drug - drug interactions: considerations - virology...

Drug - Drug Interactions: considerations

Anca Streinu-Cercel MD PhDNational Institute for Infectious Diseases Prof. Dr. Matei Bals,

Carol Davila University of Medicine and PharmacyBucharest, Romania

Treatment Challenges in HCV - special populations

2nd Central and Eastern European Meeting on Viral Hepatitis and Co-Infection with HIV

Why DDI?

• Recent statistics report that nearly 70% of the American population consumes at least one prescription drug, a number which was only 48% in 2010. 1

• 20% of them are on five or more drugs2.

1. Kollewe J. World's 10 bestselling prescription drugs made $75bn last year.http://www.theguardian.com/business/2014/mar/27/bestselling-prescription-drugs (2014) Date of access: 02/09/2014. [Ref list]

2Mayo Clinic Nearly 7 in 10 americans are on prescription drugs. http://www.sciencedaily.com/releases/2013/06/130619132352.htm (2013) Date of access: 02/09/2014. [Ref list]

IFN-free drugs Up to 99%

Medscape, Hepatitis C, http://emedicine.medscape.com/article/177792-overview

In 2012-14, the FDA, EMA and JMHLW each published a guideline that recommends a programme of in vitro studies (using human liver microsomes, hepatocytes and other cell types) to be conducted for compounds under development to assess their potential effects on CYP and UGT enzymes and clinically relevant (ITC recommended) uptake and efflux transporters.

https://www.quotientbioresearch.com/sector/pharmaceuticals/ddi-assessment?gclid=Cj0KEQjw7Ne_BRDRmP2ojKfzv98BEiQAPuqPyejFdY3J7KCOJs9f3Sk5uSwwzlJ31chmy-K-cN7skCkaAgLz8P8HAQ

https://www.quotientbioresearch.com/sector/pharmaceuticals/ddi-assessment?gclid=Cj0KEQjw7Ne_

• “Transferring knowledge from clinical trials to real life can sometime be challenging and not totally overlapping.

• Cloning all the resources is a real challenge in real life. • So when we starting treating HCV patients –hard to treat

or hard to cure patients with the new highly-effective interferon-free treatment we identified a need: for managing comorbidities and most of all for managing treatment for comorbidities: DDI. “

The management of drug drug interaction – A Streinu-Cercel & all, article in press: revistafarmacia.ro

DDI

• If we want to offer a highly effective treatment to HCV patients/ co infected patients, we have to manage the DDI issue

Definition of Terms

• Drug-nutrient interaction: the result of the action between a drug and a nutrient that would not happen with the nutrient or the drug alone

• Food-drug interaction: a broad term that includes drug-nutrient interactions and the effect of a medication on nutritional status

Food-Drug Interaction

• For example, a drug that causes chronic nausea or mouth pain may result in poor intake and weight loss

Key Terms• Bioavailability: degree to which a drug or other

substance reaches the circulation and becomes available to the target organ or tissue

• Half-life: amount of time it takes for the blood concentration of a drug to decrease by one half of its steady state level

• Side effect: adverse effect/reaction or any undesirable effect of a drug

Drug Interaction:

• The pharmacologic or clinical response to the administration of a drug combination different from that anticipated from the known effects of the two agents when given alone

• May be harmful: toxicity, reduced efficacy• May be beneficial: synergistic combinations,

pharmacokinetic boosting, increased convenience, reduced toxicity, cost reduction

Types of Drug Interactions

Pharmacodynamic• Related to the drug’s effects in the body• One drug modulates the pharmacologic effect of

another: additive, synergistic, or antagonistic

Pharmacokinetic• What the body does with the drug• One drug alters the concentration of another• Usually mediated by cytochrome P450 (CYP)

Consider the Medication’s passage through the body

GOALS of HCV treatment

• to achieve sustained eradication of HCV =>the persistent absence of HCV RNA inserum 6 months or more after completingantiviral treatment.

• to prevent progression– to cirrhosis and decompensated liver disease

requiring liver transplantation.– hepatocellular carcinoma

Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Sept 2016

http://www.hcvguidelines.org/

Medscape, Hepatitis C, http://emedicine.medscape.com/article/177792-overview

Approved HCV DAA s in Europe in 2016 and ribavirin

Who should be treated and when?

European Association for the Study of the Liver. EASL Recommendations on Treatment of Hepatitis C 2016. Journal of Hepatology. 2016;63:199–236

Comorbidities

• Similar to the non-HCV-infected population

• Common comorbidities: hypertension, dysliproteinaemia or atrial arrhythmia.

• Some comorbidities: diabetes and thyroid disorders – extrahepatic manifestations of HCV infection

Maasoumy B, Port K, Serrano B, et al. The Clinical Significance of Drug-Drug Interactions in the Era of Direct-acting Anti-viral Agents Against Chronic Hepatitis C. Aliment Pharmacol Ther. 2013;38(11-12):1365-1372

Smolders E, de Kanter C, de Knegt, R et al. Drug–Drug Interactions Between Direct-Acting Antivirals and Psychoactive Medications. Clin Pharmacokinet. 2016

Smolders E, de Kanter C, de Knegt, R et al. Drug–Drug Interactions Between Direct-Acting Antivirals and Psychoactive Medications. Clin Pharmacokinet. 2016

www.hep-druginteractions.org(University of Liverpool)

• Coinfection HIV/HCV – higher rate of HCV persistence, faster progression to cirrhosis and end-stage liver disease, and higher HCV RNA levels

• Coinfection HIV/HCV – lower responses to PEG-IFN and RBV

Hepatitis C Guidance: AASLD-IDSA Recommendations for Testing, Managing, and Treating Adults Infected, With Hepatitis C Virus AASLD/IDSA HCV Guidance Pane

PATIENTS WITH HIV/HCV COINFECTION

http://www.aasld.org/

http://www.idsociety.org/

Antiretroviral therapy

• PIs are metabolized by the cytochrome P450 (CYP) enzyme system. All are inhibitors of CYP3A4, ranging from weak inhibition to very potent inhibition.

• NNRTIs - inducers of CYP3A enzymes (efavirenz -the most potent inducer of the class)

Kiser J, Burton J, Everson G. Drug–drug interactions during antiviral therapy for chronic hepatitis C. Nat Rev Gastroenterol Hepatol. 2013;10(10):596–606

Drug-drug interactions between HCV DAAs and HIV antiretrovirals.

EASL Recommendations on Treatment of Hepatitis C 2016. J Hepatol (2016), http://dx.doi.org/10.1016/j. Jhep 2016.09.001

http://dx.doi.org/10.1016/j

• Antiretroviral drug switches, when needed, should be done in collaboration with the HIV practitioner. (Class I, Level A)

• Daclatasvir requires dose adjustment with ritonavir-boosted atazanavir (a decrease to 30 mg daily) and efavirenz or etravirine (an increase to 90 mg daily). (Class IIa, Level B)

• Simeprevir should be used with antiretroviral drugs with which it does not have clinically significant interactions: abacavir, emtricitabine, enfuvirtide, lamivudine, maraviroc, raltegravir, (and probably dolutegravir), rilpivirine, and tenofovir. (Class IIa, Level B)

• Ledipasvir/sofosbuvir can be used with most antiretrovirals. Because ledipasvir increases tenofovir levels, concomitant use mandates consideration of creatinine clearance (CrCl) rate and should be avoided in those with CrCl below 60 mL/min. Tenofovir alafenamide (TAF) may be an alternative to TDF during ledipasvir/sofosbuvir treatment. (Class IIa, Level C)

PATIENTS WITH HIV/HCV COINFECTION Recommendations





•Paritaprevir/ritonavir/ombitasvir plus dasabuvir should be used with antiretroviral drugs with which they do not have substantial interactions: atazanavir, dolutegravir, emtricitabine, enfuvirtide, lamivudine, raltegravir, and tenofovir. (Class IIa, Level C)

•The dose of ritonavir used for boosting of HIV protease inhibitors may need to be adjusted (or held) when administered with paritaprevir/ritonavir/ombitasvir plus dasabuvir and then restored when HCV treatment is completed. The HIV protease inhibitor should be administered at the same time as the fixed-dose HCV combination. (Class IIa, Level C)


PATIENTS WITH HIV/HCV COINFECTION Recommendations




• Antiretroviral treatment interruption to allow HCV therapy is Not Recommended. (Class III, Level A)

• Sofosbuvir-based regimens should NOT be used with tipranavir. (Class III, Level B)

• Paritaprevir/ritonavir/ombitasvir plus dasabuvir should NOT be used with darunavir, efavirenz, ritonavir-boosted lopinavir, ritonavir-boosted tipranavir, etravirine, nevirapine, cobicistat, or rilpivirine. (Class III, Level B)

• Paritaprevir/ritonavir/ombitasvir with or without dasabuvir should NOT be used in HIV/HCV-coinfected individuals who are not taking antiretroviral therapy. (Class III, Level B)

• Ribavirin should NOT be used with didanosine, stavudine, or zidovudine. (Class III, Level B)

• Simeprevir should NOT be used with cobicistat, efavirenz, etravirine, nevirapine, or any HIV protease inhibitor. (Class III, Level B)


PATIENTS WITH HIV/HCV COINFECTION Regimens Not Recommended




HBV co-infection • Patients should be treated with the same

regimens, following the same rules as HCV monoinfected patients (B1)

• If HBV replicates at significant levels before, during or after HCV clearance, concurrent HBV nucleoside/ nucleotide analogue therapy is indicated (B1)

Hepatitis C Guidance: AASLD-IDSA Recommendations for Testing, Managing, and Treating Adults Infected, With Hepatitis C Virus AASLD/IDSA HCV Guidance Pane

Comorbidities





Drug-drug interactions betweenHCV DAAs and cardiovascular drugs.


• Simvastatin and to a lesser extent atorvastatin –metabolised by CYP3A4.

• CYP3A4 inhibitors may increase the plasma concentration of these statins, increasing the risk of adverse reactions such myopathy and/or rhabdomyolysis.

• Fluvastatin, pravastatin and rosuvastatin are not significantly metabolised by CYP3A4 and are less susceptible to CYP interactions.

• CYP3A4 inducers may reduce the effectiveness of some statins; therefore, lipid profiles should be monitored if co-prescribed.

Drug-drug interactions between HCV DAAs and lipid lowering drugs.

UpToDate. Statins: Actions, side effects, and administration

Drug-drug interactions between HCV DAAs and

lipid lowering drugs.

UpToDate. Statins: Actions, side effects, and administration


Comorbidities





PATIENTS WITH DIABETES

http://www.hep-druginteractions.org/printable_charts

• Citalopram and escitalopram – selective serotonin reuptake inhibitors and both are metabolized by multiple isoenzymes (CYP450 2C19, 3A4, and 2D6). The inhibition of a single isoenzyme may not appreciably decrease their clearance.

• Sedatives that show a marked change in AUC and that should not be coadministered include midazolam

• CYP3A is also involved in the metabolism of sertraline and mirtazepine.

• Older anticonvulsants such as phenytoin, carbamazepine, and phenobarbital are strong inducers of cytochrome P450 3A4

PATIENTS WITH PSYCHIATRIC DISORDERS

Mauss S, Klinker H. Drug-Drug Interactions in the Treatment of HCV Among People Who Inject Drugs. Clin Infect Dis. 2013;57(2):S125-S128


Drug-drug interactions between HCV DAAs and central nervous system drugs.

PATIENTS WITH HEMATOLOGIC DISORDERS

Cyclosporin and tacrolimus are CYP3A and P-gp substrates


What else are we missing?

• Habits diets/ cuisine

Food on the map of DDI

North American cuisine has the most negative interactions (10.242‰) with drugs from the category ‘Antiinfectives for systemic use'. In other words, 10 out of 1,000 patients could possibly have negative effects when being administered this category of drugs. Similarly, European cuisines (Western Europe, Northern Europe and Eastern Europe) have the most negative interactions with drugs from the same category (‘Antiinfectives for systemic use'). On the other hand, the cuisines from Southern Europe, Asia, Latin America and Africa negatively interact mostly with drugs from the categories ‘Blood and blood forming organs' and ‘Various'.

Jovanovik M, Bogojeska A, Trajanov D, Kocarev L. Inferring Cuisine - Drug Interactions Using the Linked Data Approach. Scientific Reports. 2016;5:9346. doi:10.1038/srep09346.

http://www.intechopen.com/source/html/41523/media/image5.png

Evaluation of Specific Drug Interactions

• What is the time-course of the interaction• Immediately or over a period of time• Is it a drug class effect• omeprazole vs. lansoprazole• Is the interaction clinically significant• Therapeutic index of drugs• Narrow or wide?• How should the interaction be managed?• DC drug? Switch to another drug? Change dose?

Drug Interactions: General Tools for Evaluation and Management

• Familiarity with metabolic pathways• Know where to locate information on interactions• Obtain thorough medication HX at each visit• Maintain high index of suspicion when:• Therapeutic response is less than expected• Toxic effects are present• Choose drugs that are less likely to interact• Consider TDM in certain situations (anti-TB TX)• Anti-TB and anti-HIV therapy

drug - drug interactions: considerations - virology...

Documents