# Presentation: 780385

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

**Uprima****®**** Presentation****TAP Holdings Inc.**

## Pharmacokinetics and Metabolism

## Apomorphine Molecule

**H**

**N**

**CH****3**

**HO**

**OH**

**• ****HCl ****	****• 1/2 H****2****O**

- Not Morphine
- Not DEA scheduled

- Pharmacokinetics & Metabolism

## Sublingual Tablet

- Rapid absorption
- Avoid first pass metabolism
- Minimize food effect

- Pharmacokinetics & Metabolism

## Plasma Concentration–Time Curves

- Pharmacokinetics & Metabolism

## Apomorphine Pharmacokinetics

**Parameter****	****2 mg SL****	****4 mg SL****	****5 mg SL****	****6 mg SL****	****1 mg SC**
**t****max**** (h)****	****0.74 (40%)****	****0.72 (44%)****	****0.68 (31%)****	****0.66 (49%)****	****0.34 (51%)**
**C****max ****(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%)**
**t****1/2**** (h)****	****2.0****	****2.8****	****3.1****	****3.1****	****2.7**

- Apomorphine Pharmacokinetics

*Mean (% CV)*

- Pharmacokinetics & Metabolism

## Dose Proportionality: Cmax and AUC 

- 4

- Cmax (ng/mL)
- or
- AUC****
- (ng•h/mL)

- Apomorphine HCI Dose (mg)

- 3

- 2

- 1

- 0

- 0

- 1

- 2

- 3

- 4

- 5

- 6

- Cmax
- AUC****

- Dose Proportionality: Cmax and AUC

- Phase I

*M98-844*

- Pharmacokinetics & Metabolism

## Distribution of Cmax Values from Uprima® (6 mg)

- n
- (N = 246)

- Apomorphine Cmax (ng/mL)

- 	ln Cmax	-2.5	-2.0	-1.5	-1.0	-0.5	0.0	0.5	1.0 	1.5	1.77
- 	Cmax	0.08	0.135	0.233	0.368	0.606	1.0	1.65	2.72	4.48	5.88

- Distribution of Cmax Values from Uprima® (6 mg)

- Pharmacokinetics & Metabolism

## Apomorphine Plasma Concentrations in Elderly

*M98-843 (Uprima**®** 5 mg)*

- Pharmacokinetics & Metabolism

## Apomorphine Disposition

- Large volume of distribution
- 85-90% protein bound, primarily to albumin
- Minimal renal excretion of parent drug
- Rapid clearance by hepatic metabolism

- Pharmacokinetics & Metabolism

## Major Metabolic Pathways for Apomorphine

- O-Sulfate

**Sulfation**

**N-Demethylation**

- Norapomorphine

**Glucuronidation**

- O- and/or N-Glucuronide

- H

- N

- CH3

- O-Glucuronide

- N-Glucuronide

- and

- HO

- OH

**Sulfation**

- O-Sulfate

- and

- N-Sulfate

**Glucuronidation**

-  Pharmacokinetics & Metabolism

## Apomorphine and Cytochrome P450

- 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

- Pharmacokinetics & Metabolism

## 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