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denucci@gdenucci.com
Arquivo
II International Workshop of Vascular
Biology
Site
www.gdenucci.com
A Importância da Farmacologia
Clínica no desenvolvimento de
novos conceitos para velhos
produtos
Simvastatin:
therapeutic improvement by
modified release dosage form ?
Simvastatin: therapeutic improvement by modified
release dosage form ?
Statins: properties
Pharmacokinetics


significant differences in absorption:
from 30 % (lovastatin) up to 98 % (fluvastatin)
extensive first-pass metabolism (gut, liver)
 relatively low (absolute) bioavailability
Advantage: substance specific "targeting"


selective/active uptake into hepatocytes
predominant excretion via bile
 goal: high concentrations in the liver ...
... at the same time low systemic exposure
Simvastatin: therapeutic improvement by modified
release dosage form ?
Undesired side effects controllable ?
Problem: non-linear pharmacokinetics


capacity of uptake into the liver limited
first-pass-metabolism (gut, liver) saturable
 over-proportional increase of BA with rising doses
500
AUC
Cmax
[ng/ml•h]
Dose proportionality
400

300

200

100
0

2 mg
10 mg
20 mg
40 mg
historical comparison
healthy subjects (n=24)
single dose, fasted
estimation of AUC and Cmax in
plasma
Simvastatin: therapeutic improvement by modified
release dosage form ?
Rationale for product optimisation
Goal: Improvement of risk/benefit-relationship
 better efficacy not needed, ...
 ... but reduction of undesired side effects
  significantly lower concentrations in plasma
Clinical development rationale
 pharmacokinetic/biopharmaceutical targets



sufficiently high "hepatic" bioavailability
reduced systemic bioavailability/exposure
question: achievable with modified release form ?
Simvastatin: therapeutic improvement by modified
release dosage form ?
Simvastatin – candidate for MR ?
Compound properties
 pro-drug and active metabolite (ß-hydroxy acid)
 very low (5 %) systemic (bio)availability


extensive first-pass metabolism
incomplete (ca. 30 %) oral absorption (?)
Essential questions for MR product development
 localisation of first-pass metabolism (liver/gut) ?
 substrate for efflux transporter P-gp ?
 sufficient absorption throughout the entire GI tract
(absorption window) ?
Simvastatin: therapeutic improvement by modified
release dosage form ?
First-pass: hepatic or intestinal ?
Indicator grapefruit juice


inhibits CYP 3A4
only in gut wall
16-fold increase of BA
P-gp substrate ?


15%
investigations, e.g.
in Caco-2 cell systems
simvastatin is a
LP (ab) compound
and P-gp substrate
15%
CYP 3A4
liver
metabolite
stomach
portal vein
100%
30%
P-gp
felodipine
CYP 3A4
luminal site
intestine
Simvastatin: therapeutic improvement by modified
release dosage form ?
Development of MR dosage form
Bioavailability
Dose proportionality
[ng/ml]
1200
[ng/ml]
40+40 mg IR
1200
80 mg ER
900
80 mg (AUC: 334)
160 mg (AUC: 876)
320 mg (AUC: 1055)
640 mg (AUC: 6966)
900
600
600
300
300
0
0
0
MR form:
3
6


9
[h]
12
0
6
12
18 [h]
significantly lower BA (AUC and Cmax)
saturation only with much higher doses
24
Simvastatin: therapeutic improvement by modified
release dosage form ?
Clinical surrogate study: 60 mg QPM
Study medication
 test: simvastatin modified release tablets, 60 mg
 reference: Zocor® IR tablets, 3x20 mg
Study conditions
 changeover, 28 subjects (18-65 y)
 patients with primary dyslipidaemia …




fasting LDL: 130-250 mg/dl
fasting TG: < 350 mg/dl
… after ambulatory dietary run-in of 4 weeks
primary: LDL; second.: HDL, total cholesterol, TG
Simvastatin: therapeutic improvement by modified
release dosage form ?
Primary parameter: LDL-cholesterol
Mean (n=28) effect curves
LDL cholesterol (mg/dl)
200
Statistics
test
175
reference
point estim.
150
conf. interval
125
Emax
99
88-104
100
Ekum
99
85-104
75 diet
active treatment
50
-1
0
1
2
time (weeks)
3
4
5
Conclusion
 superimposable effect vs. time curves …
 … therapeutic equivalence proven (n=28!)
Simvastatin: therapeutic improvement by modified
release dosage form ?
Outcome of proof of concept study
Findings (for MR preparation)
 significantly lower systemic exposure (Cmax)
 nevertheless identical (equivalent) efficacy
 concept perfectly confirmed
Potential benefit of MR form: risk reduction
 certain trend towards less frequent AEs
 better safety profile could not be proven so far
 however, improved safety margin very likely
Simvastatin: therapeutic improvement by modified
release dosage form ?
Our conclusion(s)
 proof of concept successful
 useful MR form ("the flatter … the better")
Open questions
 modified release dosage form/formulation


further reduction of systemic exposure/extent of BA ?
efficacy of the MR form

equivalent efficacy even with lower dosage ?
AristoCon: 2005: Simvastatin project
Synthesis and structures of bis-phosphocholine
compounds.
Synthesis and structure of bis(phosphocholine)-hexane.
Synthesis and structures of bis-phosphocholine compounds.
Structures of bis(phosphocholine) compounds with different linkers.
See Supplementary Information for details.
Clinical treatment with a CRP inhibitor could
be started immediately upon admission to
hospital following acute myocardial
infarction— this would precede the acute
phase CRP response, which starts about 6
h after onset of pain and peaks at about 50
h (refs 8, 9).
Structure of the complex of CRP with 1,6-bis(phosphocholine)hexane.
Structure of the complex of CRP with 1,6-bis(phosphocholine)hexane
Structure of the complex of CRP with 1,6-bis(phosphocholine)hexane