Antiretroviral Therapy Drug- Drug Interactions

Antiretroviral Therapy Drug- Drug Interactions Todd Wills, MD Assistant Professor of Internal Medicine Division of Infectious Disease and International Medicine University of South Florida Faculty, Florida Caribbean AETC Disclosure of Financial Relationships This speaker has the following significant financial relationships with commercial entities to disclose: • Research Support: • Tibotec • Pfizer • Gilead This slide set has been peer-reviewed to ensure that there are no conflicts of interest represented in the presentation. Why are HIV/AIDS Patients at Risk? • Use of 3 and 4 drug antiretroviral regimens • Multiple agents for treatment/prevention of various opportunistic infections • Patient living longer and being treated for other chronic diseases (e.g. diabetes, CAD) • Many antiretroviral agents have a profound effect on the cytochrome P450 enzyme system Metabolism • Drugs enter GI tract • P-glycoproteins • Transporter proteins- “pumps” • Meds may promote – decrease drug levels • Meds may inhibit – increase drug levels Metabolism • After leaving GI tract • May be bound or unbound to proteins • Bound – not bioavailable to tissues • Nutritional deficits • Efficiency and site of action may be altered • Hepatic Metabolism • Cytochrome P450 system • Enzymes to facilitate metabolism • > 20 variants Hepatic Metabolism • Metabolism may occur by one or more of the enzymes • CYP3A4 most frequently utilized by ART • Inhibitors • Inducers Drug Interactions • Multifactorial • Sex • Age • Race/ ethnicity • Pregnancy • Hormone levels • Body size • Alcohol use • Co-morbidities Drug Interactions • Co-infection with Hepatitis B or C • Reduces enzyme activity in liver • Up to 80% reduction for some enzymes • PIs affected • Need to consider when prescribing 2nd and 3rd line therapies • NNRTIs and NRTIs less affected Classifications of Interactions • Pharmacokinetic • Absorption • Mg and Al antacids impair IDV absorption • Distribution • TMP/SMX displaces warfarin from protein binding • Metabolism • Rifampin induces CYP450 metabolism of PIs • RTV “boosting” • Excretion • Pharmacodynamic • Additive • Increased bone marrow toxicity of ZDV + GCV • Synergistic • HAART effect greater than additive monotherapy • Antagonistic • ZDV and D4T reduces antiviral effect NRTI Related Interactions • Both additive and synergistic • Eliminated by the kidneys • Minimal impact from CYP450 • No interactions with NNRTIs or PIs • Abacavir – alcohol use may increase level • Tenofovir • Can decrease Atazanavir levels – must boost • Atazanavir/Lopinavir – minimal increase of TDF NRTI Related Interactions • Zidovudine and Stavudine – Antagonistic • Didanosine • Buffered formulations (solution and tablet) • Impair absorption of quinolones, tetracyclines, atazanavir • Must be taken at separate times • Enteric Coated • Increased DDI AUC with tenofovir co-administration • Must lower DDI EC dose • Watch for emergence of didanosine related toxicities NNRTI Related Interactions • Can increase or decrease PIs (especially EFV) • Nevirapine –CYP3A4 induction • Requires dose escalation • May decrease efficacy of OCPs • Levels may be reduced with rifampicin co-administration (rifabutin preferred) • Efavirenz – CYP3A4 induction +/- inhibition • EFV dose increase required with rifampicin • Rifabutin dose increase when used with EFV • Very long half-life PI Related Interactions • Potent inhibitors of CYP3A4 • Ritonavir • Most potent inhibitor of CYP3A4 among PIs • Used clinically to pharmacokinetically enhance other PIs • Inhibits P-glycoprotein transport in the GI tract, increases absorption of other meds thereby enhancing “boosting” effect PI Related Interactions • • • • • Saquinavir – mildest inhibitory effect ATV,f-AMP, IDV, NFV – moderate inhibitors RTV and NFV induce their own metabolism f-AMP + LPV – reduced levels of both Tipranavir – CYP3A4 inducer • Decreases levels of other PIs Drugs That Should Not Be Given With PIs • • • • • • • Simvastatin Lovastatin Astemizole Terfenadine Cisapride Pimozide Bepridil • St. John’s Wort • Rifampin (except ritonavir) • Rifapentine • Midazolam • Triazolam • Ergot alkaloids •Additionally the following should not be given with ritonavir: amiodarone, flecainide, propafenone, quinidine, alfuzosin, voriconazole •Proton pump inhibitors and Irinotecan should not be used with atazanavir Fusion Inhibitors • Enfuvirtide • No known interactions with other antiretrovirals Antimicrobials • Macrolides • Erythromycin and Clarithromycin • Inhibit CYP3A4 and p-glycoproteins • Erythro with other inhibitors • 5x increased risk of sudden cardiac death • Study not related directly to ART • Azithromycin has minimal impact Antifungals • – azoles • CYP3A4 and p-glycprotein inhibitors • Increases levels of other meds • Other CYP3A4 inhibitors can increase azoles • Care with combination of voriconazole with RTV or EFV • Change voriconazole to 400 bid, efavirenz 300 mg qhs when combined • Flucon < Itra or Ketoconazole Antimycobacterial Drugs • Rifampicin is potent inducer of CYP450 system • Leads to clinically significant reduction in most PI levels • Clinically significant reductions of nevirapine levels • May be used with NRTIs, efavirenz, and enfuvirtide • With proper dose adjustments Rifabutin can be used with most antiretrovirals Acid-Lowering Drugs • Proton Pump Inhibitors • Do not use with Atazanavir • Up to 76% reduction in plasma concentration • OTC antacids • Can use within 1-2 hrs of ART • Buffered or enteric coated medications • Caution with Atazanavir Other Drug Classes • Anticonvulsants • Monitor drug levels • Avoid phenytoin, carbamazapine, and phenobarbitol (inducers) with PIs and NNRTIs • Depakote, gabapentin, lamotrigine, and Keppra have minimal interactions • HMG-CoA Reductase Inhibitors • Metabolized by CYP450 system • Simvastatin levels increased up to 40-fold with concurrent PI use • Safest drugs: pravastatin, low dose atorvastatin, rosuvastatin, fluvastatin Other Drug Classes • Calcium Channel Blockers • Levels may increase with PIs • Immunosuppressives – PIs increase levels • Benzodiazepines • Midazolam and triazolam – inc. levels with CYP450 inhibitors • Fatal respiratory depression • Caution with alprazolam (Xanax), diazepam (Valium), zolpidem (Ambien) • Lorazepam (Ativan) and temazepam (Restoril) safer Other Drug Classes • Antidepressants • Tricyclics more likely to be involved • SSRIs - Prozac, Paxil, Zoloft, Lexapro • Levels may be increased by inhibitors – leading to seizures, arrhythmias, coma • PIs, especially RTV- may need to decrease SSRIs Other Drug Classes • Erectile Dysfunction Drugs • • • • Metabolized by CYP3A4 Sildenafil, vardenafil, tadalafil Concentrations increased by four-fold with PIs Low BP, dizziness, fainting, headaches, vision disturances, and priapism • May have decreased levels of ED drugs with EFV Other Drug Classes • Oral Contraceptives • Impacted by CYP34A agents • EFV, NVP, NFV, RTV, LPV – decrease levels of estrogen • May use OCP that contain progesterone only Recreational and Street Drugs • Few studies • RTV can increase ecstasy (MDMA) levels • Agitation, seizures, tachycardia, cardiac arrest • Liver disease may worsen • Other amphetamines – crystal meth • GHB + RTV + SQV = death • Opiates including Methadone – PIs, NNRTIs – reduce plasma conc. • Monitor for withdrawl • Cocaine – no significant interactions with ART Alternative Remedies • Few studies • Garlic – inhibits +/- induces CYP3A4 • Potential 50% reduction in SQV levels (gel caps) • Limited information with NNRTIs and PIs • Milk Thistle – used for Hep C and Hep B • unknown • St.John’s Wort – inducer of CYP3A4 and pglycoproteins • One study – decreased levels of IDV • US guidelines – no use with NNRTIs and NRTIs Adverse Effects NRTIs • Zidovudine – HA, GI, bone marrow suppression • Didanosine – GI intolerance, pancreatitis • Stavudine – peripheral neuropathy • Zalcitabine - peripheral neuropathy • Abacavir – HA, GI, hypersensitivity reaction NNRTIs • Nevirapine - rash, liver • Delavirdine - rash • Efavirenz – teratogenic in primates, CNS, rash PIs • • • • Indinavir – nephrolithiasis Ritonavir – GI intolerance Nelfinavir – diarrhea Fosamprenavir – GI intolerance, HA • Lopinavir/ritonavir – GI intolerance Drug Interaction Resources • www.hiv-druginteractions.org • hivinsite.ucsf.edu • http://hivinsite.ucsf.edu/insite?page=ar-00-02 • www.aidsinfo.nih.gov (DHHS HIV Treatment Guidelines, TB Guidelines)