Pharmacokinetics of HMGCoA Reductase Inhibitors

1
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. 199891202-205.
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. 199891202-205.
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
  (gt1 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 199864369.
7
Diltiazem Lovastatin High Variability in
Magnitude
Azie NE et al. Clin Pharmacol Ther 199864369.
8
Drug Interaction Errors
Prescribers Knowledge
A B
Computer Screening
Pharmacists 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
200038883-887
11
Impact of the CYP2D6 Metabolic Pathway on
Simvastatin Safety
N88

• CYP2D6 pathway is polymorphic
• No functional enzyme
• 5-10 caucasians
• 1-2 African Am.
• Inhibitors include
• Quinidine
• Fluoxetine/Paroxetine
• Amiodarone
• Diphenhydramine
• Ritonavir
• Terbinafine

100
80
75
Probability of Intolerance ()
50
46
25
17
0
wt/wt
wt/mut
mut/mut
Mulder AB et al. Clin Pharmacol Ther
200170546-51
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
200121175-184.
13
Drug Interaction Errors
Prescribers Knowledge
A B
Computer Screening
Pharmacists 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 S
moking Alcohol
Dose Duration Dosing Times Sequence Route Dos
age Form
CLINICAL OUTCOME OF DRUG INTERACTIONS
HIGH VARIABILITY
Adapted from Hansten. Science Medicine.
1998516-25.
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
200121163-168.
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 198423172.
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. 2000132595.
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 gt normal range

Singh N et al. JAMA 20002832822-2825.
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
200067157. 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
199966358-366.
21
Different Grapefruit Products Have Varying
Amounts of CYP3A4 Inhibitor
67-dihydroxybergamottin
Type of Grapefruit Juice
NOTE Large variability within types, 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
1997251228-1233.
22
Drug Interaction Errors
Prescribers Knowledge
A B
Computer Screening
Pharmacists 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
200198853-860.
24
Drug Interaction Errors
Prescribers Knowledge
A B
Computer Screening
Pharmacists 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
20002098-99.
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 1996109346.
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 1997277296.
28
Drug Interaction Errors
Prescribers Knowledge
A B
Computer Screening
Pharmacists 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) è Digoxin 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 1996165322.
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
20016158-61.
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