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

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Barbara Bopp, Ph.D.Manager, Drug Metabolism and
Pharmacology
Uprima PresentationTAP Holdings Inc.
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Pharmacokinetics and Metabolism
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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

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Plasma ConcentrationTime Curves
Phase IM98-844
Pharmacokinetics Metabolism
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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
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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
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Apomorphine HCI Dose (mg)
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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)
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Apomorphine Plasma Concentrations in Elderly
Pharmacokinetics Metabolism
M98-843 (Uprima 5 mg)
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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

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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
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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

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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