Transcript Uprima Presentation TAP Holdings Inc. Barbara Bopp, Ph.D.

Uprima®
®
Uprima
Presentation
TAP Holdings Inc.
Barbara Bopp, Ph.D.
Manager, Drug Metabolism and Pharmacology
E001451 Primary 1
5/20/2016
Uprima®
Pharmacokinetics
and Metabolism
E001451 Primary 2
5/20/2016
Uprima®
Pharmacokinetics & Metabolism
Apomorphine Molecule

Not Morphine

Not DEA scheduled
OH
HO
• HCl • 1/2 H2O
N
H
CH3
E001451 Primary 3
5/20/2016
Uprima®
Pharmacokinetics & Metabolism
Sublingual Tablet

Rapid absorption

Avoid first pass metabolism

Minimize food effect
E001451 Primary 4
5/20/2016
Uprima®
Phase I
M98-844
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
5/20/2016
Uprima®
M98-844
Pharmacokinetics & Metabolism
Apomorphine Pharmacokinetics
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%)
2.0
2.8
3.1
3.1
2.7
t1/2 (h)
E001451 Primary 6
5/20/2016
Uprima®
Phase I
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
5/20/2016
Uprima®
Pharmacokinetics & Metabolism
Distribution of Cmax Values from Uprima® (6 mg)
90
80
70
60
n
(N = 246)
50
40
30
20
10
0
ln Cmax
Cmax
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
0.5
1.0
1.5
1.77
0.08
0.135
0.233
0.368
0.606
1.0
1.65
2.72
4.48
5.88
Apomorphine Cmax (ng/mL)
E001451 Primary 8
5/20/2016
Uprima®
Pharmacokinetics & Metabolism
Apomorphine Plasma Concentrations in Elderly
M98-843 (Uprima® 5 mg)
1.4
1.2
64-82 y
19-40 y
1.0
ng/mL
0.8
0.6
0.4
0.2
0.0
0
2
4
Hours after Dose
6
8
E001451 Primary 9
5/20/2016
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
5/20/2016
Uprima®
Pharmacokinetics & Metabolism
Major Metabolic Pathways for Apomorphine
O-Glucuronide
and
N-Glucuronide
Glucuronidation
OH
O-Sulfate
HO
Sulfation
N
N-Demethylation
H
Sulfation
O-Sulfate
and
N-Sulfate
CH3
Glucuronidation
Norapomorphine
O- and/or N-Glucuronide
E001451 Primary 11
5/20/2016
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
5/20/2016
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
5/20/2016