KITSO AIDS Training Program Lecture 7: Drug-Drug Interactions in ARV Therapy delivered by Dr. Daniel J. Baxter, ACHAP

Drug Interactions Potential for drug interactions is significant in the HIV infected patient. May be an important cause of treatment failure. Overlapping toxicities may increase the risk of adverse events. Beneficial drug interactions are increasingly being used to enhance efficacy and reduce toxicity. What is the importance of Drug-Drug Interactions Safe and effective drug therapy requires that drugs are delivered to their site of action in a concentration that yields efficacy without toxicity. This optimal concentration is also called the therapeutic window. The effect of some drugs can be altered markedly by the administration of other agents. ARV therapy is a complex medication involving the administration of several different agents, some of which require special attention concerning simultaneous food intake, others have to be given several times per day. In addition patients requiring ART often need management of opportunistic infections, which by its own might consist of multiple drug therapies. Not uncommonly HIV /ADIS patients need up to 10 different drugs per day e.g. to treat tuberculosis and other concurrently occuring OIs. The pill/drug burden is enormous and potential for interaction is large. Suboptimal ARV concentration due to D-D-I might be the cause of treatmemt failure, conversely toxic drug level due to D-D-I leading to delayed clearance of ARV drugs or overlapping toxicities of concomitant medications increases the risk of side effects. Drug interactions are increasingly studies for their potential of enhancing efficacy and thus reducing toxicity of some medications addition patients requiring ART often need management of opportunistic infections, which by its own might consist of multiple drug therapies. Not uncommonly HIV /ADIS patients need up to 10 different drugs per day e.g. to treat tuberculosis and other concurrently occuring OIs. The pill/drug burden is enormous and potential for interaction is large. Drug interactions are increasingly studies for their potential of enhancing efficacy and thus reducing toxicity of some medications.

Lecture Overview Review of mechanisms of drug interactions. Interactions between antiretroviral agents and other drugs. Interactions between antiretroviral agents. Overlapping toxicities. Management principles. I will first review with you the mechanisms of Drug drug interactions, Then I will describe interactions between ARV drugs and other concomittantly given therapies Followed by description of interaction between ARV drugs themselves and Finally touch on the problem of overlapping toxicities

Drug Therapeutics In order for any drug, including ARVs, to exert a therapeutic effect, the blood and tissue level of that drug must be at a certain therapeutic level over a certain period of time. If the blood and tissue levels of ARVs are not at a therapeutic level, viral replication will not be suppressed and treatment failure will result.

The plasma concentration of free drug is a result of 4 successively occurring and partly overlapping processes and eventually determines the amount of effective drug available to equilibrate with the the target cells at the site of action. When the plasma concentration is plotted against time a curve characteristic for a special drug is obtained. drug The overall exposure achieved after a single dose giving a singe dose of drugs is measured by the Area under the plasma concentration curve (AUC). The potential response to the drug depends on the magnitude (peak) and duration of available drug level. The pharmacokinetic characteristics of a drug are described by terms such as the bioavailability of the drug, the maximum plasma level, the time to reach the peak plasma level, the trough level when repeated doses are given, the half time of the drug, the plasma binding and the clearance rate. The therapeutic range is the range of drug concentration in which the probability of an efficacious effect is greater than the probability of toxicity. The maximum effect achieved at optimal drug concentration is the E max. Further increase I drug concentration will achieve no increase in response. What does pharmacokinetics mean?: Pharmacokinetics describe the journey/passage of the drug through the body from entering the body to its excretion. On the road there are some important stations where different drugs can meet: An important station for orally taken drugs is the GIT where the drug has to be absorbed. , Then other potential interactions occur when drugs are distributed through the body, a very important place for drug interactions is the liver where drugs are metabolized or changed and the kidney where they are excreted. Drug Blood Level Time

NRTI Metabolism NRTIs are cleared through the kidneys. Dose adjustment of NRTIs is necessary in patients with significant renal failure. Consult with pharmacist or HIV specialist concerning dose adjustment.

Absorption Gastrointestinal pH neutral environment: ddI acid environment: NFV neutral environment: ddI Is there any interaction between food and ARV drugs? Fortunately, little requirements concerning food intake have to fulfilled. The major exception is the drug DDI! Drug absorption in the gastrointestinal tract after oral administration is influenced by gastric acidity, the presence of other compounds and the motility of the GIT. Delayed or reduced absorption influence the blood concentration by impacting on the level or time when peak concentration is reached. Of relevance for ART and drugs used in the management of OI is the ph level in the stomach required for optimal absorption of ddI , indinavir or ketoconazol. DDI requires a neutral ph environment and the ddI tablet already comes with an antacid buffer that is designed to optimize that environment when given on an empty stomach. Indinavir and ketoconazol require an acid environment for dissolution and absorption; they therefore are best given on an empty stomach and their absorption is reduced when antacids or Histamine H2 blocker that reduce gastric acidity are used. Fluconazol is not influenced by an increase in gastric ph. Gastrointestinal absorption of drugs is impaired e.g. when the simultaneous administation of 2 compounds induces formation of unabsorbable complexes: e.g. Aluminium ions, present in antacids, form complexes with tetracycline, preventing absorption. Similarily, Fe blocks tetracycline absorption, when co-administered. Fortunately interactions at the level of absorption are only few, however they are significant for efficacy of some drugs.

Interactions between ARV Drugs and other Drugs The most important area of interactions between ARV drugs and other medications involves the process of drug metabolism in the liver.

Drugs cleared by Cytochrome P450 Antiretroviral drugs NNRTI Protease Inhibitors Anti-infectious agents e.g. Ketoconazole Rifampicin Dapsone Oral contraceptives Anti-histamines Anticoagulants Warfarin Lipid lowering drugs Simvastatin Lovastatin Anticonvulsive drugs Carbamazepine Phenytoin Phenobarb ACTIVE DRUG Cytochrome P450 There are many different enzymes involved in clearing drugs. One of the most important is the P450 family. Many different classes of drugs are cleared from the body by this system. The other very important pathway to clear drugs is the Cytochorme P450 pathway. More than 20 Isoenzymes of the CYP450 are known, they reside in the enteric mucosa and most imortantly in the liver. Cytochrome p450 isoenzymes have specificity for groups of drugs, the C450 3A4 being the most important involved in metabolism of ARV drugs. As Cytochrome p450 plays a central role in drug metabolism, there is a long list of drugs that use this important pathway. Among them are NNRTI and PI, several antibiotics and antitb drugs, antiepileptic drugs, lipid lowering drugs, hormones and many more. InactiveDRUG

Enzyme Induction/Inhibition New substances e.g., proteins Broken down in the body, with the help of ENZYMES Food, drinks, drugs, etc. Waste products The clearance process by the p450 enzymen family can be increased or inhibited by other substances. INDUCED (increased) OR INHIBITED (blocked)

Hepatic Metabolism of Drugs The liver’s metabolism of drugs is not at a fixed rate and varies from drug to drug and from person to person. One of the things which can increase or decrease the rate of the liver’s metabolism of a given drug is other drugs. Many drug-drug interactions involve the way one drug affects the liver’s metabolism of another drug.

Enzyme Induction/Inhibition Drugs such as Rifampicin or NVP induce (activate) the P450 enzyme system and therefore increase the liver’s metabolism of drugs that use the P450 enzyme system, thereby decreasing their blood level more rapidly. Drugs such as protease inhibitors or Ketoconazole inhibit (suppress) the P450 enzyme and therefore decrease the liver’s metabolism of drugs that use the p450 enzyme system, thereby keeping their blood level higher for a longer period of time.

NVP Drug Interactions Drug NVP Interaction Comment Rifampicin NVP  No dose adjustment of NVP. Oral Contraceptives O/C  Use alternative or additional contraception. Ketoconazole NVP , Keto  Not recommended, use alternate antifungal drug. Ergotamine Compounds CONTRAINDICATED

EFV Drug Interactions Drug EFV Interaction Comment Rifampicin EFV  Dose adjustment of EFV may or may not be indicated. Ergotamine compounds CONTRAINDICATED

Protease Inhibitor Drug Interactions Comment Rifampicin PI  Boosted RTV/SQV recommended Ketoconazole RTV: Keto  IDV: IDV  Do not exceed Keto dose of 200 mg/day Dose adjust IDV NFV no adjustment Oral Contraceptives O/C  RTV, NFV: Use alternative or additional contraception IDV: no adjustment Ergotamine Compounds St John’s Wort Lovastatin, Simvastatin, * CONTRAINDICATED *Pravastatin can be used safely with protease inhibitors.

NRTI Drug Interactions AZT Do not combine with d4T. ddI Antacids and cimetidine might increase absorption. 3TC No significant drug interactions. d4T Do not combine with AZT.

Interactions between ARV Drugs

Interactions between ARV drugs Drug Combinations Comments NRTI combinations Do not combine AZT and d4T NRTI + NNRTI No significant interactions NRTI + PI ddI + NFV: optimal absorption environment differs PI combinations Possible pharmacological enhancement

PI Boosting Among the PIs, RTV is the most potent inhibitor of the P450 enzyme system. A low dose of RTV (“r”) will increase the level of SQV or LPV when given concurrently. SQV & LPV Inactive drug RTV The other very important pathway to clear drugs is the Cytochorme P450 pathway. More than 20 Isoenzymes of the CYP450 are known, they reside in the enteric mucosa and most imortantly in the liver. Cytochrome p450 isoenzymes have specificity for groups of drugs, the C450 3A4 being the most important involved in metabolism of ARV drugs. As Cytochrome p450 plays a central role in drug metabolism, there is a long list of drugs that use this important pathway. Among them are NNRTI and PI, several antibiotics and antitb drugs, antiepileptic drugs, lipid lowering drugs, hormones and many more.

PI boosting The combination RTV/ SQV or LPV/r has multiple benefits: Reducing the pill burden and dosing frequency. Improving the medication adherence. Reducing risk of toxicity. Reducing cost. Used in trials and practice since 1996, mainly in salvage regimens Studies have found that when saquinavir was combined with ritonavir, there was enhanced bioavailability, and decreased systemic clearance of saquinavir, increasing the AUC of saquinavir by 30 to 50 –fold.(Merry C et al, 1997)

Interactions of Anti-TB Treatment and ARV Therapy

Anti-tuberculosis Agents and ARVs Rifampicin Rifampicin is the most potent P450 inducer and lowers plasma levels of NNRTIs and PIs. NNRTI levels are lowered from 30-37%; this reduction is usually not clinically significant. However, there may be occasional patients in whom rifampicin lowers the blood level of NVP or EFV to a greater extent, such that treatment failure could result. PI levels are lowered by up to 90%, which is clinically significant. Of special importance is the interaction of NNRTI and PIs with rifampicin as rifampicin is part of the national regimen to treat Tb in Botswana. Tb is a major cause of morbidity in HIV infected persons. Rifampicin in a strong inducer of the P450 enzyme system and it causes increases clearance of NNRTI and PIs, conversely PIis and NNRTI, being inhibitors of the system will increase the level of Rifampicin. Limited clinical experience exists fro certain combinations of ARV and Tb medications and favorable results were shown for rifampicin containing Tbregimens and two Pis and a regimen containing 2NRTI and efavirenz, in which the EFC does was elevated to 800 mg.

Anti-tuberculosis Agents and ARVs (2) Favorable clinical experience: 2 NRTIs + EFV (600 mg OD) / NVP (200 mg BD) + Rifampicin regimen (Guidelines recommend EFV 800mg dose if weight is greater than 60kg. Other specialists believe 600mg dose is adequate.) Combination RTV/SQV (400mg/400mg BD) + Rifampicin regimen What combinations are possible and safe? Dose adjustment necessary when using NNRTI and Rifampicin.

Anti-tuberculosis Agents and ARVs (3) Because of serious drug-drug interactions between rifampicin and protease inhibitors, patients who develop TB while on second-line regimen must be referred to a specialist for evaluation.

Anti-tuberculosis Agents and ARVs (4) Rifampicin can lower LPV/r (Kaletra) levels by 75%. Possible options include: - Extra RTV boosting - Change to SQV/RTV (400mg/400mg BD) HIV specialist should be consulted. What combinations are possible and safe? Dose adjustment necessary when using NNRTI and Rifampicin.

Overlapping Toxicities

Overlapping Toxicities Bone Marrow Toxicity Pancreatitis Nephrotoxicity Hepatotoxicity AZT Hydroxyurea Anti-cancer drugs Sulfonamides Pyrimethamine Primaquine Gancyclovir ddI 3TC d4T RTV Alcohol Aminoglycosides Amphotericin Foscarnet EFV NVP Protease Inhibitors Fluconazole Ketoconazole INH Rifampicin alcohol Many drugs used in the management of HIV disease may have similar adverse effects and must be used with caution and careful monitoring. Overlapping toxicities between ARV drugs and other drugs in management of OI include th epotential for bone marrow suppression, pancreatitis, peripheral neuropathy, hepatoxicity, rash, eye toxicity and diarrhea.

Overlapping Toxicities (2) Neuropathy Rash Diarrhea Eye Toxicity DDI d4T INH Alcohol NVP EFV Sulfonamides Dapsone NFV ddI RTV LPV/r Clindamycin Ethambutol

Case 1 A patient has recovered well from severe immune deficiency (baseline CD4 56, weight 41 kg) since started on (AZT+3TC) + NVP. Her weight is now 59 kg. She is now menstruating regularly and has a partner. What contraception do you recommend? Interaction O/C and NVP: possible advice O/C plus condom

Case 2 A patient with a CD4 of 63 and severe oral candidiasis is started on (AZT+3TC) + NVP. She also receives Ketoconazole 200mg. Interaction Ketoconazole and NVP: Oral suspension antifungal preparation or Fluconazole recommended

Case 3 A patient with known migraine and on treatment with Dihydroergotamin will start HAART with (AZT+3TC) + EFV. Interaction Ergotamin and EFV: Ergotamine CONTRAINDICATED Prophylaxis with propranolol or amitriptyline

Case 4 A patient with KS is started on ART with (AZT+3TC) + NVP. Six weeks after HAART initiation, the patient presents with pallor and a HB of 3.9 g%. He also receives cotrimoxazole and chemotherapy for his KS. Overlapping toxicity: Cotrimoxazole, AZT, and chemotherapy

Case 5 A patient has been on (AZT+3TC) + NVP. Five months after initiation symptoms of TB appear, and the sputum AFB result comes back positive. Interaction between Rifampicin and NVP: Potentially decreased NVP effect. National Program guidelines recommend NO drug modification.

Case 6 Female patient on 3rd month of ATT should now be initiated on first line HAART. What regimen do you recommend? Potential Interaction between Rifampicin and NVP, but no dose adjustment recommended.

Case 7 A patient presents with a CD4 of 36, wasting syndrome and oral candidiasis. You want to initiate HAART. On questioning about other medications he takes, he mentions that he also receives a tea from a traditional doctor which he takes every morning. Traditional medicine and ARV drugs Unknown interactions

Traditional Medicine None of the medications (teas, herbs, tablets, concoctions, etc.) given within the context of traditional/spiritual healing in Botswana have been studied with regard to their content and/or potential effect on ARV medications and their toxicities.

Summary

Recommended Dosing with Regard to Meals Take on empty stomach: ddI Take with food NFV Food independent AZT 3TC d4T NVP EFV LPV/r Only few ARV drugs need special recommendation in regard to food intake. As mentioned earlier ddi and and IND should be given on empty stomach in order to achieve desired blood concentration (for different reasons though). The other ARV drugs are much more forgiving.

Review Drug Interactions when Prescribing… ATT Oral contraceptives Ketoconazole Ergotamine Protease inhibitors and ATT

Management of Drug Interactions Knowledge of drug-drug interactions continues to evolve. Consult guidelines i.e., www.hiv-druginteractions.org or www.HIVinsite.org Potentially harmful interactions occur in a small proportion of patients. Drug-drug interactions must be considered in the DD of unexpected responses to drugs.

Management of Drug Interactions (2) A thorough drug history including non-prescription drugs and alternative or traditional therapies must be taken at each follow-up visit. Drug-drug interactions are one of the causes of treatment failure. Drug-drug interactions must be considered in the DD of unexpected responses to drugs.