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AAVPT/ECVCP Workshop on Bioequivalence Issues in Veterinary Medicine
Potomac, June 2010
Should licking behavior be
factored into topical product
bioequivalence trials?
A. Bousquet-Mélou & P.L. Toutain
National Veterinary School, Toulouse, France
BE Workshop 2010 - 1
The beginning of a strange story
• Comparison of PK profiles of doramectin and
ivermectin pour-on formulation in cattle
– 24 young beef cattle
– 2 groups (parallel design)
BE Workshop 2010 - 2
Doramectin vs. ivermectin:
pour-on administration (500 µg/kg)
AUC range (ng.day.mL-1)
Concentrations (ng/mL)
DORAMECTINE
40
104-258
30
IVERMECTINE
51-182
Highly variable drugs
20
Doramectin
10
Ivermectin
0
0
10
Time (days)
20
30
BE Workshop 2010 - 3
Pour-on formulations of
endectocides are HVD products
• It is generally accepted that a drug or a drug
product exhibiting within-subject variability of
30% or greater in the measure of the AUC or
Cmax can be classified as a highly variable drug
or drug product.
• For this highly variable drug product, it is very
difficult to demonstrate BE using standard
design/sample size
BE Workshop 2010 - 4
Crossover or parallel design for PO
formulations of endectocides?
Crossover design
Parallel design
• Within-subject variability
• Between- plus within-subject
variability
• Difficult for very long half-life • Attractive for very long half-life
(long washout period)
Parallel design / Within subject variability
?
Cloned twin cattle
BE Workshop 2010 - 5
Parallel design with cloned cattle
• Hypothesis : cloned twin cattle can be considered as
replicates of the same animal
• Question : Is a parallel design with pairs of cloned cattle
statistically equivalent to a conventional crossover design ?
Measure of the repeatability and reproducibility of ivermectin
kinetics in 6 pairs of monozygotic twins
BE Workshop 2010 - 6
Pharmacokinetics homogeneity of twin cattle:
IV ivermectin study
– very high intra-pair reproducibility of ivermectin
disposition (CV=5%)
– Cloned cattle could be considered as replicates
of the same animal for a BE trial
Ivermectin (ng/mL)
1000
PO are highly variable drug product
100
10
1
0.1
0
200
400
600
Time (h)
800
1000
1200
BE Workshop 2010 - 7
Plasma concentrations (ng/mL)
Inter-occasion variability for the PO formulation
in a given subject
40
period I
period II
period IV
35
30
25
20
15
10
5
0
0
10
20
30
40
50
Time (day)
it was concluded that the erratic absorption of IVM was not of genetic
origin and that the intra-animal variability for PO formulations would
unlikely be much lower than the inter-animal variability.
BE Workshop 2010 - 8
What is the origin of the large intra-individual
variability of the drug exposure after a pour-on
administration ?
• There was a secondary question in this experiment:
Is it possible to compute, using only faecal clearance
(easily obtainable after any route of administration), the
total amount of drug eliminated by the faeces
(environmental issue) ?
Total amount eliminated by faeces
= Faecal clearance  AUC(plasma)
BE Workshop 2010 - 9
The faecal clearance of IVM after a
PO administration
Faecal clearance
Rate of drug eliminated in feces
Plasma concentration
!
Plasma clearance
>>
Overall rate of drug elimination
Plasma concentration
Conceptually impossible if the plasma is the only
driving force for ivermectin excretion into feces
BE Workshop 2010 - 10
Faecal elimination of IVM: PO vs SQ
Similar inconsistent results from observational study on higher fecal
concentrations of ivermectin reported following pour-on application than
SQ injection (Herd et al. 1996, Int. J. Parasitol. 26: 1087)
!
s.c.
s.c.
pour-on
pour-on
IVM
Plasma
pour-on
s.c.
Faeces
Metabolism
BE Workshop 2010 - 11
Origin of the high “faecal exposure”
Licking behaviour
Skin
IVM
Plasma
Faeces
Metabolism
BE Workshop 2010 - 12
1
Origin of the high “faecal exposure”
• Hypothesis: licking behavior
plays a role
Licking is a form of grooming behavior directed
to the skin.
Cattle can lick themselves (self-licking) or
another conspecific animal (mutual/social or allogrooming). Cattle can lick most areas of their
body and mutual licking (social grooming) has a
social meaning, helping to establish and maintain
social bonds within the herd.
Licking cattle
According to (Sato et al. 1991) heifers and steers
had 15.0 and 15.2 social licking interactions per
hour which lasted for 37.8 and 41.0 s.
BE Workshop 2010 - 13
Licking vs. non-licking cattle:
Pour-on Administration
6 pairs of twin
cattle
Starsky
LICKING (n=6)
Hutch
NON-LICKING (n=6)
BE Workshop 2010 - 14
1
Results : plasma disposition after
pour-on administration
•
•
Bioavailability
Half-life
– lickers:
144 ± 3h (no flip-flop)
– non lickers: 363 ± 16h (flip-flop)
– lickers:
33 ± 18%
– non lickers: 19 ± 4.9%
50
40
Licking
30
Non-licking
20
10
Concentrations (ng/mL)
Ivermectin (ng/mL)
60
100
10
1
0.1
0
0
10
20
30
40
50
60
0
10
20
30
40
50
60
Time (day)
Time (days)
Laffont et al., Int J Parasitol, 2001
BE Workshop 2010 - 15
A model of ivermectin disposition after a pour-on
formulation administration
Assumption: the 2 twin cattle are analyzed as the “same individual”
observed twice
500 µg/kg Pour-on
Laffont et al., Vet Res, 2003
ingestion 58 - 87%
55 %
Oral absorption
22 %
Plasma
IVM
13 % of the
dose
FECES
7 - 14 % of the
dose absorbed
by skin
overall bioavailability
F total = 18 - 68 %
BE Workshop 2010 - 16
PO formulation are actually oral
route of administration
• By the means of pharmacokinetic modeling, we
estimated that from 58 to 87% of the PO dose was
actually ingested, while only 7-14% was absorbed
percutaneously (Laffont et al. Vet Res, 2003).
• By modeling plasma vs time curves, it was
estimated that 78 to 82% of the total drug amount
recovered in the bloodstream was due to oral
ingestion after licking (Sallovitz et al., unpublished
data).
BE Workshop 2010 - 17
BE Workshop 2010 - 18
Material and methods
• 4 pairs of twin cattle
IVM DORA
IVM MOXI
DORA MOXI
Control
Dose : 500 µg/kg
Blood and fecal samples
BE Workshop 2010 - 19
Results: plasma exposure
Treated
Nontreated
Plasma conc. (ng/mL)
Doramectin
Ivermectin
Moxidectin
4
10
10
8
8
3
6
6
2
4
4
2
2
0
0
0
10
20
30
40
50
1
0
0
10
20
30
40
50
0
10
20
30
40
50
Time (day)
BE Workshop 2010 - 20
Lanusse group results
Direct measurements of different MLs in
GIT (fluids, mucosa) confirmed that PO
formulation of MLs are extensively
orally ingested by cattle allowed to lick.
BE Workshop 2010 - 21
Peak concentrations
Duodenal
Plasma
Bile
Mucosa
Fluid
SC treatment
36 ng/mL
80 ng/mL
53 ng/g
22 ng/mL
Pour-on treatment
Ratio Pour-on / SC
13 ng/mL
17.6 ng/mL
65 ng/g
239 ng/mL
0.37
0.22
1.23
10.9
Plasma
36
13
Duodenal
Mucosa
53
65
Duodenal
Fluid
22
SC
Pour-On
Orally ingested
moxidectin
239
BE Workshop 2010 - 22
BE Workshop 2010 - 23
LICKING IN TOPICALLY TREATED GRAZING CATTLE
DRM availability (AUC)
-Assessment of DRM concentrations in intestinal content-
>138%
600
500
DRM
oral
ingestion
400
300
<40%
200
100
0
SC
Pour-on Pour-on
non-lickers lickers
Sallovitz J, Lifschitz A, Lanusse C. Vet Parasitol. 2005 ;133:61-70
BE Workshop 2010 - 24
10-day LICKING RESTRICTION PERIOD:
DOR in gastrointestinal contents in GRAZING ANIMALS
DRM availability (AUC)
700
>300%
600
500
>1900%
Non-lickers
Free lickers
400
300
200
100
0
Abomasal
fluid content
Duodenal
fluid content
BE Workshop 2010 - 25
General conclusion
• At the herd level, and considering the 2
sources of drug ingestion (self- and allolicking), the oral (licking) route is the main
pathway for an endectocide poured on the
back of cattle, to enter the plasma and to
have a systemic effect
BE Workshop 2010 - 26
What is actually a PO drug
product
• A Pour-on administration is not a truly
individual topical treatment but also a
collective oral treatment raising for BE
testing not only a question of high variability
but also a question of population dimension
as for all collective oral treatments
BE Workshop 2010 - 27
Concerns raised by this
behavior-driven drug disposition
• Efficacy
– Drug resistance
•
•
•
•
Safety
Environment
Regulation (GLP study)
Bioequivalence
BE Workshop 2010 - 28
Questions addressed
1.
2.
Requirement or not of an in vivo BE
Average BE: should licking behavior be factored into
topical product bioequivalence trials?
• “Licking effect” vs. “licking X formulation interaction
effect”
3. PO products are HVD products: scaling average BE
(SABE)
4. PO products are collective treatments: is really
average BE appropriate ?
5. GLP (lab) or GCP (field) conditions to perform a PO
BE trial?
BE Workshop 2010 - 29
Question 1: Is there or not a
requirement for an in vivo BE for
Pour-on formulations or can BE
be considered as self-evident ?
BE Workshop 2010 - 30
Criteria for Waiver of In Vivo
Bioequivalence Study : FDA
•
Categories of products which may be eligible
for waivers include, but are not limited to, the
following:
–
–
–
1. Parenteral solutions (IV, SQ, IM).
2. Oral solutions…..
3. Topically applied solutions intended for local
therapeutic effects. Other topically applied dosage
forms intended for local therapeutic effects for nonfood animals only.
•
–
PO formulation are mainly for systemic effect
4.Inhalant volatile anesthetic solutions.
BE Workshop 2010 - 31
NOROMECTIN (ivermectin) Pour-On
for Cattle
FREEDOM OF INFORMATION SUMMARY
AN ORIGINAL ABBREVIATED NEW ANIMAL DRUG APPLICATION (ANADA)
ANADA 200-272
Based on the formulation characteristics of the generic product, Norbrook
Laboratories Ltd. was granted a waiver from the requirement for an in
vivo bioequivalence study for NOROMECTIN (ivermectin) Pour-On for
Cattle. The generic product is administered as pour-on (topical) contains
the same active ingredient in the same concentration and dosage form as
the pioneer product, and contains no inactive ingredients that may
significantly affect the absorption of the active ingredient. The
pioneer product IVOMEC (ivermectin) Pour-on for Cattle, the subject of
Merial Ltd’s NADA 140-841, was approved on December 4, 1990.
BE Workshop 2010 - 32
Criteria for Waiver of In Vivo
Bioequivalence Study : EMEA
• No waiving for PO formulations
• Several generic PO dossiers were granted
a marketing authorization in EU after a
successful demonstration of BE
– Crossover design with 10 to 24 animals under
GLP conditions
BE Workshop 2010 - 33
Question 2: Should licking
behavior be factored into topical
product bioequivalence trials?
BE Workshop 2010 - 34
A licking effect
The 2 formulations (A and B) are BE in both free-licking
and non-licking groups
AUC
A
B
A
B
Licker
Non Licker
Licking effect is not an issue for average BE
testing
BE Workshop 2010 - 35
Interaction licking X formulation
The 2 formulations (A and B) are BE in non-licking
condition but not in free-licking condition
AUC
B
A
BE in non lickers
A B
not BE in lickers e.g. due to the
poor taste of test formulation
Interaction is an issue
BE Workshop 2010 - 36
Question 3: How to manage BE for
Highly Variable Drug Products ?
BE Workshop 2010 - 37
Types of Bioequivalence
• Average Bioequivalence (ABE)
– Current regulatory requirement
• Population Bioequivalence (PBE)
– Prescribability
• Individual Bioequivalence (IBE)
– Switchability
Average BE:
concerns raised by licking
• Due to the high inter-individual variations,
how is it possible to demonstrate a
bioequivalence with the currently
recommended interval (0.8-1.25) ?
– If CV% = 45%  84 to 140 subjects are necessary
BE Workshop 2010 - 39
Available Options
Bioequivalence of Highly Variable PO products
1.
2.
3.
4.
5.
–
Prevent licking: no due to a possible bias
Increase number of subjects: possible but costly and
inefficient
Multiple dose (steady-state) studies: no
Replicate design to determine intra-individual variability:
possible but long washout
Widen the a priori BE interval 80-125 for both AUC and
Cmax (scaled average BE)
Need for point estimate constraint
BE Workshop 2010 - 40
How to establish average BE for a HVD
product: scaling average BE (SABE)
 0.223

BE limits, upper, lower  EXP 
  wr 
 

w0


* w0 is the SD at which the BE limits are permitted to
be widened (set by FDA to 0.2) (20%)
* wr is either the residual SD (ABE) or the SD of the
reference product (replicate design) e.g 0.4 (40%)
A priori BE interval for PO formulation:
0.64-1.56
BE Workshop 2010 - 41
Limitations of ABE
• Focuses only on population average
• Ignores distribution of the metric
• Does not address the right question for
a collective treatment as it is the case
for a PO formulation.
Question 4: Is really average BE
appropriate for PO formulations of
endectocides ?
BE Workshop 2010 - 43
Types of Bioequivalence
• Average Bioequivalence (ABE)
– Current regulatory requirement
• Population Bioequivalence (PBE)
– Prescribability
• Individual Bioequivalence (IBE)
– Switchability
!
Question of the experimental unit :
Are observations on one animal independent of the
presence of other animals ?
Situations where the dose depends on the animal
behavior, in interaction with others in the group
 Oral collective treatments
 Pour-on of endectocides
BE Workshop 2010 - 45
Situations where the dose depends on the animal
behavior, in interaction with others in the group
“ Unlike traditional dosage forms where the administration
(intake) is under the control of the investigator …intake is
dependant upon animal behavior
The inconsistent intake … influenced by animal … behavior,
is a determinant of rate and extent of drug exposure …
This source of variability complicates the assessment of
formulation effects … the inherent nature of … is that intake
is free choice.
… the times of intake and the duration of intake … are
dictated by the animal.”
BE Workshop 2010 - 46
Population BE (PBE)
• Population BE is a method for widening
the BE limits using total variance (sum
of within-and between animal variance)
for test and reference products (σ2TT
and σ2TR ) (US FDA , 2001)
BE Workshop 2010 - 47
Question 5: Value of laboratory
(GLP) vs field (GCP) condition to
demonstrate a BE
BE Workshop 2010 - 48
Regulatory concerns raised by licking
• BE trial is a “clinical trial” performed in lab
conditions!!!
• Is there a possible interaction between lab
conditions and field conditions vs.
formulations?
– i.e.2 formulation can be BE in lab conditions
(thanks to preventing licking) but not in field
conditions)
BE Workshop 2010 - 49
OECD principles of GLP
• According to the OECD the principles of GLP have been
developed to promote not only the quality but also the
validity of test data.
• Validity of results requires the absence of a major bias
– e.g. . the presence of factors in the experimental design that
cause the results to deviate systematically from those that would
have been observed in regular husbandry conditions.
• Validity of the results requires that inter-animal and intraanimal variability should be considered as a biological
fact, not as a noise that should be reduced or even
deliberately suppressed in an experimental setting while
these behaviors are actually major factors of drug
disposition in the target population
BE Workshop 2010 - 50
Regulatory concerns raised by licking
• How to explain that none of Lab trials
(including GLP) revealed the phenomenon?
• Is ignoring the main mechanism of a drug
disposition synonymous to good science?
• Population kinetics (in field conditions) would
have immediately evidenced this
phenomenon
BE Workshop 2010 - 51
BPL or GCP conditions to perform a
PO BE trial?
• BE trials need to be performed in a representative
clinical environment, not an artificial experimental
environment
• To replace GLP practices by Good Clinical
Practices (GCP) could be a solution to prevent bias
• Currently BE should be conducted in accordance
with good laboratory practice (GLP) regulations
both under FDA and EMEA regulations.
– in the last draft version of the future EMEA guidelines
(March 2009), it states: “Bioequivalence studies should
be conducted under Good Laboratory Practice (GLP)
and/or Good Clinical Practice (GCP), as appropriate”.
BE Workshop 2010 - 52