The New England Journal of Medicine Drug Therapy Metabolic Interactions All HIV-protease inhibitors and non-nucleoside re- verse-transcriptase inhibitors that have been approved A LASTAIR J.J. WOOD, M.D., Editor by the Food and Drug Administration (FDA), as well as those that are investigational drugs, are metabolized INTERACTIONS AMONG DRUGS by the cytochrome P-450 enzyme system, primarily FOR HIV AND OPPORTUNISTIC by the 3A4 isoform (CYP3A4), and each of these drugs may alter the metabolism of other antiretroviral INFECTIONS and concomitantly administered drugs.15 The cyto- chrome P-450 system consists of at least 11 families of STEPHEN C. PISCITELLI, PHARM.D., enzymes, classified by number, of which 3 (CYP1, AND KEITH D. GALLICANO, PH.D. CYP2, and CYP3) are important in humans.16 The RUG interactions are an important factor in families are further divided into subfamilies, denoted the treatment of patients with human im- by a capital letter (e.g., CYP3A). Individual proteins munodeficiency virus (HIV) infection. The within a subfamily, called isozymes or isoenzymes, are D 16 complexity of current drug regimens for such pa- identified by a second number (e.g., CYP3A4). tients requires that clinicians recognize and manage Drugs can be classified as cytochrome P-450 sub- drug interactions. Antiretroviral drug regimens typ- strates, inhibitors, or inducers. However, some drugs, ically consist of three or four antiretroviral drugs but such as ritonavir, nelfinavir, and efavirenz, may have may include even more. In addition, patients may re- properties of all three, depending on the specific com- ceive other drugs for supportive care, treatment of op- bination (Table 2). Substrates are drugs metabolized portunistic infections, and immunomodulation, as well through this enzyme system, and the plasma concen- as alternative drugs obtained from health care pro- trations of such drugs may be increased or decreased viders other than their primary provider. Drug inter- by other drugs. Inhibition of cytochromes is usually actions are often unavoidable in HIV-infected patients reversible and competitive, in that the substrate and because of the drug classes involved and the number inhibitor compete for the same site on the enzyme. of drugs prescribed. In this article we review the clin- Inhibition also occurs by irreversible inactivation of ically important interactions among drugs used to the enzyme, leading to pharmacologic effects that are treat HIV infection, provide an overview of the pri- prolonged until new enzyme can be synthesized.19 mary mechanisms of drug interactions, and discuss Drugs that inhibit cytochromes cause decreased clear- ways to prevent or minimize the adverse effects of ance and increased plasma concentrations of substrate such interactions on clinical care. drugs, and the effects may be greater if inhibitory me- tabolites accumulate during multiple dosing. MECHANISMS OF DRUG INTERACTIONS Drugs that induce cytochromes increase the rate Drug interactions can be either pharmacokinetic of hepatic metabolism of other drugs by increasing or pharmacodynamic in nature. Pharmacokinetic in- the transcription of cytochrome messenger RNA teractions alter the absorption, transport, distribution, (mRNA), which in turn leads to the production of metabolism, or excretion of a drug. In therapy for more enzyme and a corresponding decrease in plas- HIV infection, pharmacokinetic interactions are often ma concentrations of drugs metabolized by the in- multifactorial. They may involve alterations in drug duced pathway. When a CYP3A4 inhibitor, such as metabolism mediated by the cytochrome P-450 sys- ritonavir, is added to another protease inhibitor, such tem, modulation of P-glycoprotein (a cellular trans- as saquinavir, plasma concentrations of the second port protein), changes in renal elimination, changes protease inhibitor increase markedly (Fig. 2A), often in gastric pH and drug absorption, and fluctuations allowing for more convenient dosing. Increased con- in intracellular drug concentrations (Table 1). These centrations may also overcome viral resistance to the processes may take place at various sites in the body drug.21 The addition of a CYP3A4 inducer, such as (Fig. 1). Pharmacodynamic interactions alter the phar- nevirapine, to indinavir or amprenavir results in a de- macologic response to a drug. The response can be crease in the area under the plasma concentration– additive, synergistic, or antagonistic. Pharmacodynam- time curve of the protease inhibitor (a measure of total ic interactions do not always modify a drug’s con- exposure). A substantial decrease could reduce trough centration in tissue fluids. plasma concentrations of the protease inhibitor to a level below the in vitro concentration required to in- hibit replication of 50 percent of viral strains (IC ), From the Clinical Pharmacokinetics Research Laboratory, Department 50 of Pharmacy, Warren G. Magnuson Clinical Center, National Institutes of with the subsequent development of resistance. Health, Bethesda, Md. (S.C.P.); and the Clinical Investigation Unit and Ot- tawa Hospital Research Institute, Ottawa Hospital, Ottawa, Ont., Canada Intestinal Metabolism and P-Glycoprotein (K.D.G.). Address reprint requests to Dr. Piscitelli at Virco Laboratories, Johns Hopkins Bayview Campus, Alpha Ctr., 3rd Fl., 5210 Eastern Ave., The liver is the primary site of drug metabolism me- Baltimore, MD 21224. diated by the cytochrome P-450 system, but CYP3A4 984 · N Engl J Med, Vol. 344, No. 13 · March 29, 2001 · www.nejm.org DRUG THERAPY TABLE 1. COMMON MECHANISMS FOR DRUG INTERACTIONS IN PATIENTS WITH HIV INFECTION.* MECHANISM EXAMPLES EFFECT CONSEQUENCES Altered intracellular activation Impairment of phosphorylation Ribavirin and zidovudine,1 zido- Interference with intracellular phos- Potential for decreased effectiveness vudine and stavudine,2 zalcita- phorylation (in vitro) and treatment failure bine and lamivudine3 Altered drug absorption and tissue distribution Chelation Fluoroquinolones with Marked reduction in quinolone AUC Reduced antimicrobial effect antacids4,5 from formation of insoluble com- plexes Change in gastric pH Indinavir and didanosine6 Impaired absorption of indinavir due Low plasma indinavir concentrations to increased pH may lead to viral resistance and treat- ment failure Induction of efflux transporters Rifampin and digoxin7 Decrease in digoxin AUC Reduced therapeutic effect Inhibition of efflux transporters Ketoconazole with saquinavir Increased CSF concentrations of Combination being studied to target and ritonavir8 saquinavir and ritonavir in relation drug delivery to CSF; clinical rele- to unbound plasma concentrations vance unknown Altered drug metabolism Induction of cytochrome P-450 Rifabutin and saquinavir9 Saquinavir AUC reduced by 47 per- Low plasma saquinavir concentrations cent may lead to viral resistance and treat- ment failure Inhibition of cytochrome P-450 Ritonavir and indinavir10 Marked increases in indinavir AUC Combination under study to optimize (hepatic and gastrointestinal) and trough concentration therapy and develop more conven- ient regimens for patients Inhibition of cytochrome P-450 Grapefruit juice and saquinavir11 Saquinavir AUC increased by 50 to Increased plasma saquinavir concentra- (gastrointestinal only) 150 percent tions, but the effect is highly variable Increase in glucuronosyltransferase Rifampin and zidovudine12 Zidovudine AUC decreased by 47 Clinical relevance unknown but may percent lead to reduced antiviral effect if tri- phosphate concentrations are also decreased Reduced renal excretion TMP-SMX and lamivudine13 Lamivudine AUC increased by 44 Dosage alteration unnecessary, since percent due to inhibition of tubu- increased lamivudine concentrations lar secretion are unlikely to have toxic effects Pharmacodynamic interactions Additive or synergistic interactions Zidovudine and ganciclovir Additive bone marrow suppression May require discontinuation or re- duced doses of one or both drugs or addition of G-CSF Combination HAART therapy Sustained viral suppression Potent therapy associated with long- term clinical and immunologic im- provement Antagonist or opposing interactions Indinavir and saquinavir14 In vitro antagonism at high doses Clinical consequences unclear *AUC denotes the area under the concentration–time curve, CSF cerebrospinal fluid, TMP-SMX trimethoprim–sulfamethoxazole, G-CSF granulocyte colony-stimulating factor, and HAART highly active antiretroviral therapy. is also present in the enterocytes of the small intes- a major site of expression of P-glycoprotein, one of tine.22 Thus, drugs that inhibit CYP3A4 may alter several membrane-bound proteins that increase the intestinal or hepatic metabolism of other drugs. The efflux of drugs from cells.25 Several protease inhibitors 20-fold increase in plasma concentrations of saquinavir are substrates for and inhibitors of P-glycoprotein26,27; caused by ritonavir is probably produced by inhibi- ritonavir is the most potent inhibitor.28,29 Both cyto- tion of CYP3A4 at both sites.20 Grapefruit juice con- chrome P-450 enzymes and P-glycoprotein can pre- tains various substances that inhibit CYP3A4-medi- sent a barrier to the absorption of orally administered ated metabolism only in the wall of the gut, mainly by drugs and have a considerable effect on drug inter- selective down-regulation of CYP3A4 protein in the actions. Figure 2B shows the effect of rifampin on plas- small intestine.23 The area under the curve for plas- ma digoxin concentrations