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Uprima ® Presentation TAP Holdings Inc. Barbara Bopp, Ph.D. Manager, Drug Metabolism and Pharmacology. Pharmacokinetics and Metabolism. Apomorphine Molecule. Pharmacokinetics & Metabolism. Not Morphine Not DEA scheduled. OH. HO. • HCl • 1/2 H 2 O. N. H. CH 3. Sublingual Tablet.

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Barbara bopp ph d manager drug metabolism and pharmacology

Uprima® PresentationTAP Holdings Inc.

Barbara Bopp, Ph.D.Manager, Drug Metabolism and Pharmacology


Pharmacokinetics and metabolism

Pharmacokinetics and Metabolism


Apomorphine molecule
Apomorphine Molecule

Pharmacokinetics & Metabolism

  • Not Morphine

  • Not DEA scheduled

OH

HO

• HCl • 1/2 H2O

N

H

CH3


Sublingual tablet
Sublingual Tablet

Pharmacokinetics & Metabolism

  • Rapid absorption

  • Avoid first pass metabolism

  • Minimize food effect


Plasma concentration time curves

2.0

2 mg

4 mg

5 mg

6 mg

1.5

Apomorphine Concentration (ng/mL)

1.0

0.5

0

8

7

0

1

2

3

4

5

6

Hours after Dose

Phase IM98-844

Plasma Concentration–Time Curves

Pharmacokinetics & Metabolism


Apomorphine pharmacokinetics

M98-844

Apomorphine Pharmacokinetics

Pharmacokinetics & Metabolism

Mean (% CV)

Parameter 2 mg SL 4 mg SL 5 mg SL 6 mg SL 1 mg SC

tmax (h) 0.74 (40%) 0.72 (44%) 0.68 (31%) 0.66 (49%) 0.34 (51%)

Cmax (ng/mL) 0.70 (54%) 1.25 (64%) 1.70 (78%) 1.91 (64%) 3.22 (52%)

AUC (ng•h/mL) 1.23 (39%) 2.37 (45%) 2.92 (51%) 3.60 (48%) 3.39 (32%)

t1/2 (h) 2.0 2.8 3.1 3.1 2.7


Dose proportionality c max and auc

Phase I

Dose Proportionality: Cmax and AUC¥

Pharmacokinetics & Metabolism

M98-844

4

3

Cmax(ng/mL)

or

AUC

(ng•h/mL)

2

1

Cmax

AUC

0

0

1

2

3

4

5

6

Apomorphine HCI Dose (mg)


Distribution of c max values from uprima 6 mg
Distribution of Cmax Values from Uprima® (6 mg)

Pharmacokinetics & Metabolism

n

(N = 246)

ln Cmax-2.5 -2.0 -1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 1.77

Cmax0.08 0.135 0.233 0.368 0.606 1.0 1.65 2.72 4.48 5.88

Apomorphine Cmax (ng/mL)


Apomorphine plasma concentrations in elderly
Apomorphine Plasma Concentrations in Elderly

Pharmacokinetics & Metabolism

M98-843 (Uprima® 5 mg)


Apomorphine disposition
Apomorphine Disposition

Pharmacokinetics & Metabolism

  • Large volume of distribution

  • 85-90% protein bound, primarily to albumin

  • Minimal renal excretion of parent drug

  • Rapid clearance by hepatic metabolism


Major metabolic pathways for apomorphine
Major Metabolic Pathways for Apomorphine

Pharmacokinetics & Metabolism

O-Glucuronide

and

N-Glucuronide

Glucuronidation

OH

O-Sulfate

HO

Sulfation

and

N

N-Sulfate

H

CH3

N-Demethylation

Sulfation

Glucuronidation

O-Sulfate

Norapomorphine

O- and/or N-Glucuronide


Apomorphine and cytochrome p450
Apomorphine and Cytochrome P450

Pharmacokinetics & Metabolism

  • Norapomorphine formation accounts for about 20% of the dose and is mediated by cytochrome P450 (CYP)

  • Metabolized by several CYP isoforms, primarily CYP1A2, CYP3A, CYP2C19

  • Inhibits CYP1A2, CYP3A, CYP2D6, but only at concentrations >1000-fold higher than Cmax

  • Low potential for CYP metabolic interactions


Apomorphine pharmacokinetics conclusions
Apomorphine Pharmacokinetics: Conclusions

  • Rapid absorption and clearance

  • Effect of variability in apomorphine pharmacokinetics was appropriately assessed through the safety and efficacy data from Phase III studies

  • No dosage adjustment is necessary for the elderly

  • Primarily metabolized by conjugation with glucuronic acid or sulfate

  • Low potential for clinically significant CYP interactions


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