Download Drug - Drug Interactions: considerations

2nd Central and Eastern European Meeting on
Viral Hepatitis and Co-Infection with HIV
Treatment Challenges in HCV - special populations
Drug - Drug Interactions:
considerations
Anca Streinu-Cercel MD PhD
National Institute for Infectious Diseases Prof. Dr. Matei Bals,
Carol Davila University of Medicine and Pharmacy
Bucharest, Romania
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
• “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 in
serum 6 months or more after completing
antiviral 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
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
www.hep-druginteractions.org
(University of Liverpool)
Smolders E, de Kanter C, de Knegt, R et al. Drug–Drug Interactions Between Direct-Acting Antivirals and Psychoactive Medications. Clin Pharmacokinet. 2016
PATIENTS WITH HIV/HCV COINFECTION
• 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
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
PATIENTS WITH HIV/HCV COINFECTION
Recommendations
•
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)
Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Sept 2016
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)
Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Sept 2016
PATIENTS WITH HIV/HCV COINFECTION
Regimens Not Recommended
•
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)
Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Sept 2016
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
• 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
Drug-drug interactions between
HCV DAAs and cardiovascular drugs.
European Association for the Study of the Liver. EASL Recommendations on Treatment of Hepatitis C 2016. Journal of Hepatology.
2016;63:199–236
Drug-drug interactions between HCV
DAAs and lipid lowering 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 coprescribed.
UpToDate. Statins: Actions, side effects, and administration
Drug-drug interactions
between HCV DAAs and
lipid lowering drugs.
European Association for the Study of the Liver. EASL Recommendations on
Treatment of Hepatitis C 2016. Journal of Hepatology. 2016;63:199–236
UpToDate. Statins: Actions, side effects, and administration
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
PATIENTS WITH DIABETES
http://www.hep-druginteractions.org/printable_charts
PATIENTS WITH PSYCHIATRIC DISORDERS
• 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
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.
European Association for the Study of the Liver. EASL Recommendations on Treatment of Hepatitis C 2016. Journal of Hepatology.
2016;63:199–236
PATIENTS WITH HEMATOLOGIC DISORDERS
Cyclosporin and tacrolimus are CYP3A and P-gp substrates
European Association for the Study of the Liver. EASL Recommendations on Treatment of Hepatitis C 2016. Journal of Hepatology.
2016;63:199–236
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
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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
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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