Transcript 2nd presentation Oosterhuis AGAH

Predictive value
and possible applications
of human microdosing
-=-
Berend Oosterhuis,
Scientific Director EDS NL
PRA International
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workshop AGAH 19 April 2008
Contents
• Are PK data from microdosing really predictive?
– literature overview
– CREAM trial
– EUMAPP project
• Applications of phase 0 microdosing
• Conclusions
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Overview microdosing literature*
Reference
Drug
Species
Method
Outcome
Lappin & Garner (2003)
Nat Drug Discov 2:233
Xceleron
1Aadrenoceptor
antagonist
oral
Human
AMS
Linear 5-50-500µg
Sandhu et al (2004) Drug
Metab Dispos 32:1254
Merck Research Labs USA
AZT analogue
Dog
AMS
Linear 0.02-1mg
Balani et al (2006) Drug
Metab Dispos 34:384
Millennium
Pharmaceuticals
Fluconazole
Tolbutamide
MLNX
Rat
LC-MS
Linear 0.001-5mg
Linear 0.001-5mg
Linear 0.01-1mg, 10 mg
Cmax, t1/2 linear,
AUC non-linear
oral+i.v.
oral
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* provided by G Lappin, Xceleron
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Overview microdosing literature*
4
Reference
Drug
Species
Method
Outcome
Yamane et al (2007)
J Chromatogr B
858:118
Fexofenadine
Human
LC-MS
Linear 0.1-60mg
Vuong et al (2007)
J Pharm Sci
Vitalea Science
Zidovudine
Human
AMS
Linear 520ng- 60mg
O’Brien, Z et al Poster
presented at AAPS
San Diego, Nov 2007
Neurocrine
Diphenhydramine
Oral+i.v.
NBI-1
oral
Human
AMS
Linear 0.1-50mg
www.speedel.com
Renin inhibitor
SPP635
oral+i.v.
Human
oral
* provided by G Lappin, Xceleron
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Linear 0.1-10mg
AMS
Linear 0.1-50mg
Overview microdosing literature
Trial by Consortium for Resourcing and Evaluating AMS
Microdosing (CREAM trial)
• Pharmaceutical Companies
–
–
–
–
Eli Lilly
Hoffmann LaRoche
Servier
Schering AG
• Xceleron (AMS)
• Pharma Bio-Research (now: PRA International EDS)
• Scientific Advisory Board (Prof. Malcolm Rowland,
chairman)
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CREAM trial: objective and design
• Objective
– test the ability to predict from microdoses (100 μg) the
pharmacokinetics of 5 known drugs at therapeutic doses
within acceptable bounds
• General design
– cross-over designs in 6 subjects per drug (2-way or 3-way)
– 14C dose (200 nCi) administered in all periods
– 14C-parent and total radioactivity assayed in plasma by AMS
– also ‘cold’ assay of parent after pharmacological doses
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CREAM trial: overall results
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CREAM trial: overall results
Drug
Was microdose predictive of therapeutic dose?
Warfarin
CL/F predicted but volume of distribution not
predictive
oral; 0.1 vs 5 mg
ZK253 Schering
oral+i.v.; 0.1 vs 50 mg
Low oral BA in human predicted
i.v. PK predictive within factor of 2
Diazepam
i.v. PK predictive
i.v.; 0.1 vs 10 mg
Midazolam
oral+i.v.; 0.1 vs 7.5 mg
BA due to 1st pass predictive
PK predictive
Erythromycin
No test (but lessons with acid-labile drugs)
oral(+i.v.) 0.1 vs 250 mg
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CREAM trial: Warfarin
Dose normalized geometric means (n=6)
10000.00
C-14 microdose
C-14 therapeutic
ng/mL/dose
Therapeutic 5 mg
T½ = 43 h
Parent microdose
Parent therapeutic
1000.00
Microdose 100µg
T½ ≈ 270 h
100.00
0
20
40
60
80
100
120
Time (h)
Clearance/F L/hr
Ther 0.26 ; micro 0.21
Literature ~ 0.2
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V/F L
Ther 17.9 ; micro 42.2
Literature ~ 10
CREAM trial: Midazolam
oral microdose versus oral therapeutic dose
concentrations dose normalised
10.00
Oral microdose
Microdose (100 µg)
Plasma concentration measured
with HPLC-AMS
Oral therapeutic dose
ng/mL/dose
1.00
0.10
Therapeutic dose (7.5mg)
Plasma concentration measured
with LC-MS
0.01
0
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2
4
6
Tim e (h)
8
10
12
14
CREAM trial: Midazolam
oral bioavailability of microdose
concentrations dose normalised
IV microdose
Oral microdose
Bioavailability = 23%
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CREAM trial: Midazolam
oral bioavailability of therapeutic dose
concentrations dose normalised
IV microdose
100 µg
Oral therapeutic
7.5mg
Bioavailability = 22%
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EU Microdose AMS Partnership Program
Published on 20 January 2006
MEDICINE, RESEARCH
Major injection of EU funds for a
microdose project
A new EU-funded project kicked off this month which aims
to bridge the gap between the laboratory and the clinic. The
EU Microdose AMS Partnership Programme (EUMAPP) aims
to boost Europe’s expertise in micodosing and its application
of AMS, or accelerator mass spectrometry, to developing
new candidate drugs ... . . .
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MGTADM 022 T 03 F
EU Microdose AMS Partnership Program
Published on 20 January 2006
MEDICINE, RESEARCH
Major injection of EU funds for a
microdose project
A new EU-funded project kicked off this month which aims
to bridge the gap between the laboratory and the clinic. The
EU Microdose AMS Partnership Programme (EUMAPP) aims
to boost Europe’s expertise in micodosing and its application
of AMS, or accelerator mass spectrometry, to developing
new candidate drugs ... . . .
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EU Microdose AMS Partnership Program
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Drug
Reason for Selection
Fexofenadine
PgP and OATP substrate
Paracetamol
Extensive phase II metabolism
Phenobarbital
Metabolic stability, Long t½
Propafenone
CYP 2D6 substrate;
Saturable first-pass
metabolism
Sumatriptan
Cytosolic monamine oxidase
metabolism
S-19812
Formation of non-selective
metabolite
Clarithromycin
CYP-3A4 and PgP substrate
EUMAPP: fexofenadine
microdose versus therapeutic dose (oral)
Mean data, error bars are standard deviation
10
ng/mL per 1 mg dose
Oral microdose (100 g)
1
Oral therapeutic dose (120 mg)
0
0
5
Results are
dose normalized to 1mg
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10
15
Time (h)
Oral micro
Oral 120 mg
20
25
EUMAPP: fexofenadine
iv microdose with/without oral therapeutic dose
IV 14C-microdose (100 g)
10000
1000
pg/mL
IV 14C-microdose (100 g) +
120 mg non-labelled oral dose
100
10
0
5
10
15
Time (h)
IV micro
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IV micro + oral ther
20
25
EUMAPP: fexofenadine
absolute oral bioavailability (microdose)
10000
IV 14C-microdose
Mean oral absolute bioavailability 38%
1000
pg/mL
Oral 14C-microdose
100
10
0
5
10
15
Time (h)
Oral micro
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IV micro
20
25
EUMAPP: fexofenadine
absolute oral bioavailability (therapeutic dose)
100
ng/mL per 1 mg dose
IV 14C-microdose + non-labelled 120 mg oral dose
Oral therapeutic dose (120 mg)
10
Mean oral absolute bioavailability 28%
1
0
0
5
10
15
Time (h)
IV micro + oral ther
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Oral 120 mg dose
20
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Applications of phase 0 microdosing
• 14 “Phase 0” microdose studies completed at PRA in last
4 to 5 years
– studies with single compound to obtain human PK in case of
uncertain or conflicting animal/in vitro PK data
– most studies comparing multiple candidates (up to 5) in parallel
– design in most studies: parallel panels –> per compound oral-iv
crossover in each panel
– one 3-way crossover to compare 3 candidates after iv dose in
same panel to select best candidate for oral prodrug
development
– one CYP3A4 “interaction” study to assess influence of ritonavir
on clearance of candidate protease inhibitor (1 mg dose)
– one study with topical administration on skin (3.8 μg dose) to
check if no systemic exposure
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Applications of phase 0 microdosing
140
Example from MD study with one
compound with uncertain oral BA
5 μg oral dose
120
Concentration (pg/mL)
100
parent
Total 14C
80
60
40
20
0
0
12
24
36
Time (Hour)
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60
72
Applications of phase 0 microdosing
Example from MD study with
5 compounds in iv-oral crossover panels :
10.000
Drug Concentration
Compound A – iv
1.000
0.100
0.010
0.001
0
12
24
36
Time (h)
Total C-14 (ng equiv/mL)
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parent A (ng/mL)
48
Applications of phase 0 microdosing
Example from MD study with
5 compounds in iv-oral crossover panels :
10.000
Drug Concentration
Compound A – iv+oral
1.000
0.100
0.010
0.001
0
12
24
36
Time (h)
Total C-14 (ng equiv/mL)
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Parent A (ng/mL)
48
Applications of phase 0 microdosing
Example from MD study with
5 compounds in iv-oral crossover panels :
Drug concentration
10.000
Compound C – iv
1.000
0.100
0.010
0.001
0
12
24
36
Time (h)
Total C-14 (ng equiv/mL)
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Parent C (ng/mL)
48
Applications of phase 0 microdosing
Example from MD study with
5 compounds in iv-oral crossover panels :
10.000
Drug concentration
Compound C – iv+oral
1.000
0.100
0.010
0.001
0
12
24
36
Time (h)
Total C-14 (ng equiv/mL)
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Parent C (ng/mL)
48
Applications of phase 0 microdosing
In February 2005 we successfully completed the first human microdosing studies of new renin inhibitors SPP630 and SPP635 for the
treatment of hypertension and for protecting end-organs such as the
heart, kidneys and blood vessels.
We made significant progress with the development of our SPP600
series by using rational drug design, state-of-the-art preclinical
models, and human microdosing to obtain early ADME information,
allowing us to ‘screen-in’ the most promising candidates for clinical
development.
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Applications of phase 0 microdosing
Press Releases
[2004-07-21 8:03]
“The microdosing approach has provided Tripep with
pivotal early human PK data on the performance of its
candidate drug much more quickly and accurately than
would have been possible using conventional
development strategies.
Encouragingly for the development of alphaHGA, the
microdose study has shown 100% oral bioavailability for
the candidate, allowing fast-tracking of the molecule into
proof-of-concept studies with an enhanced chance of
success and significantly reduced risk.”
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Applications of phase 0 microdosing
Two posters presented the results of a microdosing study in
man to assess the pharmacokinetics and the concentrations
of AR-709 in key lung compartments in healthy male
volunteers.
.........
Very importantly AR-709 achieves high concentrations in
bronchial mucosa (BM), epithelial lining fluid (ELF) and
alveolar macrophages (AM), the three key compartments of
the lungs where pathogens can reside and replicate.
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Concluding remarks
• For the large majority of compounds tested so far
(n>20) there was good agreement between PK for
microdose versus pharmacological dose
• AMS is unique analytical tool; total radioactivity data
give added value
• Microdosing can help in decision making in early drug
development
• Small / emerging pharma companies take the lead in
applying Phase 0 microdosing for early candidate
screening/selection
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