Download Absorption

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.
Lecture Overview
• Review of mechanisms of drug interactions.
• Interactions between antiretroviral agents and other
drugs.
• Interactions between antiretroviral agents.
• Overlapping toxicities.
• Management principles.
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.
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
acid environment:
NFV
neutral environment:
ddI
Interactions between
ARV Drugs and
other Drugs
Drugs cleared by Cytochrome P450
Antiretroviral drugs
NNRTI
Protease Inhibitors
Anti-infectious agents e.g.
ACTIVE
DRUG
Cytochrome P450
Ketoconazole
Rifampicin
Dapsone
Oral contraceptives
Anti-histamines
Anticoagulants
Warfarin
Inactive
DRUG
Lipid lowering drugs
Simvastatin
Lovastatin
Anticonvulsive drugs
Carbamazepine
Phenytoin
Phenobarb
Enzyme Induction/Inhibition
Food,
drinks,
drugs,
etc.
Broken down
in the body,
with the help
of ENZYMES
INDUCED (increased)
OR
INHIBITED (blocked)
New
substances
e.g., proteins
Waste
products
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
Rifampicin
EFV Interaction
EFV 
Ergotamine compounds
Comment
Dose adjustment of EFV may or
may not be indicated.
CONTRAINDICATED
Protease Inhibitor Drug Interactions
Drug
Interaction
Comment
Rifampicin
Ketoconazole
PI 
RTV: Keto 
IDV: IDV 
Boosted RTV/SQV recommended
Oral
Contraceptives
O/C 
RTV, NFV: Use alternative or
additional contraception
IDV: no adjustment
Ergotamine Compounds
St John’s Wort
Lovastatin, Simvastatin, *
Do not exceed Keto dose of 200
mg/day
Dose adjust IDV
NFV no adjustment
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
SQV & LPV
RTV
Inactive
drug
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.
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.
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.
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
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.
Overlapping Toxicities
Overlapping Toxicities
Bone
Marrow
Toxicity
Pancreatitis
Nephrotoxicity Hepatotoxicity
AZT
Hydroxyurea
Anti-cancer
drugs
Sulfonamides
Pyrimethamine
Primaquine
Gancyclovir
ddI
3TC
d4T
RTV
Sulfonamides
Alcohol
Aminoglycosides
Amphotericin
Foscarnet
EFV
NVP
Protease
Inhibitors
Fluconazole
Ketoconazole
INH
Rifampicin
alcohol
Overlapping Toxicities (2)
Neuropathy
Rash
Diarrhea
Eye Toxicity
DDI
d4T
INH
Alcohol
NVP
EFV
Sulfonamides
Dapsone
NFV
ddI
RTV
LPV/r
Clindamycin
Ethambutol
ddI
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
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.
Management of Drug Interactions (2)
• A thorough drug history including nonprescription 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.