The pharmacokinetics of moxidectin after oral and subcutaneaous administration to sheep

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The pharmacokinetics of moxidectin after oral and

subcutaneaous administration to sheep

M. Alvinerie, E. Escudero, J.F. Sutra, C. Eeckhoutte, Pierre Galtier

To cite this version:

Original

article

The

_{pharmacokinetics}

of

moxidectin after

oral

and subcutaneous

administration

to

_sheep

Michel Alvinerie

a

Elisa

Escudero

b

_{Jean-François}

Sutra

a

Claudine Eeckhoutte

Pierre Galtier

’

Laboratoire de

_{pharmacologie-toxicologie,}

Inra,

180, chemin de Tournefeuille, BP 3, 31931 Toulouse cedex 9, France

!

Department

de

_Farmaco!ogia

_y

_Terapeutica,

Facultad de Veterinaria,

30071

_Espinardo,

Murcia,

Spain

(Received 4 December 1997;

accepted

15

_January

1998)

Abstract-The

_{pharmacokinetic}

_parameters of moxidectin were determined in ten

_{sheep following}

a

_single

subcutaneous or oral drench at a dose _{of 0.2 mg.}

_kg

The

_plasma

kinetics were best fit-ted

_by

a _{two-compartment} model. Moxidectin was detected in the

_plasma

at the first

_sampling

time

( I h) and thereafter for at least 60 d. The AUC were similar after both treatments

_indicating

the

same

_{bioavailability}

for the two routes of administration. The oral route was characterized

_by

a

higher

Cmax value (28.07

ng-mL-

1

)

than after subcutaneous

_{injection (8.29}

_ng.mL-

₁

₎

and

_by

significantly

faster

_absorption

as indicated

_by

Tmax of 0.22 d and 0.88 d for oral and subcutaneous

administrations,

respectively.

The most

_striking

result of this

_experiment

was the

_longer

mean

res-idence time

_reported

for the subcutaneous route, i.e. 16.80 d as

_compared

to 12.55 d for the oral drench. This difference is in _agreement with

_previous

studies

_{demonstrating}

the

_longer

anthelmintic

efficacy

of the subcutaneous route in

_comparison

with oral administration. © Inra/Elsevier, Paris moxidectin /

_sheep

/

_{pharmacokinetic}

/ _efficacy / persistence

*

Correspondence

and

_reprints

Tel.: (33) 05 61 28 51 37; fax: (33) OS 61 28 53 10; e-mail: malviner@toulouse.inra.fr Résumé -

_{Étude pharmacocinétique}

de la moxidectine

_après

administration orale ou

sous-cutanée chez le mouton. Les

_{paramètres pharmacocinétiques}

de la moxidectine ont été déterminés chez dix moutons recevant une même dose de 0,2

_ing-kg-

₁

par voie sous-cutanée ou _{par voie}

orale.

_{L’analyse pharmacocinétique}

a été réalisée

_grâce

à un modèle

_{bicompartimental.}

La moxi-dectine a été détectée dans le

_plasma

lors du

_{premier prélèvement (I h)}

_{et jusqu’à 60 j après}

l’administration. Les aires sous la courbe sont _{similaires pour les deux voies d’administration}

que par une

_{absorption plus rapide}

_{illustrée par les valeurs des Tmax}

_qui

sont

_{respectivement}

de

0,22 et

_{0,88 j}

pour la voie orale et la voie sous-cutanée. Le résultat le

_plus

_surprenant de cette étude réside dans la

_{plus longue}

rémanence de la voie sous-cutanée (MRT = 16,8

j) comparée

à celle de la voie orale (MRT = 12,6 j). Cette différence est en accord avec des études antérieures démontrant une

_{plus longue}

efficacité des

_{anthelmintiques}

lors d’une administration

sous-cuta-née

_{comparativement}

à la voie orale. @ Inra/Elsevier, Paris

moxidectine / mouton /

_{pharmacocinétique}

/ efficacité / rémanence

1. INTRODUCTION

Moxidectin is a

_macrocyclic

lactone

produced

by

the _{non-cyanogenous}

_species

Streptomyces

cyanogri.seus

and modified

by

chemical

_synthesis

to

_give

a broad

spectrum

antiparasitic

drug

for the con-trol of both internal and external

_parasites

of domestic animals

[4, 7J.

Moxidectin is

chemically

related to

_milbemycin;

the molecular structure includes a fused

cyclo-hexane

_{tetrahydrofuran}

_ring,

a

_bicyclic

6,6-membered

spiroketal

and a

cyclohex-ene

_ring

fused to the 16-membered

macro-cyclic ring.

Moxidectin is the

23-(0-methyloxime)

derivative of nemodectin and differs

_structurally

from ivermectin

in

_having

no _sugar

_moiety

at the C- 1 3

position

and in

_having

an unsaturated side-chain at the C-25

_position.

These differ-ences confer

_{significantly}

different

phys-ical and

_{pharmacological properties}

in the

two

_drug

_types. Moxidectin is much more

lipophilic

in nature than avermectin and

is

_mainly

stored in the fat. _{This appears}

to have an

_accumulatory

effect and results in a

_longer

mean residence time for the

drug

in the

_body,

as has been demonstrated

in cows

_{[3, 10].}

There is no information

regarding

its

_{pharmacokinetic}

_parameters in

_{sheep, although}

it is licensed as an oral drench or an

_injectable

formulation in this

species.

The

_present

_study

was,

therefore,

under-taken to determine the

_{plasma profile}

of moxidectin in

_plasma

when

_given

_by

the oral route and

_by

subcutaneous

_injection

in

sheep

and to correlate the

pharmacoki-netic

_parameters

with the

_persistence

of

activity

noted in

_previously

described

stud-ies [9].

] .

2. MATERIALS AND METHODS

2.1. Animals and

_drug

administration

Ten young adult Lacaune

sheep weighing

23 ± 2

_kg

were obtained from a flock which

had been reared under

_{parasite-free}

conditions from birth.

_They

were allocated into two groups of five and

_provided

with

_hay,

concentrates

and water ad _{libitum. Each group received} moxidectin

_(cydectin°,

Fort Dodge

Interna-tional, Paris, France) either _{subcutaneously} as

a I %

_{injectable cydectin}

solution or as a 0.1 % oral

_cydectin

drench at a dose rate of 0.2

_mg.kg-

_l

_according

to the manufacturer’s recommendations.

Blood

_samples

for analyses were collected

from the

_sheep

at 1, 2, 4, 8, 12 and 24 h and 1.5, 2, 3, 4, 5, 6, 8, 10, 15, 21, 25, 30, 35, 40, 50 and 60 d after

_injection.

Blood was collected in

heparinized

tubes,

by jugular

vein puncture.

Centrifugation

was

_performed

within I h of

sampling,

and the

_{plasma samples}

stored at

- 18°C until

chromatographic analysis.

2.2.

_Analytical

method

The

_{plasma samples}

were

_analyzed

for moxidectin concentration

_using

a

_newly

described method _{12]. Briefly,} I mL of

ace-tonitrile and 0.25 mL of water were added to

I mL of

_plasma.

After

_mixing

for 20 min, the

samples

were

_centrifuged

at 2 _{000 g for} 2 min,

cartridge.

After

_washing

with water, the

mox-idectin was eluted with 1.0 mL of methanol. The eluate was

_evaporated

to

_dryness

under a

gentle nitrogen stream, and the residue dis-solved in 100 _NL

_{N-methylimidazole}

solution in acetonitrile _{(1:1, v/v). Here,} 150

_1xL

tritluo-roacetic

_anhydride

solution in acetonitrile (1:2, v/v) was added to initiate the derivatization. After _completion of the reaction _(< 30 _s), an

aliquot

( 100

!uL)

of this solution was

_injected

directly

into the

_{chromatograph.}

The mobile

phase consisted of acetic acid (0.2 % in _water), methanol and acetonitrile (4:15:50, v/v/v) at a

flow rate of I.5 mL.min-1

_through

a

_supelcosil

C18 column (3 pm; 4.6 mm i.d. x 150 _mm) with fluorescence detection at an excitation

wavelength

of 383 nm and an emission

wave-length

of 447 nm _(RF.55 I tluorescence detec-tor, Shimadzu,

Kyoto, Japan).

The

quantifica-tion limit of the method was 0.1

_ng.mL-1

of

plasma

with a coefficient of variation of 6.95 %

(inter-day variability).

2.3. Data

_analysis

The

_{following triexponential equation}

was

fitted to the

_plasma

concentration versus time data

_using

a _program

_adapted

from Multi [ 161:

in which

_A

_j

_,

A, and

_A

₃

are the

_intercepts,

C the

plasma

concentration at time t, ka is the esti-mated first order rate constant of moxidectin

absorption

and a and

_{(3 are}

the first order rate constants for moxidectin distribution and

elim-ination,

respectively.

The mean residence time

(MRT) was calculated

_by

the linear

_trapezoidal

rule without

_{extrapolation}

to

_infinity.

3. RESULTS AND DISCUSSION

Following

a subcutaneous or oral administration of 0.2

_mg’kg!

of

mox-idectin,

the _parent

_drug

was detected in the

_plasma

of

_sheep

over a

_period

of 60

days (figure

I).

The calculated

pharma-cokinetic _parameters are listed in table I. Moxidectin was detected at the first

sam-pling

time,

I

_{h post}

treatment in

_plasma

of both

_orally

and

_{subcutaneously}

dosed

sheep.

However after oral administration the Cmax

(28.07

ng.mL-

1

)

and Tmax

of

_{absorption compared}

to subcutaneous

administration with lower values of Cmax

(8.29

ng.mL-

1

)

and a

_longer

value of

Tmax

_{(0.88 d).}

All

_plasma

concentrations

decreased

_{progressively}

thereafter

_during

the intermediate and terminal

_phases

char-acterized

_by

similar half-life values.

The shorter MRT obtained

_following

oral administration

_{( 12.55 d)}

when

com-pared

to subcutaneous administration

( 16.8 d)

suggest that

the slower

_absorption

process

characterizing

subcutaneous

absorption

could

_par4icipate

in the

_longer

remanence of the

_drug

in the animal

organ-ism. Similar results were

_reported

for

iver-mectin in

_sheep

[6].

This difference results in a substantial

_broadening

of the

_plasma

concentration and

_persistence

of the

_drug

in the case of the subcutaneous route. In

our

_results,

subcutaneous administration

for

_example

_resulting

in

_plasma

concen-trations

_exceeding

2

_ng.mL-

₁

for 18 d and

compared

to 8 d for the oral route. The AUC of moxidectin

_following

SC

(1 12

ng-d-mL-

1

)

or oral administration

(99

iig.d.mL-

1

)

were observed to be

sim-ilar for both routes of administration due to

the faster oral

_absorption

_process

_{by using}

oral route. This result differs from that

obtained for ivermectin

_[I]

where it

showed a 59 % lower

_{bioavailability}

for the oral route than for subcutaneous administration. The reasons for such dif-ferences are still unclear - the _stronger

lipophilic

properties

of moxidectin may increase oral

_absorption

_[SJ.

Interestingly,

whatever the route of

administration,

moxidectin has a

_longer

mean residence time in

_sheep

than

iver-mectin - 7.8 d

_{[ I 1 J. A}

similar difference was observed

_by

others in cows

_[10]

and

horses

_[14].

It has been

_suggested

that such a difference could be related to dif-ferences in the

_{liposolubility}

of the two

drugs, resulting

in a

_longer

half life of

moxidectin in

fat,

which may then act as a

drug

reservoir that contributes to the

_long

persistence

of this

_drug

in the

_body

_[3].

_].

The kinetic

_parameters

obtained for

mox-idectin in

_sheep

in the current trial

_agreed

well with those obtained in cows and

horses and

_clearly

demonstrated the

_longer

persistence

of this

_drug

when

_compared

to ivermectin.

The duration of

_efficacy

of moxidectin

against parasites

in

_sheep

_{[ 131}

_may

origi-nate from the fact that it remains

_longer

in the

_plasma.

Even

_though

the

anthelmintic

_efficacy

was not evaluated

pres-ence of measurable

_drug

_plasma

concen-trations for 2 months is of interest. Anthelmintic

_activity

is

_generally

related

to the _presence of an active concentration of the

_drug

at the site of action for a

suit-able

_period

of time

[12]. The

ability

of

pharmacokinetic

studies to assess the

anthelmintic

_efficacy

of

_drugs

relies on the

_assumption

that the

_plasma

concen-tration

_profile

reflects the active concen-tration

_profile

at the site of action. The link between these two

_parameters

has been established for ivermectin

[ 15]

and estimated with relative

_certainty

for

mox-idectin.

The

_comparative

efficacies of the two

routes of administration have been studied

in

_{sheep by}

several authors

[8, 9].

It is

interesting

to note the

_longer

duration of anthelmintic

_efficacy

of the subcutaneous

administration.

_Although

both formula-tions of moxidectin showed excellent

activity

against

T. circumcita and H.

cun-tortus with almost 100

_{°I° etficacy}

_against

the abdominal

_parasites

_{for up} to 35 d

after treatment, the

efficacy

of moxidectin

I %

_{injectable against}

T.

_{colul!riforn2i.r}

was much

_higher

_(>

99

_%)

than the oral

drench. It was

_highly

effective _up to 21 d d

after treatment and

_produced

a moderate reduction in worm burden for up to 35 d after treatment

_[9].

_Having

established a

link between the

_plasma

concentration of moxidectin and its

_efficacy,

_{it is easy} to

see that

_during

this

_period

the

_plasma

con-centrations obtained

_by

subcutaneous route

were 4-l

ng!mL-!,

i.e. two-fold

_higher

than those obtained

_by

oral route

(2.5-0.6

ng.mL-1

).

This correlation

_clearly

demon-strated the

_relationship

between

_plasma

concentration and moxidectin

_efficacy.

In

conclusion,

this

_study

demonstrated

that both subcutaneous or oral routes of moxidectin administration in

_sheep

gen-erated the same

_quantity

of the

_drug

in the

body.

Nevertheless the

_persistence

of the

drug

was

_higher

with the subcutaneous administration. This

_{longer persistence}

was in _agreement with the

comparative

efficacy

of this route.

This is a

_{good example}

of the useful-ness

_{of pharmacokinetic}

_{investigations}

in

order to

_{improve therapeutic}

treatments.

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