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

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Manager, Drug Metabolism and Pharmacology. Uprima Presentation. TAP Holdings Inc. Uprima ... Pharmacokinetics & Metabolism. E001451 Primary 9. Uprima ... – PowerPoint PPT presentation

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


1
Barbara Bopp, Ph.D.Manager, Drug Metabolism and
Pharmacology
Uprima PresentationTAP Holdings Inc.
2
Pharmacokinetics and Metabolism
3
Apomorphine Molecule
Pharmacokinetics Metabolism
  • Not Morphine
  • Not DEA scheduled

OH
HO
HCl 1/2 H2O
N
H
CH3
4
Sublingual Tablet
Pharmacokinetics Metabolism
  • Rapid absorption
  • Avoid first pass metabolism
  • Minimize food effect

5
Plasma ConcentrationTime Curves
Phase IM98-844
Pharmacokinetics Metabolism
6
Apomorphine Pharmacokinetics
M98-844
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?
(ngh/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
7
Dose Proportionality Cmax and AUC
Phase I
Pharmacokinetics Metabolism
M98-844
4
3
Cmax (ng/mL) or AUC? (ngh/mL)
2
1
Cmax AUC?
0
0
1
2
3
4
5
6
Apomorphine HCI Dose (mg)
8
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 Cmax 0.08 0.135 0.233 0.368 0.606 1.0 1
.65 2.72 4.48 5.88
Apomorphine Cmax (ng/mL)
9
Apomorphine Plasma Concentrations in Elderly
Pharmacokinetics Metabolism
M98-843 (Uprima 5 mg)
10
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

11
Major Metabolic Pathways for Apomorphine
Pharmacokinetics Metabolism
O-Glucuronide
N-Glucuronide
and
Glucuronidation
OH
O-Sulfate
HO
Sulfation
and
N
N-Sulfate
H
N-Demethylation
CH3
Sulfation
Glucuronidation
O-Sulfate
Norapomorphine
O- and/or N-Glucuronide
12
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 gt1000-fold higher than Cmax
  • Low potential for CYP metabolic interactions

13
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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