Amy Lee, PharmD Candidate

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.

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.

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.

Of note, with dolutegravir and other agents in its class, polyvalent drugs have been shown to cause chelation-type drug interactions.

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.

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.

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.

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.

Dolutegravir plasma concentrations were decreased with both calcium carbonate and ferrous fumarate under fasted conditions by 37% to 39% and 54% to 57%, respectively.

 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.

 On the contrary, under fed conditions with concomitant therapy, plasma concentrations of dolutegravir were similar to that of the antiretroviral’s concentration alone.

 The same was true when dolutegravir was administered 2 hours prior to the polyvalent dose.

 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.

Similarly, a study conducted by Patel et al examined the effects of metal cation-containing antacids on the plasma concentration of dolutegravir.

 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.

 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.

 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.

 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.

 is a PharmD candidate at ACPHS who is completing the VALOR program at the ASVMC.

 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

Song I, Borland J, Arya N, Wynne B, Piscitelli S. Pharmacokinetics of dolutegravir when administered with mineral supplements in healthy adult subjects. 

 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. 

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.

.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

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. 

 2011;66(7):1567-1572. doi.org/10.1093/jac/dkr139.

Articles

Common medications containing polyvalent cations should be separated to prevent decreased absorption of the HIV therapy.

Dolutegravir Is Susceptible to Chelation-Type Interactions

Warfarin has been the gold standard for oral anticoagulation therapy for more than 50 years.

 Drawbacks to warfarin therapy, however, include a narrow therapeutic window with a low median lethal dose, many potential drug—drug/diet/disease interactions, and necessary frequent blood draws and individualized dosing to monitor the international normalized ratio (INR). The INR is calculated from prothrombin time, which is used to assess the time that a clot takes to form. An elevated INR can lead to an increased risk of hemorrhage, whereas a decreased INR can indicate ineffectiveness of the blood thinner and can lead to stroke and thromboembolism.

 The introduction of direct oral anticoagulants (DOACs) has reduced the need for routine INR monitoring as a result of a more predictable pharmacokinetic profile and a wider therapeutic window with fixed dosing.

 Although the need for monitoring has decreased, the potential for interactions still exists with the new oral anticoagulants.

Warfarin is the most commonly prescribed oral anticoagulant. However, it is known to interact with many foods, herbal supplements, and OTC and prescription medications. It is particularly important to monitor warfarin carefully because of a narrow therapeutic window and variability in individual response. Concomitant administration of drugs that decrease or increase the INR and warfarin can lead to an elevated risk of hemorrhage or thrombotic event, respectively. A major consideration of warfarin drug interactions is metabolism by cytochrome P 450 (CYP) enzymes. Warfarin is primarily metabolized by CYP2C9 with minor metabolism by CYP2C8, 1A2, 3A4, 2C18, and 2C19. When warfarin is administered with inhibitors of CYP3A4, such as statins, except pravastatin and rosuvastatin, which are not metabolized by CYP450 enzymes, the INR is increased.

 Other medications that cause clinically relevant increases in the INR because of CYP enzyme inhibition include amiodarone (1A2, 3A4, and 2C9), diltiazem (3A4), fenofibrate (3A4), propafenone (3A4), and propranolol (1A2).

 Another consideration is the protein-binding nature of warfarin. Warfarin is 99% plasma protein bound to albumin. Therefore, other medications that are highly protein bound, such as amlodipine and ibuprofen, can cause displacement of warfarin from protein-binding sites, leading to increased anticoagulant activity and INR.

 Consumption of excess foods high in vitamin K, such as leafy green vegetables, can decrease the INR.

 Study results have shown that herbal supplements also induce or inhibit certain enzymes associated with warfarin metabolism. For example, St John’s wort induces CYP1A2, 3A4, and 2C9, resulting in a decreased INR.

 Additionally, clinicians must also consider pharmacodynamic interactions when prescribing warfarin concomitantly with other medications that increase bleeding risk. These include nonsteroidal anti-inflammatory drugs (NSAIDs), because of their inherent ability to cause bleeding as a result of cyclooxygenase 1 inhibition, and serotonin norepinephrine reuptake inhibitors (SNRIs), because of the role of serotonin in platelet aggregation.

 Frequent monitoring of the INR is crucial in maintaining safe and therapeutic levels of anticoagulation in patients on warfarin and interacting medications.

DOACs are highly effective anticoagulants in the treatment of deep vein thrombosis and pulmonary embolism, as well as in stroke prevention associated with atrial fibrillation, and require less monitoring than warfarin. The DOACs comprise 2 groups: direct factor Xa inhibitors, including apixaban (Eliquis), exoxaban (Savaysa), and rivaroxaban (Xarelto); and direct thrombin (factor IIa) inhibitor, dabigatran (Pradaxa). Similar to warfarin, DOACs have a potential for drug interactions with medications that may increase bleeding risk and with strong P-glycoprotein (P-gp) and CYP3A4 inducers and inhibitors. As DOACs are substrates of P-gp, an efflux transporter, coadministration with a P-gp inducer or inhibitor can significantly affect the absorption of the DOAC.

 All DOACs have drug—drug interactions with other anticoagulants, antiplatelets, chronic NSAIDs, estrogen derivatives, and SNRIs. Estrogen derivatives, in particular, may prevent DOACs’ efficacy, resulting in an increased risk of thromboembolism.

Apixaban is primarily metabolized by CYP3A4 and is a substrate of P-gp. Administering apixaban with inhibitors of CYP3A4 and P-gp, such as carbamazepine, itraconazole, ketoconazole, rifampin, ritonavir, and St John’s Wort, may increase the overall exposure of apixaban and therefore increase the risk of unwanted bleeding.

 This drug—drug interaction has specific clinical recommendations. If a patient is receiving 5- or 10-mg twice-daily dosing of apixaban that is to be administered with a CYP3A4 and P-gp inhibitor, clinicians should reduce the apixaban dose by half, to 2.5 or 5.0 mg twice daily, respectively.

 On the other hand, inducers of CYP3A4 and P-gp would decrease exposure of apixaban, subsequently increasing the risk of stroke and other thrombotic events. Concomitant use with strong inducers should be avoided.

 Apixaban is not associated with inducing or inhibiting CYP3A4 or P-gp, as the metabolic clearance of medications administered with apixaban is not affected.

 Because of an increased risk of bleeding, physicians should closely monitor the benefit versus risk of apixaban administered with antiplatelet agents, aspirin, chronic NSAIDs, fibrinolytics, and heparin.

Rivaroxaban is primarily metabolized by CYP3A4 and is a substrate of P-gp. Concomitant use of rivaroxaban with known combined CYP3A and P-gp inhibitors should be avoided. Rivaroxaban may also increase the risk of bleeding with concomitant use with medications that inhibit hemostasis, including anticoagulants, aspirin, fibrinolytics, NSAIDs, P2Y12 platelet inhibitors, selective serotonin reuptake inhibitors, and SNRIs.

 In vitro data suggest that rivaroxaban does not induce or inhibit CYP3A or inhibit P-gp and will therefore not affect the administered substrates or pharmacokinetics of CYP3A or P-gp.

Edoxaban is predominantly unchanged in plasma with minimal metabolism via CYP3A4 but is a substrate of P-gp.

 Concomitant use with known P-gp inhibitors, such as amiodarone, cyclosporin, erythromycin, ketoconazole, quinidine, and verapamil, may increase the area under the curve and peak plasma concentration of edoxaban. Coadministration with other anticoagulants, antiplatelets, and long-term NSAIDs is associated with an increased risk of bleeding and is not recommended.

Dabigatran is not an inducer, inhibitor, or substrate of CYP450 enzymes but is a substrate of P-gp. Therefore, clinicians should avoid or dose-adjust concomitant administration of dabigatran with inducers or inhibitors of P-gp enzymes based on the creatinine clearance (CrCl) and induction or inhibition. Patients with a CrCl <30 mL/min should avoid concurrent use of any P-gp inhibitor, such as amiodarone, quinidine, and verapamil with dabigatran.

 Clinicians should also monitor dabigatran with coadministration with other anticoagulants, antiplatelets, and NSAIDs for increased risk of bleeding. HMG- CoA reductase inhibitors, such as atorvastatin, lovastatin, and simvastatin, may enhance the anticoagulant effect of dabigatran and require additional monitoring. 

Anticoagulants, including DOACs and vitamin K antagonists, are subject to interactions when administered with foods, herbal supplements, and other OTC and prescribed medications. Patients on warfarin therapy should monitor their INR frequently, especially when adding medications that may interact with warfarin. Although DOACs may require less monitoring and be safer than warfarin, clinicians must still consider potential drug—drug interactions because of CYP metabolism and/or P-gp interactions. Additional information regarding CYP and inducers, inhibitors, and transporter substrates is available at the FDA website.

 Pharmacists must carefully assess potential interactions in patients on anticoagulation therapy to prevent placing them at an increased risk of hemorrhagic or thrombotic event.

 are PharmD candidates at Albany College of Pharmacy and Health Sciences (ACPHS) in New York and are completing the VA Learning Opportunities Residency program at the Albany Stratton VA Medical Center (ASVMC) in New York.

 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 ASVMC. She coordinates and precepts in the VA Learning Opportunities Residency 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, FCCP, FASHP, FFSMB,

 is CEO and founder of Remitigate LLC and the owner and managing editor of paindr.com. He is also an adjunct associate professor at WNEUCPHS, an adjunct associate professor of pharmacy practice and pain management at ACPHS, and the director of the PGY-2 pain residency at ASVMC.

Conway SE, Hwang AY, Ponte CD, Gums JG. Laboratory and clinical monitoring of direct acting oral anticoagulants: what clinicians need to know. 

 2017;37(2):236-248. doi: 10.1002/phar.1884. 

American Association for Clinical Chemistry. Prothrombin time and international normalized ratio (PT/INR). Lab Tests Online website. 

labtestsonline.org/tests/prothrombin-time-and-international-normalized-ratio-ptinr

 Bauer KA. Pros and cons of new oral anticoagulants. 

2013;2013:464-470. doi: 10.1182/asheducation-2013.1.464.

Di Minno A, Frigerio B, Spadarella G, et al. Old and new oral anticoagulants: food, herbal medicines and drug interactions. 

 2017;31(4):193-203. doi: 10.1016/j.blre.2017.02.001.

Coumadin [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Co; 2017. 

packageinserts.bms.com/pi/pi_coumadin.pdf

Jiang X, Williams KM, Liauw WS, et al. Effect of St John’s wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. 

 2004;57:592—599. doi: 10.1111/j.1365-2125.2003.02051.x.

Wegrzyn E, Fudin J. Carefully assess bleeding risk in patients on antidepressants. 

pharmacytimes.com/publications/issue/2019/march2019/carefully-assess-bleeding-risk-in-patients-on-antidepressants

. Published March 19, 2019. Accessed September 23, 2019.

Stöllberger C, Finsterer J. Relevance of P-glycoprotein in stroke prevention with dabigatran, rivaroxaban, and apixaban. 

 2015;40(suppl 2):140-145. doi: 10.1007/s00059-014-4188-9.

Eliquis [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Co; 2012. 

Xarelto [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals Inc; 2011. 

janssenlabels.com/package-insert/product-monograph/prescribing-information/XARELTO-pi.pdf

Savaysa [prescribing information]. Parsippany, NJ: Daiichi Sankyo Inc; 2015. www.

accessdata.fda.gov/drugsatfda_docs/label/2015/206316lbl.pdf

Pradaxa [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc; 2011. www.

accessdata.fda.gov/drugsatfda_docs/label/2011/022512s007lbl.pdf

Drug development and drug interactions: table of substrates, inhibitors and inducers. FDA website. www.

fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers

Patients on this therapy should monitor their INR frequently, especially when adding other medications.

Watch for Interactions With Warfarin

The protein kinase inhibitor drug class has been rapidly expanding the past 5 years, reaching more than 40 individual medications. Protein kinase inhibitors, including tyrosine, serine, and threonine kinase inhibitors, can act on a variety of targets within the body to allow for targeted cancer treatment. As many of these new drugs are oral medications metabolized by the liver, it is important to consider drug drug interactions (DDIs) with many common medications. Protein kinase inhibitors have been documented to have pharmacodynamic and pharmacokinetic DDIs. These interactions can lead to malabsorption with altered gastric pH, deviations in metabolism by cytochrome (CYP) P450 enzymes, and interactions leading to QT prolongation.

The majority of protein kinase inhibitors undergo significant metabolism by CYP450 enzymes, particularly CYP450 3A4 (CYP3A4). When administered concurrently with inducers or inhibitors of CYP3A4, the plasma concentration of the kinase inhibitor may be altered. CYP3A4 inducers, such as carbamazepine, phenytoin, rifampin, and St John’s wort, decrease serum levels and reduce the overall area under the curve (AUC) of the substrate kinase inhibitor, resulting in decreased therapeutic efficacy. CYP3A4 inhibitors, such as antifungals (ketoconazole, itraconazole), certain antivirals (boceprevir, cobicistat, ritonavir, etc), grapefruit juice, and macrolide antibiotics (clarithromycin and erythromycin but not azithromycin), can lead to an increase in AUC of the substrate kinase inhibitor, resulting in greater toxicity and adverse events.

Table 1 illustrates recommendations for concomitant use of protein kinase inhibitors and CYP3A4 inducers and inhibitors, as obtained from FDA regulatory documents.

 A handful of kinase inhibitors have been shown to have minimal or no interaction with CYP3A4 inducers and inhibitors, and these are afatinib, alectinib, binimetinib, dacomitinib, lenvatinib, and trametinib.

Pharmacokinetically, many protein kinase inhibitors demonstrate pH-dependent solubility. Medications such as H2-receptor antagonists, proton pump inhibitors, and short-acting antacids actively increase gastric pH. This prevents pH-dependent absorption, which decreases the AUC and maximum concentration (Cmax) of the protein kinase inhibitor (table 2). A reduction in AUC and Cmax may lead to decreased efficacy and clinical outcomes. In many cases, avoiding concomitant use of gastric acid—reducing agents and protein kinase inhibitors and is recommended.

Many protein kinase inhibitors require transportation through various processes, including passive diffusion and adenosine triphosphate—binding cassette transporters, such as p-Glycoprotein (P-gp), thus leading to P-gp inhibition. Pharmacokinetically, known in vitro substrates of P-gp such as digoxin, fexofenadine, and quinidine may undergo an increase in AUC via P-gp inhibition with protein kinase inhibitor use. For example, the AUC of digoxin increases about 80% with concomitant use with lapatinib, which may affect its narrow therapeutic index.

 This has particular implications in the treatment of breast cancer, as many chemotherapy agents are substrates of P-gp. Pazopanib used with paclitaxel increased the exposure of paclitaxel by about 26%.

 Although results of preclinical studies illustrate that protein kinase inhibitors may possess some capability to counteract P-gp—mediated multidrug resistance, there is also a greater risk of adverse effects, because of the accumulation of cytotoxic drugs in the body.

 Although not completely elucidated, the potential for critical P-gp interactions between protein kinase inhibitors and chemotherapy in the treatment of breast cancer should be considered.

Several protein kinase inhibitors have been associated with the pharmacodynamic effect of prolonging the QT interval. Most protein kinase inhibitors have been evaluated for QT prolongation through well-documented clinical trials. According to an article from Drug Safety, the QT-prolonging effects of tyrosine kinase inhibitors may be due to “off-target class III electrophysiologic effects, possibly related to the presence of a fluorine-based pharmacophore.”

 Tasigna (nilotinib), in particular, has a boxed warning for QT prolongation, and medications associated with prolonging the QT interval should not be used in conjunction with Tasigna. Overall, evaluating the risk of QT prolongation associated with protein kinase inhibitors is critical in reducing the risk of DDI (table 2).

Concomitant administration of protein kinase inhibitors with gastric acid—reducing agents or inducers or inhibitors of CYP3A4 may have clinically significant effects on the serum concentration of the protein kinase inhibitor, leading to effects on efficacy and safety. Protein kinase inhibitor use and the potential for P-gp inhibition or induction should be considered, especially for narrow therapeutic index medications, including cytotoxic medications. Certain protein kinase inhibitors have also been shown to prolong the QTc interval; therefore, care should be taken when administering them simultaneously with other agents that can lead to QTc prolongation. By recognizing the pharmacokinetic and pharmacodynamic interactions of these particular groups of medications in combination with protein kinase inhibitors, pharmacists can recommend agents and/or doses that may be safer for the patient and provide appropriate therapeutic efficacy.

 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 ASVMC. She coordinates and precepts in the VA Learning Opportunities Residency intern program and is an adjunct advanced pharmacy practice experience preceptor for ACPHS and Western New England University College of Pharmacy and Health Sciences in Springfield, Massachusetts.

van Leeuwen RW, van Gelder T, Mathijssen RH, Jansman FG. Drug-drug interactions with tyrosine-kinase inhibitors: a clinical perspective. 

. 2014;15(8):e315-e326. doi: 10.1016/S1470-2045(13)70579-5.

Drugs @FDA: FDA approved drug products. FDA website. www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed 19 Jul 2019.

Beretta GL, Cassinelli G, Pennati M, Zuco V, Gatti L. Overcoming ABC transporter-mediated multidrug resistance: the dual role of tyrosine kinase inhibitors as multitargeting agents. 

. 2017;142:271-289. doi: 10.1016/j. ejmech.2017.07.062.

Shah RR, Morganroth J, Shah DR. Cardiovascular safety of tyrosine kinase inhibitors: with a special focus on cardiac repolarization (QT interval). 

 2013;36(5):295-316. doi: 10.1007/s40264-013-0047-5.

Medications in this drug class can alter the safety and efficacy of co-administered medications.