be workshop 2010 - 1 should licking behavior be factored into topical product bioequivalence trials?...

BE Workshop 2010 - 1

Should licking behavior be factored into topical product

bioequivalence trials?

Should licking behavior be factored into topical product

bioequivalence trials?

A. Bousquet-Mélou & P.L. Toutain

National Veterinary School, Toulouse, France

AAVPT/ECVCP Workshop on Bioequivalence Issues in Veterinary Medicine Potomac, June 2010


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)


Doramectin vs. ivermectin: pour-on administration (500 µg/kg)

Highly variable drugs

DORAMECTINE IVERMECTINE

AUC range (ng.day.mL-1)

104-258 51-182

302010000

10

20

30

40

Time (days)

Doramectin

Ivermectin

Concentrations (ng/mL)

30201000 302010000

10

20

30

40

0

10

20

30

40

Time (days)

Doramectin

Ivermectin

Concentrations (ng/mL)


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


Crossover or parallel design for PO formulations of endectocides?

• Difficult for very long half-life

(long washout period)

Crossover design Parallel design

• Within-subject variability • Between- plus within-subject variability

• Attractive for very long half-life

Parallel design / Within subject variability?

Cloned twin cattle


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


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

Time (h)

Iver

mec

tin

(n

g/m

L)

0.1

1

10

100

1000

0 200 400 600 800 1000 1200

Time (h)

Iver

mec

tin

(n

g/m

L)

0.1

1

10

100

1000

0 200 400 600 800 1000 1200

PO are highly variable drug product


Inter-occasion variability for the PO formulation in a given subject

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.

0

5

10

15

20

25

30

35

40

0 10 20 30 40 50

Time (day)

Pla

sma

con

cen

trat

ion

s (n

g/m

L)

period I

period II

period IV

0

5

10

15

20

25

30

35

40

0 10 20 30 40 50

Time (day)

Pla

sma

con

cen

trat

ion

s (n

g/m

L)

period I

period II

period IV


• 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) ?

What is the origin of the large intra-individual variability of the drug exposure after a pour-on

administration ?

Total amount eliminated by faeces = Faecal clearance AUC(plasma)


Faecal clearance Plasma clearance

The faecal clearance of IVM after a PO administration

Rate of drug eliminated in feces

Plasma concentration

Overall rate of drug elimination

Plasma concentration

Conceptually impossible if the plasma is the only driving force for ivermectin excretion into feces!

>>


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)

Plasma IVM Faeces

Metabolism

s.c.

pour-on pour-on

s.c.

!

pour-on

s.c.


Skin

Metabolism

Plasma

12

Faeces

Licking behaviour

IVM

Origin of the high “faecal exposure”


• Hypothesis: licking behavior plays a role

Origin of the high “faecal exposure”

Licking cattle

Licking is a form of grooming behavior directed to the skin.

Cattle can lick themselves (self-licking) or another conspecific animal (mutual/social or allo-grooming). 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.

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.


Licking vs. non-licking cattle: Pour-on Administration

LICKING (n=6) NON-LICKING (n=6)

Starsky Hutch

6 pairs of twin cattle

14


Results : plasma disposition after pour-on administration

• Bioavailability– lickers: 33 ± 18%– non lickers: 19 ± 4.9%

• Half-life– lickers: 144 ± 3h (no flip-flop)– non lickers: 363 ± 16h (flip-flop)

Licking

Non-licking

Ive

rme

ctin

(n

g/m

L)

Time (days)

0

10

20

30

40

50

60

0 10 20 30 40 50 60

Laffont et al., Int J Parasitol, 2001

0.1

1

10

100

0 10 20 30 40 50 60

Time (day)

Co

nce

ntr

ati

on

s (n

g/m

L)


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

Plasma overall bioavailability

7 - 14 % of thedose absorbed

by skin

55 %

13 % of the dose

IVM

FECES

F total = 18 - 68 %

Laffont et al., Vet Res, 2003

Oral absorption22 %

ingestion 58 - 87%


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).


Material and methods

• 4 pairs of twin cattle

IVM DORA IVM MOXI DORA MOXI Control

Dose : 500 µg/kg

Blood and fecal samples


Results: plasma exposure

IvermectinDoramectin Moxidectin

Pla

sma

con

c. (

ng

/mL

)

Time (day)

Treated

0

2

4

6

8

10

0 10 20 30 40 500

2

4

6

8

10

0 10 20 30 40 500

1

2

3

4

0 10 20 30 40 50

Non-treated


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.


DuodenalMucosa

5365

Mucosa53 ng/g

Duodenal

65 ng/g

1.23

80 ng/mL

Bile

17.6 ng/mL

0.22

SC

Pour-OnPlasma36

13

36 ng/mLSC treatment

Plasma

Peak concentrations

13 ng/mLPour-on treatment0.37Ratio Pour-on / SC

Fluid22 ng/mL

239 ng/mL

10.9

DuodenalFluid 239

22

Orally ingested moxidectin

DuodenalMucosa

5365

Mucosa53 ng/g

Duodenal

65 ng/g

1.23

80 ng/mL

Bile

17.6 ng/mL

0.22

SC

Pour-OnPlasma36

13


Plasma

Peak concentrations


Fluid22 ng/mL

239 ng/mL

10.9

DuodenalFluid 239

22


DuodenalMucosa

5365

Mucosa53 ng/g

Duodenal

65 ng/g

1.23

80 ng/mL

Bile

17.6 ng/mL

0.22

SC

Pour-OnPlasma36

13


Plasma

Peak concentrations


Fluid22 ng/mL

239 ng/mL

10.9

DuodenalFluid 239

22

DuodenalMucosa

5365

Mucosa53 ng/g

Duodenal

65 ng/g

1.23

DuodenalMucosa

5365

DuodenalMucosa

5365

Mucosa53 ng/g

Duodenal

65 ng/g

1.23

Mucosa53 ng/g

Duodenal

65 ng/g

1.23

80 ng/mL

Bile

17.6 ng/mL

0.22

80 ng/mL

Bile

17.6 ng/mL

0.22

SC

Pour-OnPlasma36

13

SC

Pour-OnPlasma36

13Plasma36

13


Plasma

Peak concentrations



Plasma

Peak concentrations


Fluid22 ng/mL

239 ng/mL

10.9

DuodenalFluid 239

22

Fluid22 ng/mL

239 ng/mL

10.9

Fluid22 ng/mL

239 ng/mL

10.9

DuodenalFluid 239

22DuodenalFluid 239

22



>138%

LICKING IN TOPICALLY TREATED GRAZING CATTLE

-Assessment of DRM concentrations in intestinal content-

DR

M

availab

ilit

y (

AU

C)

0

100

200

300

400

500

600

SC Pour-onnon-lickers

Pour-onlickers

DRMoral

ingestion

<40%

Sallovitz J, Lifschitz A, Lanusse C. Vet Parasitol. 2005 ;133:61-70


>1900%

>300%

10-day LICKING RESTRICTION PERIOD:DOR in gastrointestinal contents in GRAZING

ANIMALS

0

100

200

300

400

500

600

700

Abomasalfluid content

Duodenalfluid content

DR

M a

vaila

bili

ty (

AU

C)

Non-lickers

Free lickers


General conclusion

• At the herd level, and considering the 2 sources of drug ingestion (self- and allo-licking), 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


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


Concerns raised by this behavior-driven drug disposition

• Efficacy– Drug resistance

• Safety• Environment• Regulation (GLP study)• Bioequivalence


Questions addressed

1. Requirement or not of an in vivo BE

2. 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?


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 ?


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 non-food animals only.

• PO formulation are mainly for systemic effect– 4.Inhalant volatile anesthetic solutions.


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.


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


Question 2: Should licking behavior be factored into topical product bioequivalence trials?


A licking effect

Licking effect is not an issue for average BE testing

AUC

Licker

Non Licker

BA

BA

The 2 formulations (A and B) are BE in both free-licking and non-licking groups


Interaction licking X formulation

Interaction is an issue

BE in non lickers

not BE in lickers e.g. due to the poor taste of test formulation

A B

B

A

The 2 formulations (A and B) are BE in non-licking condition but not in free-licking condition

AUC


Question 3: How to manage BE for Highly Variable Drug Products ?

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


Available OptionsBioequivalence of Highly Variable PO products

1. Prevent licking: no due to a possible bias2. Increase number of subjects: possible but costly and

inefficient3. Multiple dose (steady-state) studies: no4. Replicate design to determine intra-individual variability:

possible but long washout5. Widen the a priori BE interval 80-125 for both AUC and

Cmax (scaled average BE)– Need for point estimate constraint


How to establish average BE for a HVD product: scaling average BE (SABE)

wr

w0

lower upper, limits, BE

223.0 EXP

* 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

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 ?

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 ?

!


Oral collective treatments

Pour-on of endectocides

Situations where the dose depends on the animal behavior, in interaction with others in the group


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 behaviorThe 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.”


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 (σ2

TT

and σ2TR ) (US FDA , 2001)


Question 5: Value of laboratory (GLP) vs field (GCP) condition to

demonstrate a BE


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)


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 intra-animal 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


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


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 - 1 should licking behavior be factored into topical product bioequivalence trials?...

Documents

drug exposure

ivermectin excretion

pairs of cloned cattle

intraanimal variability

long halflife parallel

faecal elimination of

interanimal variability

cloned cattlehypothesis