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Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents

Drug Interactions

Overview

(Last updated: April 8, 2015; last reviewed: April 8, 2015)

Pharmacokinetic (PK) drug-drug interactions between antiretroviral (ARV) drugs and concomitant medications are common, and may lead to increased or decreased drug exposure. In some instances, changes in drug exposure may increase toxicities or affect therapeutic responses. When prescribing or switching one or more drugs in an ARV regimen, clinicians must consider the potential for drug-drug interactions—both those that affect ARVs and those that ARVs affect on other drugs a patient is taking. A thorough review of concomitant medications in consultation with a clinician with expertise in ARV pharmacology can help in designing a regimen that minimizes undesirable interactions. Recommendations for managing a particular drug interaction may differ depending on whether a new ARV is being initiated in a patient on a stable concomitant medication or a new concomitant medication is being initiated in a patient on a stable ARV regimen. The magnitude and significance of interactions are difficult to predict when several drugs with competing metabolic pathways are prescribed concomitantly. When prescribing interacting drugs is necessary, clinicians should be vigilant in monitoring for therapeutic efficacy and/or concentration-related toxicities.

Mechanisms of Pharmacokinetic Interactions


PK interactions may occur during absorption, metabolism, or elimination of the ARV and/or the interacting drugs. The most common mechanisms of interactions are described below and listed for each ARV drug in Table 17.

Pharmacokinetic Interactions Affecting Drug Absorption

The extent of oral absorption of drugs can be affected by the following mechanisms: 

  • Acid reducing agents, such as proton pump inhibitors, H2 antagonists, or antacids, can reduce the absorption of ARVs that require gastric acidity for optimal absorption (i.e., atazanavir [ATV] and rilpivirine [RPV]).  
  • Products that contain polyvalent cations, such as aluminum, calcium, magnesium-containing antacids, supplements, or iron products, can bind to integrase inhibitors (INSTI) and reduce absorption of these ARV agents.
  • Drugs that induce or inhibit the enzyme CYP3A4 or efflux transporter p-glycoprotein in the intestines may reduce or promote the absorption of other drugs.

Pharmacokinetic Interactions Affecting Hepatic Metabolism

Two major enzyme systems are most frequently responsible for clinically significant drug interactions. 

  1. The cytochrome P450 enzyme system is responsible for the metabolism of many drugs, including the non-nucleoside reverse transcriptase inhibitors (NNRTI), protease inhibitors (PI), CCR5 antagonist maraviroc (MVC), and the INSTI elvitegravir (EVG). Cytochrome P450 3A4 (CYP3A4) is the most common enzyme responsible for drug metabolism, though multiple enzymes may be involved in the metabolism of a drug. ARVs and concomitant medications may be inducers, inhibitors, and/or substrates of these enzymes. 
  2. The uridine diphosphate (UDP)-glucuronosyltransferase (UGT) 1A1 enzyme is the primary enzyme responsible for the metabolism of the INSTIs dolutegravir (DTG) and raltegravir (RAL). Drugs that induce or inhibit the UGT enzyme can affect the PKs of these INSTIs.

Pharmacokinetic Enhancers (Boosters)


PK enhancing is a strategy used to increase exposure of an ARV by concomitantly administering a drug that inhibits the enzymes that metabolize the ARV. Currently in clinical practice, two agents are used as PK enhancers: ritonavir (RTV) and cobicistat (COBI). Both of these agents are potent inhibitors of the CYP3A4 enzyme, resulting in higher drug exposures of the co-administered ARV metabolized by this pathway. Importantly, RTV and COBI may have different effects on other CYP or UGT metabolizing enzymes and drug transporters. Complex or unknown mechanisms of PK-based interactions preclude extrapolation of RTV drug interactions to certain COBI interactions, such as interactions with warfarin, phenytoin, voriconazole, oral contraceptives, certain HMG-CoA reductase inhibitors (or statins), and other drugs.

Other Mechanisms of Pharmacokinetic Interactions


Knowledge of drug transporters is evolving, elucidating additional drug interaction mechanisms. For example, DTG decreases the renal clearance of metformin by inhibiting organic anion transporters in renal tubular cells. Similar transporters aid hepatic, renal, and biliary clearance of drugs and may be susceptible to drug interactions. ARVs and concomitant medications may be inducers, inhibitors, and/or substrates of these drug transporters.

Tables 18-20b provide information on known or suspected drug interactions between ARV agents and commonly prescribed medications based on published PK data or information from product labels. The tables provide general guidance on drugs that should not be co-administered and recommendations for dose modifications or alternative therapy.  
 

Table 17.  Mechanisms of Antiretroviral-Associated Drug Interactions

Pharmacokinetic interactions may occur during absorption, metabolism, or elimination of the ARV and/or the interacting drugs. This table does not include a comprehensive list of all possible mechanisms of interactions for individual ARV drugs (e.g., transporters); however, the table lists the most common mechanisms of interactions and focuses on absorption and CYP and UGT1A1 mediated interactions.

Note: Ellipses ( … ) indicate that there are no clinically relevant interactions by these mechanisms.

Table 17. Mechanisms of Antiretroviral-Associated Drug Interactions
ARV Drugs by Drug Class Mechanisms That May Affect or Be Affected by Oral Absorption of ARV Drugs  Enzymes That Metabolize or Are Induced or Inhibited by ARV Drugs Other Mechanisms of Drug Interactions 
   Increasing Gastric pH  Cationic Chelation P-glyco-protein   CYP Substrate  CYP Inhibitor CYP Inducer   UGT1A1  
Integrase Strand Transfer Inhibitors (INSTIs)
Dolutegravir
(DTG)
... Concentration decreased by products containing polyvalent cations (e.g., Ca, Mg, Al, Fe, Zn) Substrate 3A4 (small contribution) ... ... Substrate Inhibitor of renal transporters OCT2 and MATE
Elvitegravir
(EVG)
... ...  3A4 ... ... Substrate ...
Raltegravir
(RAL)
... ... ... ... ... Substrate ...
Pharmacokinetic (PK) Enhancers (Boosters)
Cobicistat
(COBI)
... ... Inhibitor 3A4 3A4, 2D6 ... ... ...
Ritonavir
(RTV)

... ... Substrate, inhibitor
3A4, 2D6
3A4, 2D6 (lesser extent)
1A2, 2C8, 2C9, 2C19
Inducer
...
Protease Inhibitors (PIs) 
Note: When PIs are co-administered with PK enhancers (boosters), the pharmacologic properties of both agents should be considered when assessing potential drug interactions.
Atazanavir
(ATV)
Concentration decreased ... Substrate, inducer, inhibitor 3A4 3A4, 2C8 (weak) ... Inhibitor ...
Darunavir
(DRV)
... ... Substrate
3A4
3A4 2C9
... ...
Fosamprenavir
(FPV)
Concentration decreased by H2 antagonist ... Substrate, inhibitor 3A4 3A4 3A4 (weak) ... ...
Lopinavir
(LPV)
... ... Substrate
3A4
3A4
... ... ...
Saquinavir
(SQV)

... ...  Substrate, inhibitor
3A4
3A4
... ...  ... 
Tipranavir
(TPV)

... ... Substrate, inducer 
3A4
2D6
3A4, 1A2, 2C19
... ...
Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz
(EFV)
... .. ... 2B6 (primary), 2A6, 3A4 2C9, 2C19, 3A4
3A4, 2B6
... ...
Etravirine
(ETR)

... ... Inducer
3A4, 2C9, 2C19
2C9, 2C19
3A4
... ...
Nevirapine
(NVP)

... ... ... 3A4, 2B6
... 3A4, 2B6
... ...
Rilpivirine
(RPV)

Concentration decreased ... ... 3A4 ... ... ... ...
 Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
Abacavir
(ABC)
... ... ... ... ... ... Substrate
Alcohol dehydrogenase substrate
Emtricitabine
(FTC)

... ... ... ... ... ... ... ...
Lamivudine
(3TC)

... ... ... ... ... ... ... ...
Tenofovir
(TDF)
... ... Substrate ... ... ... ... Competition of active renal tubular secretion
Zidovudine
(ZDV)

... ... ... ... ... ... ... Glucuronidation 
CCR5 Antagonist
Maraviroc
(MVC)

... ... Substrate
3A4
... ... ... ...
Fusion Inhibitor
Enfuvirtide
(T20)

... ... ... ... ... ... ... ...
Key to Abbreviations: Al = aluminium; ARV = antiretroviral; Ca = calcium; CYP = cytochrome P; Fe = iron; MATE = multidrug and toxin extrusion transporter; Mg = magnesium; OCT2 = organic cation transporter 2; UGT1A1 = uridine diphosphate glucuronosyltransferase; Zn = zinc 

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