Pharmacokinetics of HMG-CoA Reductase Inhibitors

1. Increased Conc. With Inhibitors HMG- CoA Lipophilic CYP450 Simvastatin Yes Yes 3A4/2D6 Lovastatin Yes Yes 3A4 Pravastatin No No No Atorvastatin Yes Yes 3A4 Cerivastatin Yes Yes 3A4/2C8 Fluvastatin Yes Yes 2C9 Pharmacokinetics of HMG-CoA Reductase Inhibitors

2. Erythromycin + Lovastatin  Multiple Organ Toxicity • 73-year-old man on lovastatin 20 mg/day x 7 years given 6 courses of erythromycin (9 g over 2 weeks) for SBE prophylaxis (crowns, fillings) • 1 day after last erythromycin dose: generalized muscular weakness, anorexia, nausea, vomiting Wong PWK et al. South Med J. 1998;91:202-205.

3. Erythromycin + Lovastatin  Multiple Organ Toxicity (cont.) • 4 days after last erythromycin dose came to ER complaining of muscle weakness and abdominal distention • He developed rhabdomyolysis, acute renal failure, pancreatitis, ileus, and elevated LFTs (the good news? his total cholesterol was 113 mg/dl) • He spent 10 days in ICU, but survived Wong PWK et al. South Med J. 1998;91:202-205.

4. Recent Changes in Simvastatin Labeling from F.D.A (US) • Myopathy reported in 6% of patients on simvastatin 80 mg/day + amiodarone in clinical trial (inhibition of CYP2D6?) • 10-fold increase in risk of myopathy when verapamil used with simvastatin 20-80 mg/day (but risk less than 1%) • Potent CYP3A4 inhibitors increase the risk of simvastatin-induced myopathy

5. Recent Changes in Simvastatin Labeling from F.D.A (US) • Avoid simvastatin with: itraconazole, ketoconazole, nefazodone, HIV protease inhibitors erythromycin, clarithromycin, or grapefruit juice (>1 liter/day) • Avoid simvastatin dose over 10 mg/d with: cyclosporine, gemfibrozil, niacin • Avoid simvastatin dose over 20 mg/d with: amiodarone, verapamil (other CYP2D6 inhbitors? diltiazem?)

6. Diltiazem + Lovastatin: High Variability in Magnitude • In a 4-way randomized crossover study10 healthy subjects took: • 20 mg lovastatin or pravastatin alone • Each statin after pretreatment with diltiazem 240 mg/day for 2 weeks • Diltiazem increased lovastatin AUC by 257%; no effect on pravastatin Azie NE et al. Clin Pharmacol Ther 1998;64:369.

7. Diltiazem + Lovastatin: High Variability in Magnitude Azie NE et al. Clin Pharmacol Ther 1998;64:369.

8. Drug Interaction Errors Prescriber’s Knowledge A + B Computer Screening Pharmacist’s Knowledge Patient Risk Factors Pharmacogenetics Drug Administration Patient Education Monitoring NO ADR Hansten PD, Horn JR. Modified from: James Reason, Human Error, 1990

9. Ethnic Differences in CYP450 Drug Metabolizing Isozymes Levy RH, Thummel KE, Trager WF, Hansten PD, Eichelbaum M. Metabolic Drug Interactions, Lippincott Williams & Wilkins, 2000.

10. Genetic Variation in CYP450 Isozymes in Humans • Numerous genetic variant alleles found in CYP450 enzymes • CYP1A2 = 7 alleles • CYP2C = 14 alleles • CYP2D6 = 70 alleles • CYP3A4 = 4 alleles • Function of most variant alleles in drug metabolism not known MacLeod SL et al. Clin Chem Lab Med 2000;38:883-887

11. CYP2D6 pathway is polymorphic No functional enzyme 5-10% caucasians 1-2% African Am. Inhibitors include Quinidine Fluoxetine/Paroxetine Amiodarone Diphenhydramine Ritonavir Terbinafine Impact of the CYP2D6 Metabolic Pathway on Simvastatin Safety N=88 100 80% 75 Probability of Intolerance (%) 50 46% 25 17% 0 wt/wt wt/mut mut/mut Mulder AB et al. Clin Pharmacol Ther 2001;70:546-51

12. Diphenhydramine  Venlafaxine Metabolism in EMs but not PMs • 9 EMs and 6 PMs given venlafaxine 18.75 mg with and without diphenhydramine 50 mg (each BID x 4 doses) • Diphenhydramine decreased venlafaxine oral clearance in EMs but not PMs Lessard E et al. J Clin Psychopharmacology 2001;21:175-184.

13. Drug Interaction Errors Prescriber’s Knowledge A + B Computer Screening Pharmacist’s Knowledge Patient Risk Factors Drug Administration Patient Education Monitoring NO ADR Hansten PD, Horn JR. Modified from: James Reason, Human Error, 1990

14. Factors Influencing Drug Interaction Outcomes PATIENT FACTORS DRUG ADMINISTRATION Genetics Diseases Diet/Nutrition Environment Smoking Alcohol Dose Duration Dosing Times Sequence Route Dosage Form CLINICAL OUTCOME OF DRUG INTERACTIONS HIGH VARIABILITY Adapted from Hansten. Science & Medicine. 1998;5:16-25.

15. Single Dose Ketoconazole Does Not Effect Citalopram • 18 healthy subjects given 40 mg citalopram alone and with a single 200 mg dose of ketoconazole • No changes in pharmacokinetics of citalopram • Citalopram metabolized by several CYP450 isozymes (3A4, 2C19, 2D6) Gutierrez M, Abramowitz W. Pharmacotherapy 2001;21:163-168.

16. Warfarin (Coumadin) + Thyroid • 13-year-old girl on chronic warfarin found to be hypothyroid and started on levothyroxine 150 mcg/day • One month later she presented with a 10-day history of headache, vomiting, and drowsiness (Pro-Time prolonged) • Subdural hematoma found, and surgical evacuation was necessary • Order of administration important Costigan et al. Clin Pediatr 1984;23:172.

17. Calcium Carbonate Inhibits Thyroxine Absorption • 49-year-old woman on thyroxine 150 mcg/day developed symptoms of hypothyroidism & increased TSH • Patient was taking Tums TID, & one Tums was taken with thyroxine • She was instructed to separate the doses, and her TSH became normal Butner LE et al. Ann Intern Med. 2000;132:595.

18. Calcium Carbonate Inhibits Thyroxine Absorption • 20 hypothyroid pts on long-term thyroxine • CaCO3 given with the thyroxine for 3 months • Modest  in serum thyroxine and modest  in serum TSH • 4 patients developed TSH > normal range Singh N et al. JAMA 2000;283:2822-2825.

19. Ritonavir (Norvir) + Alprazolam (Xanax) - Time-Dependent Interaction - • 8 healthy subjects took alprazolam 1 mg alone & with ritonavir (4 doses over 48 hrs) • Ritonavir  alprazolam half-life, AUC, sedation • Previous study of long-term ritonavir found  alprazolam effect Greenblatt DJ et al. Clin Pharmacol Ther 2000;67:157. Abst.

20. Morning Grapefruit Juice: Small  in Evening Lovastatin Levels • 16 subjects took PM lovastatin 40 mg after 3 days of 8 oz. AM grapefruit juice • AUC of lovastatin doubled • (Range: 1.2-4.3 fold) Rogers JD et al. Clin Pharmacol Ther 1999;66:358-366.

21. Different Grapefruit Products Have Varying Amounts of CYP3A4 Inhibitor 6`7`-dihydroxybergamottin Type of Grapefruit Juice NOTE: Large variability withintypes, except Tropicana Ruby Red (5 to 9 lots/sources for each type) (Florida Pink: range 1.4 to 45.2) Schmiedlin-Ren P et al. Drug Metab Disposit 1997;25:1228-1233.

22. Drug Interaction Errors Prescriber’s Knowledge A + B Computer Screening Pharmacist’s Knowledge Patient Risk Factors Drug Administration Patient Education Monitoring NO ADR Hansten PD, Horn JR. Modified from: James Reason, Human Error, 1990

23. Do Antibiotics Impair Oral Contraceptive Efficacy? • Analysis of 199 articles (1966-1999) • Rifampin clearly reduces OC efficacy • Results equivocal for other antibiotics • Some patients have marked reductions in ethinyl estradiol conc. with antibiotics (eg, tetracyclines, penicillins) • Such patients cannot be identified in advance, so caution is advised Dickinson BD et al. Obstet Gynecol 2001;98:853-860.

24. Drug Interaction Errors Prescriber’s Knowledge A + B Computer Screening Pharmacist’s Knowledge Patient Risk Factors Drug Administration Patient Education Monitoring NO ADR Hansten PD, Horn JR. Modified from: James Reason, Human Error, 1990

25. Vaginal Miconazole (Monistat) Increases Warfarin Effect • 53 YO woman stabilized on warfarin started on miconazole (200 mg vaginal tablet daily) • Ecchymosis on day 3 • Positive rechallenge, dechallenge, rechallenge • Similar cases reported with acenocoumarol Thirion DJG, Zanetti LAF. Pharmacotherapy 2000;20:98-99.

26. Miconazole Oral Gel  MarkedIncrease in Warfarin Effect • 5 cases of marked  in INR 7-15 days after starting miconazole • Bleeding occurred in 4 of the 5 patients • Miconazole probably swallowed & absorbed Pillans P et al. N Zealand Med J 1996;109:346.

27. Nefazodone (Serzone) + Simvastatin (Zocor) è Myositis • 44 YO man on simvastatin 40 mg/d began nefazodone 200 mg/d • At 30 days: dark urine, Rx for UTI • At 60 days: severe myalgias • Avoid CYP3A4 inhibitors in patients on simvastatin or lovastatin Jacobson RH et al. JAMA 1997;277:296.

28. Drug Interaction Errors Prescriber’s Knowledge A + B Computer Screening Pharmacist’s Knowledge Patient Risk Factors Drug Administration Patient Education Monitoring Defenses ADR Latent Failures Hansten PD, Horn JR. Modified from: James Reason, Human Error, 1990

29. Itraconazole (Sporanox)èDigoxin Toxicity • 67 year-old man on digoxin started on itraconazole 200 mg BID • 10 days later he was admitted with nausea, vomiting, gray blurry vision • Serum digoxin level 6.6 ng/mL • Several similar cases published Cone LA et al. West J Med 1996;165;322.

30. Edna St. Vincent Millay in “Huntsman, What Quarry?” Upon this gifted age, in its dark hour, Rains from the sky a meteoric shower Of facts.... They lie unquestioned, uncombined. Wisdom enough to leech us of our ill Is daily spun, but there exists no loom To weave it into fabric...

31. Fluconazole (Diflucan)-induced Carbamazepine (Tegretol) Toxicity • A 3-year-old boy on chronic therapy with carbamazepine given amoxicillin • Two weeks later he was found to have thrush and was started on fluconazole • On the third day of fluconazole, he was found unresponsive by his parents • Serum carbamazepine was markedly increased on admission • This interaction was on only 1 of 12 computer systems in area pharmacies Cook AM et al. J Pediatr Pharmacol Ther 2001;6:158-61.

32. Computerized Drug Interaction Screening Systems: Problems • Too many interactions on system • Important interactions missing • Lack of information on risk factors • Management options seldom given • Failure to account for differences in members of drug classes • Excessive lag time for inclusion of new interactions • Failure to capture OTCs & Herbals • Simple errors