Download

World Inventia Publishers

J

ournal of

S

cientific

R

esearch in

P

harmacy

http://www.jsrponline.com/

Vol. 6, Issue 6, 2017 ISSN: 2277-9469

USA CODEN: JSRPCJ

Review Article

AN INSIGHT INTO DRUG-DRUG INTERACTIONS INVOLVING ANTIRETROVIRAL AND ANTIMALARIAL DRUGS

Sunitha G.N 1_{*, B.M.V. Swamy} 2_{, D. Satyavati Dulipalia} 3_{, Girish Gudi} 1

* 1 _{Glenmark Pharmaceuticals Limited, Research Scientist, DMPK, Glenmark Pharmaceuticals Limited, A 607, TTC Industrial Area,} MIDC, Mahape, Navi Mumbai-400 709, INDIA.

2 _{East Point college of Pharmacy, Virgo Nagar Post, Avalahalli, Bengaluru, Karnataka, INDIA.}

3_{Brilliant Grammar School Educational Society's Group of Institutions-Integrated Campus (Faculty of Pharmacy),} Hayathnagar, Hyderabad, Telangana, INDIA.

Received on: 02-06-2017; Revised and Accepted on: 23-06-2017

ABSTRACT

H

uman immunodeficiency viral (HIV) infection and malaria are two of the most pernicious diseases prevalent in developing countries. HIV patients are more vulnerable to diseases like malaria due to their immunosuppression status. Treatment of HIV infection in this setting will require co-administration of antiretroviral (ARV) and antimalarial (AM) drugs.This treatment is often complex because of the combination of drugs used, multidrug resistance and drug interactions. The ARV and antimalarial drugs potentially interact and could cause toxicity or loss of efficacy, leading to mortality. To maximize the clinical benefit and minimize potential toxicity of ARVs and co-administered medications, it is important for clinicians to recognize significant drug-drug interactions (DDIs).Usually, the potential for drug interactions is investigated in vitro and then followed by in vivo studies. Many of these interactions involve inhibition or induction of metabolizing enzymes and transporters. The present review is an attempt to summarize the known and potential DDIs between ARV and antimalarial drugs and the invitro tools used to evaluate potential DDIs.

KEYWORDS: Drug-Drug Interaction, HIV drugs, Antimalarial drugs, Induction, Inhibition, Toxicity.

INTRODUCTION

D

rug-drug interactions are an important and widely under-recognized source of medication errors that normally occurs due to poly pharmacy practice. Multiple drug therapy increases the complexity of therapeutic management and thereby the risk of clinically important DDIs, which can both induce the development of adverse drug reactions or reduce the clinical efficacy. DDI represents major risk to patients and one of the major reasons for attrition of drug development or withdrawal from the market. DDI evaluation for a new drug generally begins with in vitro studies to determine whether a drug is a substrate, inhibitor, or inducer of metabolizing enzymes. The results of in vitro studies will inform the nature and extent of in vivo studies that may be required to assess potential interactions.Studies may also be performed to verify the suitability of a proposed dose adjustment or to confirm a lack of interaction with a commonly co-prescribed drug in the target population. Therefore, drug interaction potential is recognized as an important consideration in the evaluation of a new molecular entity (NME) and is an integral part of drug development and regulatory review prior to NME’s market approval.

It is estimated that 25.8 million people in Africa live with HIV while Malaria affects 300 to 500 million individuals annually in developing countries [1]_{. Two decades of research have shown that} HIV-related immune suppression is correlated with increased malaria infection, burden, and treatment failure [3]_{. Given this extensive} overlap with resulting high levels of co-infection, interactions between the two diseases have major implications for the treatment, care and prevention of both. Therefore, the management of HIV

*Corresponding author:

Sunitha G.N

Glenmark Pharmaceuticals Limited, Research Scientist, DMPK, Glenmark Pharmaceuticals Ltd,

A 607, TTC Industrial Area, MIDC, Mahape, Navi Mumbai-400 709, INDIA.

*E-Mail: [email protected]

infection in these settings will require multiple concurrent medications, with a potential for drug interactions and overlapping toxicities. Understanding the mechanisms of drug interactions will assist all clinicians in avoiding these serious, often preventable, events.

Current therapy recommended by the World Health Organization (WHO) for malaria includes the use of artemisinin derivatives, such as artesunate and artemether or fixed dose combination of artemether-lumefantrine [2]_{. For the treatment of HIV} presently, WHO recommends a first-line regimen that includes a thiacytadine analogue (either lamivudine[3TC] or emtricitabine), a companion nucleoside reverse-transcriptase inhibitor (NRTI) (either Zidovudine [AZT], tenofovir [TDF], abacavir [ABC], or d4T), and a nonNRTI (NNRTI) either Efavirenz [EFV] or Nevirapine [NVP]. Second-line regimens include 2 previously unused NRTIs (didanosine, TDF, ABC, 3TC, and/or AZT) coupled with either a ritonavir (RTV)–boosted protease inhibitor (PI) (either lopinavir, saquinavir, indinavir, atazanavir, or fosamprenavir) or unboosted nelfinavir.

Pharmacokinetic interactions of ARVs with antimalarials involve mostly NNRTIs and PIs which are included in first- or second-line therapy for HIV. Artemether, lumefantrine and lopinavir are all primarily metabolised by the same cytochrome P450(CYP) iso-enzyme, CYP3A4. Ritonavir is a potent inhibitor of CYP3A4 creating the potential for clinically significant DDIs [3]_{. The recent role out of} ARV therapies and new antimalarials, such as artemisinin combination therapies (ACT), raise additional concerns regarding possible synergistic and antagonistic effects on efficacy and toxicity. As access to ARVs and ACTsincrease, the importance of defining the interaction between antimalarials and ART becomes more urgent and studies evaluating the potential interactions between NNRTIs or PIs with antimalarials are needed.

Drug-Drug Interaction Overview:

An interaction is said to occur when the effects of one drug is changed by the presence of another drug(s), food, drink or an environmental chemical. When a therapeutic combination of drugs could lead to an unexpected change in the condition of the patient, this would be described as an interaction of potential clinical significance. The net effect of the combination may be synergism or additive effect of one or more drugs, antagonism or negative effect of one or more drugs, alteration of effect of one or more drugs or the production of idiosyncratic effects.

Drug-drug interactions can lead to changed systemic exposure, resulting in variations in drug response of the co-administered drugs. In addition to co-administration of other drugs, concomitant ingestion of dietary supplements or citrus fruit or fruit juice could also alter systemic exposure of drugs, thus leading to adverse drug reactions or loss of efficacy. Therefore, it is important to evaluate potential drug interactions prior to market approval as well as during the post marketing period.DDIsare important in drug development especially during fixed drug combination or multiple drug therapy to treat various diseases. DDIs may be pharmacokinetic or pharmacodynamic in nature, as illustrated in Table 1.

Table No. 1: Description and Examples of Common Mechanisms of Drug Interactions [4]

Type of Interaction Description Example

Pharmacokinetic Absorption Concurrent therapy or food results in increase or

reduction in drug absorption, thereby increasing or decreasing bioavailability

Atazanavir taken with magnesium/

aluminium-containing antacids can significantly reduce atazanavir absorption

Distribution Concurrent therapy leads to protein-binding

displacement, altering the activity of either drug Sulfamethoxazole/trimethoprim can displace warfarin from its protein-binding sites, increasing INR (International normalised ratio)

Metabolism Therapy induces or inhibits CYP450 enzymes,

thereby increasing or decreasing drug concentration Rifampicin can induce CYP3A4 and cause marked reductions in Protease inhibitor concentrations Excretion Concurrent therapy results in enhanced or decreased

renal excretion of drug Probenecid taken with penicillin can reduce renal elimination of penicillin Pharmacodynamic

Additive Concurrent therapy results in additive drug effect Additive bone marrow suppression with concurrent use of zidovudine and ganciclovir

Synergistic Concurrent therapy results in an exponential

increase in drug effect Concurrent use of indinavir, lamivudine, and zidovudine results in their combined effect being greater than the sum of their individual effects

Antagonistic Concurrent therapy leads to reduced drug effect for

both drugs Concurrent use of zidovudine and stavudine reduces antiviral effect

The main objectives of DDIs interaction studies are to determine whether potential interactions between the investigational drug and other drugs exist. It is also useful to evaluate whether the potential for such interactions indicates

1) need for dosage adjustments 2) additional therapeutic monitoring 3) contraindication to concomitant use 4) other measures to mitigate risk

Pharmacokinetic drug-drug interactions (PDDI), in which the pharmacokinetic clearance of one drug is altered by a co-administered drug, can be divided mechanistically into two general categories [5].

1) Inhibitory PDDI - the inhibition of the metabolic clearance of one drug by a coadministered drug, and

2) Inductive PDDI, the enhancement of the metabolic clearance of one drug by a coadministered drug.

Three mechanism based approaches are commonly used in the evaluation of the drug-drug interaction potential of a drug.

a) Identification of metabolic pathways

b) Evaluation of inhibitory potential for drug metabolizing enzymes

c) Evaluation of the induction potential for drug metabolizing enzymes

cDNA expressed enzymes, microsomes,hepaotcytes and liver slices are important tools in the in vitro evaluation of DDI potential.

Role of CYP 450 mediated inhibition and induction in drug interactions:

The CYP450 family of heme-containing monooxygenases are responsible for the oxidative metabolism of endogenous and exogenous compounds. Cytochrome P450 (CYP) enzymes, particularly CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, are responsible for the bulk of the metabolism of known drugs in humans.Cytochrome P450 (CYP) inhibition and induction are the key mechanisms in DDIs. Drugs that induce or inhibit CYP450 enzymes may decrease or increase, respectively, concentrations of concurrently administered drugs that are CYP450 substrates. Changes in drug concentrations resulting from drug interactions can lead to treatment failure or toxicities. Inhibition of these enzymes by co-administered drugs has led to the removal of several drugs from the market during the past 12 years (Table 2).

Table No. 2: Examples of drugs withdrawn because of CYP-related DDIs [6]

Drugs Name Therapeutic use Safety problem Year withdrawn

Terfenadine Allergy QTc prolongation 1998

Mibefradil Hypertension QTc prolongation 1998 Bromfenac Nonsteroidal anti-inflammatory drug Toxicity 1998

Astemizole Allergy QTc prolongation 1999

Cisapride Heartburn QTc prolongation 2000

Alosetron Irritable bowel syndrome Toxicity 2001

Cerivastatin Hyperlipidaemia Toxicity 2001

Nefazodone Antidepressant QTc prolongation 2003

Enzyme inhibition occurs when the inhibitor drug binds to the CYP isoenzyme and prevents binding (and therefore metabolism) of the substrate drug. For most drug interactions, the inhibition is due to reversible, competitive binding. Most inhibition interactions occur rapidly but maximal effect will take several weeks if the drug has long half-life. When the inhibitor is stopped it is released from the binding

sites as it is cleared from the body so inhibition interactions usually resolve quite quickly unless the drug has a long half-life. Some inhibition interactions are due to irreversible or non-competitive binding but these are generally less important.

therefore an increased amount of the induced enzyme. The metabolic capacity of the isoenzyme is therefore increased. The enzyme-inducing agent increases the velocity of the drug metabolic reaction. The process of enzyme induction requires new protein synthesis, so its maximum effect is not reached for 2-3 weeks after starting the enzyme-inducer; likewise, the effect may take some weeks to wear off when the enzyme-inducer is stopped. Rifampicin is such a potent enzyme inducer that significant induction occurs in just a few days and takes several weeks to wear off. Primary human hepatocytes may represent the most appropriate experimental system for the evaluation of CYP induction in humans.

Use of Preclinical Data to Guide Clinical Drug interaction studies:

[7]

In vitro studies can be used to identify drug combinations that may result in large changes in exposure, either for one drug or for both. The observation of a substantial in vitro interaction can be a strong signal indicating an in vivo investigation is warranted. In addition, in vitro data allows the results of in vivo studies to be readily generalized based on the mechanism of interaction. Use of in vitro studies followed by in vivo interaction studies to assess

potential interactions, has become an integral part of drug development and regulatory review.

With increased understanding of the mechanisms of drug transport, metabolism, and elimination, in vitro data have been increasingly used to assess potential risk for drug interaction (Figure 1), The Food and drug Administration’s 2006 draft guidance (Drug Interaction Studies – Study Design, Data Analysis, and Implications for Dosing and Labeling) helped codify this concept and laid out strategies for how in vitro data can be used to screen for potential metabolic interactions and on how to use in vitro data to decide which clinical interaction studies should be run.

The study of DDIs for a new drug generally begins with in vitro studies to determine whether a drug is a substrate, inhibitor, or inducer of metabolizing enzymes. The results of in vitro studies will inform the nature and extent of in vivo studies that may be required to assess potential interactions (Figure 1). In addition to the evaluation of metabolic drug interactions, the role of transporters in drug interactions should be evaluated. Along with clinical pharmacokinetic data, results from in vitro studies may serve as a screening mechanism to rule out the need for additional in vivo studies, or provide a mechanistic basis for proper design of clinical studies using a modelling and simulation approach.

Fig. 1: Decision tree that describes the need for in-vivo metabolism based interaction studies based on in vitro metabolism, DDIs, and/or other appropriate pharmacokinetic data (Adapted from FDA guidance (2012)

Classification of drug as an enzyme inhibitor based on basic model:

The potential of an investigational drug to inhibit CYP enzymes is usually investigated in vitro using human liver tissues such as human liver microsomes or cDNA-expressed microsomes to determine the inhibition mechanisms (e.g., reversible or time-dependent inhibition) and inhibition potency (e.g., Ki).

The R value is dependent on the in vitro inhibition parameters and the maximum inhibitor concentration [I] that can be achieved in vivo with the highest dose.This basic static model(Figure 2) has two major uses. First, it eliminates unnecessary clinical studies when the R value is below the threshold of 11 (for orally administered drugs that may inhibit CYP3A) or 1.1. Second, it allows rank ordering of inhibition potential across different CYP enzymes for the same drug so that in vivo DDIs evaluations can be prioritized. In contrast to reversible inhibition, the R value (Figure 2) for time-dependent inhibition (TDI) is time-dependent on the rate constant for enzyme degradation, in addition to inhibitor exposure level and the

TDI parameters (kinact and KI). If in vitro results suggest a TDI potential (e.g., R>1.1), an in vivo study is recommended.

Classification of drug as enzyme inducer based on basic model:

Human hepatocytes continue to be the system of choice for evaluating enzyme induction in vitro. Hepatocyte preparations from at least three (3) donors are recommended. The changes in the mRNA level of the target gene should be used as an endpoint. Initially, CYP1A2, CYP2B6, and CYP3A should be evaluated in vitro. If the in vitro induction results are positive according to predefined thresholds using basic models (Figure 2), the investigational drug is considered an enzyme inducer and therefore further in vivo evaluation may be warranted.

Fig. 2: General scheme of model-based prediction: The investigational drug (and metabolite present at >25% of parent drug AUC) as an interacting drug of CYP enzyme (Adapted from FDA guidance (2012)

Interactions between antiretrovirals and antimalarial drugs:

Malaria and HIV co-infections are prevalent in many resource limited countries. Despite recent achievements in research, both diseases still entail global health problems. Furthermore, their overlapping geographical distribution raises concerns and challenges for potential immunological, clinical and therapeutic interactions. WHO recommends artemisinin based combination treatment (ACT) for malaria and ARVs for treating HIV/AIDS. Although there is a potential for DDIs as these agents share common metabolic pathways, limited information is yet available regarding how such interactions might affect the efficacy and safety of these treatments when used concomitantly [8]_.

ARVs are among the most therapeutically risky drugs for DDIs, due to potent inhibition or induction of liver enzymes such as the cytochrome P450 isoenzymes (CYP450), which metabolize a broad array of other medications. DDIs involving PIs and NNRTIs are more likely to be attributable to hepatic metabolic pathways than DDIs involving NRTI, which in some cases can be due to competition for renal tubular secretion. Clinically significant DDIs involving ARVs are common, these have the potential for an adverse impact on ARV exposure or may result in increased exposure to ARVs or co-administered drugs, precipitating drug toxicity or greater severity and incidence of adverse reactions. HIV has a considerable impact on malaria, affecting parasitaemia, disease severity (in areas of unstable transmission) and mortality during pregnancy. Some of the known interactions between ARVs and antimalarials are shown in Table 3.

Table No. 3: Known or suspected interactions between antimalarial drugs and selected World Health Organization recommended first or second-line ARVs [8]

Predicted or known interactions with selected ARVs

NRTI NNRTI PI

Drugs Metabolized by Induces Inhibits

AZT NVP EFV LPV/r NFV SQV/r

Quinine CYP3A4, 2C19 CYP2D6, maybe 2C8, 2C9 - ++ ++ ++ ++ ++

Chloroquine CYP2C8, 2D6, 3A4 CYP2D6 - + + ++ + ++

Mefloquine CYP3A4 CYP3A4 (weak) - + + + + +

Pyrimethaminesulfadoxine Hepatic enzymes 2C8, 2C9, 2D6 - + + ++ + ++

Chlorproguanil dapsone CYP2C19 - + + ++ + ++

Primaquine CYP1A2, 2D6, 3A4 - + + + + +

Artesunate-Amodiaquine CYP3A4, 2A6 - ++ XX XX ++ XX

Artemether-Lumefantrine CYP3A4 CYP2C19, 3A4 - ++ ++ ++ XX XX

Artemether-Halofantrine CYP3A4 CYP2C19, 3A4 - ++ ++ XX XX XX

Atovaquone-Proguanil Glucuronidation + + + ++ + ++

Doxycycline CYP3A4 CYP3A4 - + + + + +

AZT, zidovudine; EFV, efavirenz; LPV/r, lopinavir boosted with ritonavir; NFV, nelfinavir; NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, nonnucleoside reverse transcriptase inhibitor; NVP, nevirapine; PI, protease inhibitor; SQV/r, saquinavir boosted with ritonavir, - no clinically significant interaction seen or expected; +, minor interaction expected; ++ interaction expected (close monitoring recommended); XX, interaction seen or expected that may contraindicate use of drugs.

Potential drug interactions need to be considered when treating malaria in people livingwith HIV/AIDS. Artemether-lumefantrine is currently the most widely used artemisinin-basedcombination therapy (ACT). As it is generally well

inHIV-infected individuals as they tend to have higher baseline parasitaemias, an independent risk factorfor antimalarial treatment failure.Since many antimalarial drugs are metabolized by cytochrome P450 isoenzymes, there are potential drug-drug interactions with PIs and NNRTIs. The use of over-the-counter and natural health products is also pervasive. The interactions between these two drug classes could be either pharmacokinetic or pharmacodynamic in nature.

Pharmacokinetic interactions between antiretroviral and antimalarial drugs:

In general, pharmacokinetic interactions involve mostly HIV PI and NNRTI classes. PI (especially RTV) areamongst the most potent inhibitors of cytochrome P450 enzymes (CYP 3A4, CYP 2B6, CYP 2D6 and others) licensed for use in humans, and their role in pharmacokinetic interactions is made more complex since some PI also induce their own metabolism (e.g. RTV, nelfinavir) and can induce other enzymes responsible for drug metabolism. PI may also inhibit the multidrug efflux transporter P-glycoprotein. These properties are utilized when RTV is added to other PI to enhance bioavailability (Saquinavir (SQV), Lopanavir (LPV) or to reduce hepatic clearance (Indinavir (IDV), amprenavir, atazanavir) through inhibition of CYP3A4 in the gut or liver, respectively. The NNRTI drugs NVP and EFV are inducers of CYP 3A4, whiledelavirdine is an inhibitor of CYP 3A4 (and has also been used to boost PI).

The following are the keyinteractions between antiretroviral and antimalarial drugs:[8, 10]

1. The quinolinemethanol class of antimalarial drugs includes quinine, the parenteral drug of choice for treatment of severe malaria, and mefloquine, an expensive quinolinemethanol effective for malaria prophylaxis and treatment. Both drugs are metabolized by CYP3A4 and cause significant concentration-related toxicities. Quinine is extensively metabolized by CYP 3A4. Exposure could be increased by RTV or RTV containing boosted PI regimens, and by delavirdine. Induction of CYP 3A4 by NVP and EFV could reduce plasma quinine exposure.

Mefloquine had variable effect on RTV metabolism: In a study of healthy volunteers,mefloquine’s pharmacokinetics were only minimally altered by RTV, despiteCYP3A4 inhibition, and co-administration led to a 31% decrease in RTV concentrations and maximal plasma concentrations (Cmax) by 36% after multiple dosing [9]_{. A case report has observed no drug interaction} between IDV or nelfinavir and mefloquine.

2. Proguanil is a prodrug and is partially activated by CYP 2C19 to cycloguanil, there is concern that inhibition of metabolism by RTV or RTV-containing boosted PI regimens will reduce pharmacological effect. However, synergy with atovaquone is related to proguanil, not cycloguanil. When the drugs are coadministered, CYP 2C19 inhibition could potentially enhance this synergistic effect, which may offset decreased cycloguanil formation.

3. Metabolism of dapsone is mainly by N-acetylation with a component of N-hydroxylation via multiple CYP P450 enzymes. Clinically, significant interactions are unlikely but cannot be excluded.

4. Artemisinins are the most rapidly acting antimalarial drugs. Artemisnin and its derivatives such as artesunate and artemether are rapidly hydrolyzed in vivo to a biologically active metabolite, dihydroartemisinin. Artemether is metabolized via CYP 3A4 to dihydroartemesinin (although both compounds have antimalarial activity, dihydroartemesinin has greater potency). Inhibition of CYP3A4 would reduce dihydroartemesinin but increase artemether and potentially increase the short half-life of artemether (1–2 h).

Artemether is commonly coformulated with either lumefantrine or halofantrine, to prevent the emergence of resistance. It is currently the most widely recommended treatment of uncomplicated malaria. Lopinavir–based ARV therapy is the commonly recommended second-line HIV treatment. Artemether and lumefantrine are metabolised by cytochrome P450 isoenzyme CYP3A4, which lopinavir/ritonavir inhibits, potentially causing clinically important DDIs.

Inhibition of halofantrine metabolism could potentially prolong QT interval; given the narrow therapeutic index of this drug, combination with PI is contraindicated and NVP and EFV should be used with caution. Lumefantrine does not seem to prolong the QT interval and is much safer than halofantrine. Nevertheless, interactions with PI and NNRTI drugs are likely, and the manufacturer’s Summary of Product Characteristics advises that coadministration of CYP 3A4 inhibitors such as PI are contraindicated. An approximately twofold rise in AUC was reported in healthy volunteers who were given lumefantrine with lopinavir/ritonavir. This interaction may be beneficial if it could be shown to reduce the marked pharmacokinetic variability of lumefantrine, or to abolish the food restrictions required with this antimalarial. Given the increasing use of lumefantrine-artemether for malaria, researchers recommend caution when using PI/NNRTI [10]_.

As per recent clinical pharmacokinetic study conducted using HIV-infected(malaria-negative) patients; antiretroviral-naïve and those stable on lopinavir/ritonavir-based ARVs, despite substantially higher lumefantrine exposure raised no safety concerns in HIV-infected patients stable on lopinavir-based ARV therapy given therecommended artemether-lumefantrine dosage [10]_{. Increased day-7 lumefantrine concentrations have} been shownpreviously to reduce the risk of malaria treatment failure, but further evidence in adult patients co-infectedwith malaria and HIV is needed to assess the artemether-lumefantrine risk.

5. Atovaquone lowers IDV exposure, reducing trough plasma concentrations by 23%. A healthy volunteer study observed an AUC decrease of 5% for IDV but an increase in atovaquone AUC of 13% and Cmax of 16% when the drugs were coadministered. No dosage adjustments are necessary for atovaquone when given with IDV. The clinical significance of lowered IDV concentrations is uncertain since these were healthy volunteer studies carried out without RTV boosting (which is no longer the preferred means of giving IDV). Moreover, clinical studies have shown higher plasma IDV in Thai patients (who have lower body weight) and, given the toxicity of IDV at higher doses, dosage adjustments are not indicated for IDV (boosted with RTV) when dosed with atovaquone or malarone [11]_.

LPV may decrease plasma concentrations of atovaquone. The clinical significance of this is not known; however, increases in atovaquone dosage may be needed. Atovaquone decreases the oral clearance of ZDV leading to a 35±23% increase in its plasma AUC. The clinical significance of this is not known, and no dose modification is recommended.

6. In a recent study, coadministration of EFV with a 3-day course of AS/AQ led to 2-4-fold increases in AQ AUC, and the study was stopped after the first 2 participants developed significant elevations of liver transaminase. Other CYP2C8 inhibitors, such as SQV and LPV, may similarly increase AQ concentrations. In addition, artemisinin antimalarial drugs may induce CYP3A4 and 2C19 enzymes. Although a 3-day course of an artemisinin may or may not significantly affect ARV concentrations, increased concentrations of the drugs with which artemisinins are coformulated may result in serious toxicities. In a study of 10 subjects, however, the addition of LPV/r to artemether/lumefantrine increased lumefantrine AUC by 193%, with no significant toxicities.

Pharmacodynamic interactions between antiretroviral and antimalarial drugs:

Disease interactions between malaria and HIV infection are common.In areas with stablemalaria, HIV increases the risk of malaria infection andclinical malaria in adults, especially in those with advancedimmunosuppression. In settings with unstable malaria,HIV-infected adults are at increased risk of complicatedand severe malaria and death[12]_{. Reports also suggest thatantimalarial}

Chloroquine suppresses HIV-1 and HIV-2 replication invitro (as does its analogue hydroxychloroquine) possibly by inhibition of HIV gp120. In vitro studiesexamining chloroquine in HIV-infected cells has shownsome additivity with ZDV and synergy with some PIdrugs in T cell lines. However, only modest anti-HIV activity has been observed for chloroquine andmefloquine and no antiviral activity for halofantrine,amodiaquine and mepacrine [14]_{; significant synergy} wasobserved between mefloquine and the PI SQV, andantagonism between chloroquine and SQV.

Overlapping syndromes or toxicity profiles may complicatethe clinical picture in malaria and HIV coinfection and render it difficult to isolate the causative factor.Typical examples include:

 Fever: Malaria, Opportunistic infections, HIV itself, drug hypersensitivity such as that encountered with ABC or NVP.

 Hepatitis: Amodiaquine, NNRTI, PI, NRTI, Background chronic hepatitis B infection.

 Renal failure: Malaria nephritis, HIV nephropathy, microsporidiosis, sulphonamides (at dosage used for P. cariniipneumonia treatment), IDV and tenofovir.

In general, there are potential interactions between HIV protease inhibitors and NNRTIs and lumefantrine, quinine and amodiaquine. However, only few drug interaction studies have been performed. These studies have varied in design and quality, utilizing both healthy volunteers and HIV-positive subjects. They may not reflect what happens in real life, particularly as the pharmacokinetics of many antimalarials alter with disease.

CONCLUSION

HIV and malaria are two diseases that are often found concomitantly in developing countries and can have a synergic negative effect on public health. Treatment of these two diseases leads to several concerns about drug–drug interactions and the potential for inducing drug resistance. Comprehensive data on interactions between ARVs and antimalarial drugs are currently lacking.

Pharmacokinetic studies looking at various combinations of antimalarials and ARVs have sofarprovided conflicting results, and most have been conducted in healthy volunteers in whom the impact on treatment efficacy is not detected. Further efficacy, safety and pharmacokinetic studies are needed patients with HIV/AIDS and malaria to assess the clinical significance of any interactions, inform treatment policies and guide safe and effective case management. The management of malaria in HIV-infected individuals needs focused research efforts because of the public health importance of these two conditions.

The metabolic pathways of many of these agents have not been elucidated, so information regarding potential drug interactions must be deduced from limited pharmacokinetic and toxicity data.In

vitro techniques to predict the role of CYP enzymes in DDIs should be considered an important tool to decrease the occurrence and magnitude of DDIs.

REFERENCES:

1. Clinical.gov.

https://clinicaltrials.gov/ct2/show/NCT00697892.

2. World Health Organization. World Malaria Report 2014; Switzerland: World Health Organization. [Available from:

http://www.who.int/malaria/publications/world_malaria_re port_2014/wmr-2014-no-profiles.pdf].

3. World Health Organization. Guidelines for the treatment of malaria. Switzerland: World Health Organization. 2015;3rd edition: [Available from:

http://www.who.int/malaria/publications/atoz/978924154 9127/en/].

4. https://www.hivguidelines.org/clinical guidelines/adult/hiv-drug-drug-interactions.

5. Albert P Li. The scientific basis of drug-drug interactions; mechanism and preclinical evaluation. Drug information journal 1998;32:657-664.

6. Larry C. Wienkers and Timothy G. Heath. Predicting in vivo drug interactions from in vitro drug discovery data. Nature reviews 2005;4:825-833.

7. https://www.fda.gov/Drugs/DevelopmentApprovalProcess/ DevelopmentResources/DrugInteractionsLabeling/ucm0804 99.htm

8. Dooley KE, Flexner C, Andrade AS. Drug interactions involving combination antiretroviral therapy and other anti-infective agents: repercussions for resource-limited countries. J Infect Dis 2008;198:948–61.

9. Paul A. Pham and Charles Flexner. Emerging antiretroviral drug interactions. J Antimicrob Chemother 2011;66:235–239. 10. Owen A, Janneh O, Bray PG, Hartkoorn RC, Baba M, Ward SA,

et al. In vitro interaction between mefloquine and saquinavir: the role of breast cancer resistance protein. In: XV International Conference on AIDS. Bangkok, July 2004; [abstract TuPeB 4588]

11. Khoo S, Back D, Winstanley P. The potential for interactions between antimalarial and antiretroviral drugs. AIDS. 2005;19(10):995–1005.

12. Malaria and HIV interactions and their implications for public health policy, a WHO publication. 2004.

13. Ter Kuile FO, Aarise ME, Verhoeff FH, Udhayakumar V, Newman RD, van Eijk AM, et al. The burden of co-infection with human immunodeficiency virus type 1 and malaria in pregnant women in sub-saharan Africa. Am J Trop Med Hyg 2004;71(Suppl 2):41–54.

14. T. Kredo, K. Mauff, L. Workman, J. S. Van der Walt, L. Wiesner, P. J. Smith, G. Maartens, K. Cohen and K.I. Barnes. The interaction between artemether lumefantrine and lopinavir/ritonavir-based antiretroviral therapy in HIV-1 infectedpatients. BMC Infectious Diseases 2016;16:30,1-13.

How to cite this article:

Sunitha G.N. et al. AN INSIGHT INTO DRUG-DRUG INTERACTIONS INVOLVING ANTIRETROVIRAL AND ANTIMALARIAL DRUGS. J Sci Res Pharm 2017;6(6):60-65.