Download Case 3 continued

Importance of Racemates and Active
Metabolites in Understanding Dose Response Relationships
James D. Coyle, Pharm.D.
Winter, 2002
Dose – Effect Relationship for Most Drugs
Plasma concentrations and airway response resulting from 0.75 mg
terbutaline, a beta-2 agonist, SQ
Sources of Dose-Response Relationship Variability
Gender
Body size
Body composition
Diet
Age
Genetics
Dose  Response
Drug
interactions
Environment
Pregnancy
Disease
Circadian rhythms
Liver
function
Kidney
function
CV function
Sources of Apparent Variability
• Active metabolites
• Administration of racemic mixtures
Case 1: Need for Dosage Adjustment
in Patients with Kidney Impairment?
• 2nd generation sulfonylureas (hypoglycemic agents)
– Glyburide (Diaeta, Micronase)
– Glipizide (Glucotrol)
• Both extensively metabolized
Glyburide: 3% excreted as unchanged drug in urine
Glipizide: <5% excreted as unchanged drug in urine
• Does the dose of these drugs need to be altered in
patients with kidney impairment?
Case 1 Continued
• Drug Information Handbook
– Glyburide: use not recommended in patients with CrCl
< 50 mL/min
– Glipizide: some investigators recommend not using if CrCl <
10 mL/min
• Why are the recommendations so different when the
fraction eliminated renally is so similar?
Case 1 Continued
• Hypothesis: glyburide has active metabolite that
accumulates in renally-impaired patients while
glipizide does not.
– Glyburide has (less potent) active metabolite that is renally
eliminated
– Glipizide has (less potent) active metabolite that is renally
eliminated
• Why are dosing recommendations different?
Case 1 Continued
• Rationale
– Approximately 36% of a glyburide dose is metabolized to its
active metabolite
– Only 2% of a glipizide dose is metabolized to its active
metabolite
Case 1 Continued
• Conclusion
Glyburide should not be used in patients with CrCl <
50 mL/min due to the accumulation of a major active
metabolite, with resulting increase in hypoglycemic
episodes. Glipizide may be used at usual doses, at
least until CrCl < 10 mL/min.
Case 2: Absence of concentration –
response relationship for albuterol
• Albuterol (Proventil, Ventolin): 2 agonist,
bronchodilator
• Many reports suggest
– Plasma concentration highly variable (15-fold) after both oral
doses and inhalation
– Plasma concentration of albuterol not correlated with
response
• Conclusion: no relationship between albuterol plasma
concentration and response?
*
Albuterol
Case 2 Continued
• Albuterol is racemic mixture of two enantiomers,
(R)-albuterol (levalbuterol) and (S)-albuterol
• R enantiomer has 100 X affinity for 2 receptor
• S enantiomer assumed to be inactive, benign.
May: oppose bronchodilatory effects
have proinflammatory effects
increase airway reactivity
Concentration vs. time for R- (lower curve) and S- (upper curve)
albuterol following single 2.50 mg nebulized dose of racemate.
Case 2 Continued
• Study of effects of levalbuterol vs. racemate (J Allergy
Clin Immunol 1998;102:943-952.
• Patients with asthma (n=328)
• Randomized to receive (by nebulization)
–
–
–
–
–
0.63 mg levalbuterol TID x 4 weeks
1.25 mg levalbuterol TID x 4 weeks
1.25 mg racemic albuterol TID x 4 weeks
2.50 mg racemic albuterol TID x 4 weeks
Placebo
• Outcome: FEV1
• Expectations?
Case 2 Continued
• Results
– 0.63 mg levalbuterol = 2.50 mg racemic albuterol
– TI for levalbuterol substantially greater
Levalbuterol 0.63 mg
Case 2 continued
• Conclusions
– Greater effect can be achieved by administering
levalbuterol alone than with same levalbuterol
dose administered as racemate
– Adverse effects can be decreased by
administering levalbuterol rather than racemate
Case 3: Different Labetalol ConcentrationResponse Curves in Women than Men?
• Labetalol HCl (Normodyne): nonselective -blocker
and 1-blocker for oral and IV use in treatment of
hypertension
• Nearly completely absorbed, oral bioavailability of
30%, 50% bound to plasma protein, extensive
conjugative and oxidative metabolism, <5%
eliminated as unchanged drug in urine
Case 3 continued
• Study of labetalol kinetics and dynamics in men vs.
women (Pharmacotherapy 2000;20:622-628).
• Hypertensive patients (untreated DBP >95 but <115
mmHg) (n=19)
• Treated with labetalol 100 mg BID, titrated up to
maximum of 800 mg BID to achieve DBP < 90 mmHg
• Primary outcome: 24 hour ABP
• Plasma concentration vs. time profile also assessed
at steady-state
Case 3 continued
Men (n=14)
Women (n=5)
Race
11 C / 3 AA
2 C / 3 AA
Age (yrs)
50.6  8.6
48.6  6.2
Weight (kg)
90.6  17.1
86.0  13.9
Labetalol
693  465
Dosage (mg/day)
680  482
Mean labetalol plasma concentrations at steady-state
Labetalol BP response in men (right of pair) and women (left of pair)
Case 3 continued
• What’s going on here?
– Concentrations are 80% higher in women
– Same BP response
Is the concentration – response relationship for labetolol
different in women compared to men?
Case 3 continued
*
*
Labetalol HCl
Case 3 continued
• Labetalol is marketed as mixture of four isomers
– R,R: most of -blocking activity which is largely responsible
for antihypertensive effects
– S,R: most of 1-blocking effects
– R,S and S,S: relatively inactive
Mean dose-corrected AUCs for labetolol stererisomers
in women and men
Women
Men
P-value
R,R
3.91
3.55
0.80
S,R
7.55
4.83
<0.05
R,S
6.99
4.25
<0.05
S,S
8.23
4.65
<0.05
Case 3 Conclusions
• Labetalol dose – response relationship same in men
and women
• SS concentrations of (R,R)-labetalol same in men
and women
• (R,R)-labetalol concentration – response relationship
same in men and women
• Higher labetalol concentrations in women due to
inactive and 1-blocking isomers
• Apparent difference in labetolol concentration –
response relationship between men and women due
to measurement of all isomers
Conclusions
• Presence of active metabolites or isomers may
complicate understanding the dose-response
relationship of drugs
• Importance depends on activities of the compounds
and their pharmacokinetic and dynamic properties
• Administration of a drug that undergoes metabolism
to an active metabolite or administration of a racemic
mixture should be viewed as the simultaneous
administration of two (or more) drugs until this factor
has been shown to be clinically unimportant