Pharmacokinetic Drug-Drug interactions

2.  Epidemiology and categorization of DDI
 Mechanisms of DDI
 Pharmacokinetic mechanisms
2

3.  “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 1”
 1Tatro DS (Ed.) Drug Interaction Facts. J.B. Lippincott Co. St. Louis 1992.
3

4.  Terfenadine (Seldane®) February 1998
 Mibefradil (Posicor®) June 1998
 Astemizole (Hismanal®) July 1999
 Cisapride (Propulsid®) January 2000
4

5.  Over 2 MILLION serious ADRs yearly
 100,000 DEATHS yearly
 ADRs 4th leading cause of death ahead of
pulmonary disease, diabetes, AIDS,
pneumonia, accidents and automobile
deaths
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6.  $136 BILLION yearly
 Greater than total costs of cardiovascular
or diabetic care
 ADRs cause 1 out of 5 injuries or deaths per
year to hospitalized patients
 Mean length of stay, cost and mortality for
ADR patients are DOUBLE that for control
patients
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7.  Drug interactions represent 3–5% of
preventable in-hospital ADRs
 Drug interactions are an important
contributor to number of ER visits and
hospital admissions
 Potential DDIs Vs. Actual DDIs
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8.  Elderly
 Polypharmacy
 Patients receiving less common and/or OTC
medications
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9.  Pharmacokinetic
 What the body does with the drug
 One drug alters the concentration of another by
altering its absorption, distribution, metabolism,
or excretion
 Pharmacodynamic
 Related to the drug’s effects in the body
 One drug modulates the pharmacologic effect of
another: additive, synergistic, or antagonistic
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10.  Absorption: G.I. motility, pH, chelate formation
 Distribution: transport proteins; penetration
into sanctuary sites, plasma protein binding
 Metabolism:
 Phase I (CYP450)
 Phase II (conjugation)
 Elimination: Renal (glomerular filtration;
tubular secretion)
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11.  DecreasedGI motility via methadone
increases didanosine (ddI) degradation and
reduces ddI bioavailability
 Increased GI motility by metoclopramide
reduces digoxin absorption
11

12.  Irreversible binding of a drug in the GI tract
 Tetracyclines, quinolone antibiotics + ferrous
sulfate (Fe+2), antacids (Al+3, Ca+2, Mg+2),
dairy products (Ca+2)
12

13.  Some drugs require an acidic environment for
optimal absorption in the GI tract
 Examples: atazanavir, itraconazole, &
ketoconazole.
 H2 blockers and PPIs reduce absorption of
these drugs
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14. 14

15.  Anion exchange resins (i.e. cholestyramine)
 Form insoluble complexes & ↓ drug
absorption
 Warfarin, digoxin, B-blockers, NSAIDS,
others
 Immunosuppressants
 Interaction could result in ↓ immunosuppressant
absorption and possible graft failure in transplant
recipients
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16.  Transport Proteins
 Efflux: extrudes drugs outside of cell
 Uptake: facilitates intracellular movement of
molecules
16

17. 17

18. Abdullah K Rabba PhD 18

19.  An ATP binding cassette protein (ABC); MDR1 gene
product
 Originally identified in MDR cancer cells
 Located in GI tract, BBB, liver, kidney, lymphocytes
etc.
 Transports many chemically diverse compounds
 Modulation of P-gp by one drug may alter the PK of
another
 Substrates: digoxin, colchicine, fexofenadine, talinolol
 Inhibitors: cyclosporine, verapamil, erythromycin,
itraconazole
 Inducers: phenobarbital, rifampin, phenytoin, St.
John’s wort
19

20. 20

21.  OATP 1B1 uptakes drug into the hepatocyte
where it then undergoes subsequent
metabolism.
 Blockade of OATP 1B1 (Lopinavir) results in
reduced metabolism and increased plasma
drug (rosuvastatin) concentrations
21

22. 22

23.  Typically occur in the liver and/or G.I. tract
 Inhibition or induction of CYP enzymes by
one drug that results in altered metabolism
(and systemic exposure) of another
coadministered medication
23

24. 24

25.  Usually by competitive binding to enzyme
site
 Typically occurs quickly; depends on the time
to steady-state of the inhibitor
25

26. 26

27.  CYP1A2: ciprofloxacin; fluvoxamine
 CYP2C8: gemfibrozil
 CYP2C9: fluconazole
 CYP2C19: omeprazole, rebeprazole,
lansoprazole
 CYP2D6: fluoxetine
 CYP3A: itraconazole, ketoconazole, HIV
protease inhibitors, clarithromycin
27

28. 28

29.  Gradual onset and offset
 Involves increased DNA transcription and synthesis of new CYP
enzymes –this takes time several days or weeks after starting an
enzyme-inducing agent.
 Onset and offset
 Depends onT ½ of inducer, time to make new CYP proteins, and rate
of degradation of CYP proteins
 (effect generally persists for days or weaks following drug withdrawal)
 Results in reduction of plasma concentration of substrate drugs
 Risk of therapeutic failure
 Induction may lead to formation of toxic metabolite
 Removal of inducer may lead to toxic concentrations of substrate
29

30.  The most powerful enzyme inducers in
clinical use are
 rifampicin
 antiepileptic agents such as barbiturates,
phenytoin and carbamazepine.
 Some enzyme inducers, notably barbiturates
and carbamazepine, can induce their own
metabolism (autoinduction).
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31.  1A2: tobacco, omeprazole, ritonavir, modafinil,
char-grilled meat
 2B6: phenobarbital, phenytoin, rifampin
 2C9: rifampin
 2C19: carbamazepine
 2D6: dexamethasone, rifampin
 CYP3A: efavirenz, nevirapine, barbiturates,
carbamazepine, rifampin, rifabutin,
glucocorticoids, phenytoin, St. John’s wort,
troglitazone
31

32. 32

33. 33

34.  During the process of distribution, drug interactions may
occur, principally as a result of displacement from protein-
binding sites.
 Displacement from plasma proteins can be demonstrated
in vitro for many drugs and has been thought to be an
important mechanism underlying many interactions in the
past.
 However, clinical pharmacokinetic studies suggest that,
for most drugs, once displacement from plasma proteins
occurs, the concentration of free drug rises temporarily,
but falls rapidly back to its previous steady-state
concentration due to metabolism and distribution.
34

35.  The time this takes will depend on the half-life of
the displaced drug.The short term rise in the
free drug concentration is generally of little
clinical significance but may need to be taken
into account in therapeutic drug monitoring.
 For example, if a patient taking phenytoin is
given a drug which displaces phenytoin from its
binding sites(valpoic acid), the total (i.e. free
plus bound) plasma phenytoin concentration will
fall even though the free (active) concentration
remains the same.
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36.  The normal adult urinary pH ranges from 4.8 to 7.5 but can
increase due to chronic antacid use
 As with drug absorption in the gut, passive reabsorption of drugs
depends on the extent to which the drug exists in the non-ionised
lipid-soluble form.
 Only the non-ionised form is lipid soluble and able to diffuse back
through the tubular cell membrane.
 Thus, at alkaline pH, weakly acidic drugs (pKa 3.0–7.5) largely exist
as ionized lipid-insoluble molecules which are unable to diffuse
into the tubule cells and will therefore be lost in the urine.
 The renal clearance of these drugs is increased if the urine is
alkalanized.
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37.  Conversely, the clearance of weak bases (pKa
7.5–10) is higher in acid urine.
 Urine alkalinisation or acidification has been
used as a means of increasing drug
elimination in poisoning with salicylates and
amphetamines, respectively.
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38.  Drugs that use the same active transport
system in the kidney tubules can compete
with one another for excretion.
 Such competition between drugs can be used
to therapeutic advantage.
 For example, probenecid may be given to
increase the plasma concentration of
penicillins by delaying renal excretion.
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39.  Increased methotrexate toxicity, sometimes life- threatening, has
been seen in some patients concurrently treated with salicylates
and some other NSAIDs.
 The development of toxicity is more likely in patients treated with
high-dose methotrexate and those with impaired renal function.
 The mechanism of this interaction may be multifactorial but
competitive inhibition of methotrexate's renal tubular secretion is
likely to be involved.
 If patients taking methotrexate are given salicylates or NSAIDs
concomitantly, the dose of methotrexate should be closely
monitored.
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40.  A number of drugs are excreted in the bile, either unchanged or
conjugated, for example, as the glucuronide, to make them more
water soluble.
 Some of the conjugates are metabolised to the parent compound
by the gut flora and are then reabsorbed.
 This recycling process prolongs the stay of the drug within the
body but if the gut flora are diminished by the presence of an
antibacterial, the drug is not recycled and is lost more quickly.
 This mechanism has been postulated as the basis of an interaction
between broad-spectrum antibiotics and oral contraceptives.
40

41.  Antibiotics may reduce the enterohepatic
circulation of ethinyloestradiol conjugates,
leading to reduced circulating oestrogen levels
with the potential for therapeutic failure.
 due to the potential adverse consequences of pill
failure, most authorities recommend a
conservative approach, including the use of
additional contraceptive precautions to cover
the short-term use of broad-spectrum
antibiotics.
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42.  Is the interaction clinically significant
 Therapeutic index of the “victim” drug
 How many drugs potentially involved?
 What is the likely time course of the interaction?
 Is inhibition/induction a class effect?
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43.  DC interacting drug, affected drug, or both?
 Switch to another drug? -Same drug class or
another?
 Change dose of affected drug?
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44.  Mrs C is a 62-year-old woman with a history of hypertension,
 atrial fibrillation and type 2 diabetes. She is a non-smoker and
 obese. Her current medication comprises flecainide 100 mg twice
 a day, aspirin 75 mg daily, simvastatin 40 mg and diltiazem 180
 mg daily. Mrs C is suffering from a respiratory tract infection
 and her primary care doctor has prescribed a 5-day course of
 clarithromycin.
 Questions
 1. Are there likely to be any clinically significant drug interactions?
 2.What advice do you give?
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45.  1. Clarithromycin is a potent inhibitor of CYP3A4 and diltiazem is a
less potent inhibitor.
 simvastatin is metabolised by cytochrome P450 (CYP3A4) and co-
administration of potent inhibitors of this enzyme may particularly
increase plasma levels of these statins and so increase the risk of dose-
related side effects, including rhabdomyolysis.
 2. Current advice is that diltiazem and simvastatin may be given
together provided the simvastatin dose does not exceed 40 mg
 daily, so it is reasonable for this therapy to be continued.
 However, clarithromycin should not be given together with
simvastatin. Myopathy and rhabdomyolysis have been reported in
patients taking the combination.
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46.  A 19-year-old woman is on long-term treatment with
minocycline 100 mg daily for acne. She wishes to start
using the combined oral contraceptive and her doctor
has prescribed a low-strength pill (containing
ethinyloestradiol 20 μcg with norethisterone 1 mg).
The doctor contacts the pharmacist for advice on
whether the tetracycline will interfere with the
efficacy of the oral contraceptive.
 Question
 Is there a clinically significant interaction in this
situation?
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47.  There is controversy about whether or not a drug
interaction occurs but if there is one it appears to be
very rare.
 The postulated mechanism is suppression of intestinal
bacteria resulting in a fall in enterohepatic
recirculation of ethinyloestradiol.
 The UK Family Planning Association advises that
women on long-term antibiotic therapy need only
take extra precautions for the first 3 weeks of oral
contraceptive use because, after about 2 weeks, the
gut flora becomes resistant to the antibiotic.
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48.  A 48-year-old man with a history of epilepsy is admitted to
hospital with tremor, ataxia, headache, abnormal thinking
and increased partial seizure activity. His prescribed
medicines are phenytoin 300 mg daily, clonazepam 6 mg
daily and fluoxetine 20 mg daily. It transpires that
fluoxetine therapy had been initiated 2 weeks previously.
The patient's phenytoin level is found to be 35 mg/L; at the
last outpatient clinic visit 4 months ago, it was 18 mg/L.
 Question
 What is the proposed mechanism of interaction between
fluoxetine and phenytoin and how should it be managed?
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49.  Fluoxetine is believed to inhibit the metabolism of
phenytoin by the cytochrome P450 isoenzyme CYP2C9,
potentially leading to increased plasma phenytoin levels.
 A review by the U.S. Food and Drug Administration
suggested that a marked increase in plasma phenytoin
levels, with accompanying toxicity, can occur within 1–42
days (mean onset time of 2 weeks) after starting
fluoxetine.
 If fluoxetine is added to treatment with phenytoin, the
patient should be closely monitored.
 Ideally the phenytoin plasma levels should be monitored
and there may be a need to reduce the phenytoin dosage.
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50.  A 42-year-old woman is on long-term treatment
with azathioprine 100 mg daily and
bendroflumethiazide 2.5 mg daily.
 The latter was discontinued after an episode of
gout but she had three further episodes over the
following year. Her doctor considers prescribing
allopurinol as prophylaxis.
 Question
 Is this likely to cause a clinically significant
interaction?
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51.  Azathioprine is metabolised in the liver to mercaptopurine
and then converted to an inactive metabolite by the
enzyme xanthine oxidase.
 Allopurinol is an inhibitor of xanthine oxidase and will lead
to the
 accumulation of mercaptopurine which can cause bone
marrow
 suppression and haematological abnormalities such as
neutropenia and thrombocytopenia.
 The dose of azathioprine should be reduced by at least
50% and close haematological monitoring is required if
allopurinol is used concomitantly.
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52.  A 68-year-old woman is on long-term treatment
with lansoprazole for gastro-oesophageal reflux
disease and warfarin for atrial fibrillation. She is
admitted with haematemesis. On direct
questioning, she also revealed that she takes
various herbal medicines which contain
chamomile, horse chestnut, garlic, feverfew,
ginseng and St John's wort.
 Question
 What drug–herb interactions may have
contributed to her presentation to hospital?
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53.  Garlic, feverfew and ginseng all inhibit platelet aggregation by
inhibiting the production or release of prostaglandins and
thromboxanes.
 In addition, chamomile and horse chestnut contain coumarin-like
constituents which can potentiate the anticoagulant effect of
warfarin.
 St John's wort is a potent enzyme inducer and may induce the
metabolism of lansoprazole via CYP2C19, thereby reducing the
effectiveness of lansoprazole.
 Although the effects of herbs individually may be small, their
combined effects may lead to serious complications.
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