Uprima®
® Uprima
Presentation TAP Holdings Inc.
Barbara Bopp, Ph.D.
Manager, Drug Metabolism and Pharmacology
E001451 Primary 1 8/12/2008
Uprima®
Pharmacokinetics and Metabolism
E001451 Primary 2 8/12/2008
Uprima®
Pharmacokinetics & Metabolism
Apomorphine Molecule
Not Morphine Not DEA scheduled
OH HO
• HCl • 1/2 H2O N
H
CH3
E001451 Primary 3 8/12/2008
Uprima®
Pharmacokinetics & Metabolism
Sublingual Tablet
Rapid absorption
Avoid first pass metabolism Minimize food effect
E001451 Primary 4 8/12/2008
Phase I M98-844
Uprima®
Pharmacokinetics & Metabolism
Plasma Concentration–Time Curves
2.0
2 mg 4 mg 5 mg 6 mg
1.5
Apomorphine Concentration 1.0 (ng/mL)
0.5
0
0
1
2
3
4
5
6
7
8
Hours after Dose
E001451 Primary 5 8/12/2008
M98-844
Uprima®
Pharmacokinetics & Metabolism
Apomorphine Pharmacokinetics
Mean (% CV)
Parameter tmax (h)
Cmax (ng/mL) AUC (ng•h/mL) t1/2 (h)
2 mg SL 0.74 (40%)
0.70 (54%) 1.23 (39%) 2.0
4 mg SL 0.72 (44%)
1.25 (64%) 2.37 (45%) 2.8
5 mg SL 0.68 (31%)
1.70 (78%) 2.92 (51%) 3.1
6 mg SL 0.66 (49%)
1.91 (64%) 3.60 (48%) 3.1
1 mg SC 0.34 (51%)
3.22 (52%) 3.39 (32%) 2.7
E001451 Primary 6 8/12/2008
Phase I
Uprima®
Pharmacokinetics & Metabolism
Dose Proportionality: Cmax and AUC
M98-844
4
Cmax (ng/mL)
or AUC (ng•h/mL)
3
2
1 Cmax AUC
0
0
1
2
3
4
5
6
Apomorphine HCI Dose (mg)
E001451 Primary 7 8/12/2008
Uprima®
Pharmacokinetics & Metabolism
Distribution of Cmax Values from Uprima® (6 mg)
90 80 70 60
n
50 40 30 20 10 0
(N = 246)
ln Cmax Cmax
-2.5
0.08
-2.0
0.135
-1.5
0.233
-1.0
0.368
-0.5
0.606
0.0
1.0
0.5
1.65
1.0
2.72
1.5
4.48
1.77
5.88
Apomorphine Cmax (ng/mL)
E001451 Primary 8 8/12/2008
Uprima®
Pharmacokinetics & Metabolism
Apomorphine Plasma Concentrations in Elderly
M98-843 (Uprima® 5 mg)
1.4 1.2 1.0 ng/mL 0.8 0.6 0.4 0.2 0.0 0 2 4 Hours after Dose
E001451 Primary 9 8/12/2008
64-82 y 19-40 y
6
8
Uprima®
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
E001451 Primary 10 8/12/2008
Uprima®
Pharmacokinetics & Metabolism
Major Metabolic Pathways for Apomorphine
O-Glucuronide and N-Glucuronide
Glucuronidation
OH HO
O-Sulfate
Sulfation
N
and
N-Demethylation
H
N-Sulfate
CH3
Glucuronidation
O- and/or N-Glucuronide
Sulfation
O-Sulfate Norapomorphine
E001451 Primary 11 8/12/2008
Uprima®
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
E001451 Primary 12 8/12/2008
Uprima®
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
E001451 Primary 13 8/12/2008