A/S, Y143H/R, E157Q, G163E/K/Q/R/S, or G193E/R. [4, 5]

Also, although indication is to take with or without food, drug levels are increased when taken with a meal, especially if this has a higher fat content (AUC increased by 33%, 41%, and 66% when administered with low-, moderate-, or high-fat meals, respectively, compared with fasting). [6]

Given the need for a twice daily dose in integrase inhibitor experienced patients to increase drug exposure it would be interesting to know whether taking it with food to maximise the PK levels in patients with existing integrase inhibitor mutations would affect outcomes.

As with all new drugs, how widely dolutegravir will be used, is likely to depend on pricing (see article below).

Dolutegravir was submitted to the European regulatory agency at the same time as to the FDA and a decision is expected later this year. [7]

References:

1. FDA press statement. FDA approves new drug to treat HIV infection. (12 August 2013).
   http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm364744.htm?source=govdelivery
2. ViiV healthcare press statement. ViiV Healthcare announces U.S. approval of Tivicay. (12 August 2013).
   http://www.gsk.com/media/press-releases/2013/viiv-healthcare-announces-u-s–approval-of-tivicay—dolutegravi.html
3. IAS update: treatment-naive and -experienced patients and drug resistance (SPRING-2, SAILING and VIKING-3 studies). HIV Treatment Bulletin, July/August 2013.
   https://i-base.info/htb/21796
4. Dolutegravir. US Prescribing Information. (August 2013).
   https://www.viivhealthcare.com/media/58599/us_tivicay.pdf (PDF)
5. Tentative phenotypic cut offs for dolutegravir: guidance for use with integrase resistance. HIV Treatment Bulletin, July/August 2013.
   https://i-base.info/htb/22022
6. Song I et al. Effect of food on the pharmacokinetics of the integrase inhibitor dolutegravir. Antimicrob Agents Chemother. 2012 March; 56(3): 1627–1629. doi: 10.1128/AAC.05739-11.
   http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3294934/
7. Dolutegravir submitted to EU, US and Canadian regulatory agencies. (17 December 2012).
   https://i-base.info/htb/20859