Dolutegravir Is Susceptible to Chelation-Type Interactions
Common medications containing polyvalent cations should be separated to prevent decreased absorption of the HIV therapy.
Dolutegravir (Tivicay), a second-generation integrase strand transfer inhibitor, is FDA approved for the treatment of HIV-1 in combination with other antiretrovirals for both treatment-experienced and treatment-naïve patients.1
Mechanistically, dolutegravir works to impede HIV DNA integration by binding to magnesium at the integrase active site, thus preventing the strand transfer step and completion of the HIV replication cycle.2,3
With all antiretrovirals, it is important to be mindful of concomitant medications that may interact with dolutegravir, resulting in either supra- or subtherapeutic doses of the latter.4 Of note, with dolutegravir and other agents in its class, polyvalent drugs have been shown to cause chelation-type drug interactions.2
Common di- and trivalent cations, such as aluminum, calcium, magnesium, and iron-containing products, can bind with dolutegravir, resulting in a poorly absorbable complex formed in the gastrointestinal tract, subsequently leading to decreased absorption of the integrase strand transfer inhibitor.2 Examples of these agents include antacids, laxatives, sucralfate, and supplements. Sucralfate works to protect the gastrointestinal tract by forming a complex with positively charged proteins, often leading to decreased absorption of many oral medications.5 The package insert of dolutegravir recommends separating administration of dolutegravir by at least 2 hours before or 6 hours after sucralfate to prevent this interaction.1
A cross-over, open-label, randomized trial conducted by Song et al analyzed the pharmacokinetics of dolutegravir in 24 healthy subjects after receiving either 1200-mg calcium carbonate (480-mg elemental calcium), 324-mg ferrous fumarate (107-mg elemental iron), or antiretroviral drug alone.2 Dolutegravir plasma concentrations were decreased with both calcium carbonate and ferrous fumarate under fasted conditions by 37% to 39% and 54% to 57%, respectively.2 The authors hypothesized that the differences seen in bioavailability between the 2 combinations may be the result of solubility differences in the dolutegravir-polyvalent complexes formed and/or iron’s greater affinity for the antiretroviral integrase binding site.2 On the contrary, under fed conditions with concomitant therapy, plasma concentrations of dolutegravir were similar to that of the antiretroviral’s concentration alone.2 The same was true when dolutegravir was administered 2 hours prior to the polyvalent dose.2 Therefore, the authors suggested that calcium and dolutegravir can be coadministered if taken with a meal or should be separated if under fasting conditions for best absorption and efficacy of dolutegravir.2
Similarly, a study conducted by Patel et al examined the effects of metal cation-containing antacids on the plasma concentration of dolutegravir.6 When dolutegravir was administered simultaneously with Maalox Advanced, which contains 400 mg of aluminum hydroxide and 400 mg of magnesium hydroxide in 5 mL, the area under the curve of dolutegravir decreased by 74% compared with dolutegravir alone. However, with staggered administration of dolutegravir 2 hours before the antacid, the area under the curve of dolutegravir was diminished significantly less, a reduction of 26% compared with dolutegravir alone.
Dolutegravir’s package insert outlines that the antiretroviral should be administered 2 hours before or 6 hours after taking medications containing polyvalent cations.1 For patients using antacids to relieve heartburn symptoms, pharmacists may consider recommending the use of either an H2 receptor antagonist or a proton pump inhibitor instead. Although the latter 2 agents may not have as fast an onset of action, there are no associated drug interactions with dolutegravir as seen with polyvalentcontaining antacids. Switching to an H2 receptor antagonist or proton pump inhibitor from an antacid may also benefit patients who are unable to comply with the recommended dosing schedule as outlined by the dolutegravir package insert.
In addition, dolutegravir is metabolized by UDP glucuronosyltransferase 1A1 with minor contribution from cytochrome P450 3A4 (CYP3A4). Inducers of these pathways can result in decreased plasma concentration of the antiretroviral.1 For example, when administered with a CYP 3A4 inducer, rifampin, the dosing frequency of dolutegravir must be increased.
It is vital to consider all drug-drug interactions that may be present and may affect the concentration of dolutegravir. By following appropriate dosing adjustments in the setting of drug interactions, pharmacists can ensure that patients are receiving an effective and safe dose of dolutegravir.
Sharon Cherian is a PharmD candidate at Albany College of Pharmacy and Health Sciences (ACPHS) in New York who has completed the VA Learning Opportunities Residency (VALOR) program at the Albany stratton VA Medical Center (ASVMC) in New York.Amy Lee is a PharmD candidate at ACPHS who is completing the VALOR program at the ASVMC.Amy T. Murdico, PharmD, BCPS, is the associate chief of pharmacy services, the PGY-1 pharmacy residency director, and the PGY-2 pain and palliative care pharmacy residency coordinator at the ASVMC. She coordinates and precepts in the VALOR intern program and is an adjunct advanced pharmacy practice experience preceptor for ACPHS and Western New England University College of Pharmacy and Health Sciences (WNEUCPHS) in Springfield, Massachusetts.Jeffrey Fudin, PharmD, DAIPM, FCCP, FASHP, FFSMB, is chief executive officer and founder of Remitigate, LLC and the owner and managing editor of paindr.com. He is also an adjunct associate professor at WNEUCPHS, and adjunct associate professor of pharmacy practice and pain management at ACPHS, and the director of the PGY-2 pain residency at ASVMC.
- Dolutegravir (Tivicay) [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; 2013. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204790lbl.pdf. Accessed January 13, 2020.
- Song I, Borland J, Arya N, Wynne B, Piscitelli S. Pharmacokinetics of dolutegravir when administered with mineral supplements in healthy adult subjects. J Clin Pharmacol. 2015;55(5):490-496. doi: 10.1002/jcph.439.
- Mercadel CJ, Skelley JW, Kyle JA, Elmore LK. Dolutegravir: an integrase strand transfer inhibitor for the treatment of human immunodeficiency virus 1 in adults. J Pharm Technol. 2014;30(6):216-226.
- US Department of Health and Human Services. Guidelines for the use of antiretroviral agents in adults and adolescents living with HIV. AIDS info website. http://www.aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-treatment-guidelines. Updated December 18, 2019. Accessed January 13, 2020.
- Sucralfate (Carafate) [prescribing information]. Bridgewater, NJ: Aptalis Pharma US, Inc; 2013. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/018333s034,019183s016lbl.pdf. Accessed January 13, 2020.
- Patel P, Song I, Borland J, et al. Pharmacokinetics of the HIV integrase inhibitor S/GSK1349572 co-administered with acid-reducing agents and multivitamins in healthy volunteers. J Antimicrob Chemother. 2011;66(7):1567-1572. doi.org/10.1093/jac/dkr139.