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

Dose Response

Age

Gender

Genetics

Environment

Body sizeBody composition

Pregnancy

Circadian rhythms

CV functionKidney function

Liver function

Drug interactions

Disease

Diet

Sources of Apparent Variability

• Active metabolites

• Administration of racemic mixtures

Case 1: Need for Dosage Adjustmentin Patients with Kidney Impairment?

• 2nd generation sulfonylureas (hypoglycemic agents)– Glyburide (Diaeta, Micronase)– Glipizide (Glucotrol)

• Both extensively metabolizedGlyburide: 3% excreted as unchanged drug in urineGlipizide: <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 Concentration-

Response 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

Dosage (mg/day)

693 465 680 482

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