Pharmacokinetic Drug-Drug interactions
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This document discusses several potential drug-drug interactions involving various medications: 1. A woman taking simvastatin, diltiazem, aspirin is prescribed clarithromycin. Clarithromycin is a strong CYP3A4 inhibitor and may significantly increase simvastatin levels, increasing risk of side effects like rhabdomyolysis. The patient's simvastatin dose should not exceed 40 mg daily while taking clarithromycin. 2. Minocycline is unlikely to reduce the effectiveness of a low-dose combined oral contraceptive. Any interaction would be due to suppressed gut bacteria and is considered very rare. 3. A man's phenytoin levels increased after starting flu
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 5
- 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 6
- 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 7
- 8. Elderly Polypharmacy Patients receiving less common and/or OTC medications 8
- 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 9
- 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) 10
- 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 13
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- 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 15
- 16. Transport Proteins Efflux: extrudes drugs outside of cell Uptake: facilitates intracellular movement of molecules 16
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- 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
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- 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
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- 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
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- 25. Usually by competitive binding to enzyme site Typically occurs quickly; depends on the time to steady-state of the inhibitor 25
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- 27. CYP1A2: ciprofloxacin; fluvoxamine CYP2C8: gemfibrozil CYP2C9: fluconazole CYP2C19: omeprazole, rebeprazole, lansoprazole CYP2D6: fluoxetine CYP3A: itraconazole, ketoconazole, HIV protease inhibitors, clarithromycin 27
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- 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). 30
- 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
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- 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. 35
- 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. 36
- 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. 37
- 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. 38
- 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. 39
- 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. 41
- 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? 42
- 43. DC interacting drug, affected drug, or both? Switch to another drug? -Same drug class or another? Change dose of affected drug? 43
- 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? 44
- 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. 45
- 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? 46
- 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. 47
- 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? 48
- 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. 49
- 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? 50
- 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. 51
- 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? 52
- 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. 53