utilisation des derives de l'artemisinine pendant la grossesse

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D D é é riv riv é é s de l s de l Art Art é é misinine misinine et Grossesse et Grossesse Wellcome Trust Wellcome Trust - - Mahidol Mahidol University University , Oxford Tropical , Oxford Tropical Medicine Medicine Research Research Programme Programme

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DDéérivrivéés de ls de l’’ ArtArtéémisinine misinine et Grossesseet Grossesse

Wellcome TrustWellcome Trust--Mahidol Mahidol UniversityUniversity, Oxford Tropical , Oxford Tropical MedicineMedicine ResearchResearch ProgrammeProgramme

Trop peu d’études thérapeutiques

PREGNANT WOMEN

12

Proportions des décès maternels lies au paludisme:

• Africaine: 0.5-23.0%• Non-Africaine: 0.6- 12.5%

Conséquences de la chimiorésistance

Morbidité

Mortalité

•Hypo endémique

•Falciparum multi-résistant

•Premunition faible

•Epidémies

•Mortalité à tout âge

•Risque accru pendant la grossesse

•Très peu d’options thérapeutiques

•Consultations prénatales depuis 1986

Frontière Birmanie-Thaïlande

Traiter, pourquoi?

P. falciparum:Maternal mortality of �

100/10,000 live birthsStrongest independent risk

factor for anaemiaLow birth weight - 123 g

reduction; all gravidaaffected

P. vivax:Increased risk anaemia –

Odds Ratio 1.91 [1.4-2.6]Low birth weight – 107 g

loss, more in multigravids

Abandon de la prophylaxieIPT menacé par la résistance

Limites des ITN

Etudes non randomisées

Tx (episodes) Année EchecsPrimaires Retraitements (<7d)

Q7 (204) 91-96 23.2% 38.6% 8%M25 (308) 91-96 28.3% 37.5% 7%AS7 (53) 92-96 N.A 9.4% 0

Etudes randomisées

Drug (n) Year Failure (95CI)% PGW(95%CI)Q7 (41) 95-97 33 (9-57) 46.9 (26-78)MAS3 (65) 2 (0.5-5) 2.3 (0-11)____________________________________________QC7 (65) 97-00 0 (0.1 -7) 39.0 (21-66)A7 (64) 0 (0.1 -7) 3.0 (0-19)____________________________________________Q7 (42) 01-03 37 (23-53) 49 (26-89)AAP (39) 5 (1-19) 6 (1-25)

PGW=person gametocyte weeks/1000 woman weeks

MFQ treatment: stillbirth risk 3,587 pregnant women, abortions excluded

• Drug N OR (95% CI) P value• MFQ vs 184• Q only 592 3.96 0.012

(1.35, 11.61)• Other antimalarial 819 4.52 0.005

(1.58, 12.92)• No malaria 1,657 3.06 0.016

(1.23, 7.60)

Nouveau-nés et nourrissons

• Age gestationnel• Examen Neurologique

et développent des enfants jusqu’à 1 an

Birth outcomes

Pregnancy Spont Still- Congen LBW Prematureoutcome Abort birth Anomaly <2.5 kg <37 wk

No malaria 87% 18% 1.4% 1.7% 13% 8%n=18,426Any antimalarial 84% 8.6% 1.5% 2.8% 17% 10%n=3,664Artemisinin 87% 5.3% 1.5% 1.8% 20% 15%n=954

1st trimester Artemisinins

• Studies in animalsFetal resorptionCardiac & limb malformations

• Antimalarials with teratogeniceffects in animals:Chloroquine –ratMefloquine - rats, mouse & rabbitPyrimethamine - rat mouse rabbit pig & hamster Quinine - rabbit pig & chinchilla.

ControlControl

DHA 0.05 µg/mLDHA 0.05 µg/mL

DHA 0.1 µg/mLDHA 0.1 µg/mL

Control

DHA 0.05 µg/mL

DHA 0.1 µg/mL

Ectoplacentalcone

1st trimester pregnancy exposures

• 111 Artemisinin treatmentsAS7 71% (79)ACT (> 80% MAS3) 29% (32)

• 108 womenAge yrs median [range] 23.5 [14-43]Primigravida 24% (26)Re-treatment previous episode 65% (70)Fever or history of fever 72% (72)Hyperparasitaemia/ severe 20% (21)Threatened abortion before treatment 11% (12)

1st trimester pregnancy outcomes

• 108 women with 8 women lost to follow-upFor the remainder, 100:

68 delivered32 spontaneous abortions (12 inevitable)

• ABORTION RATES (if enrolled in 1st trimester)NO MALARIA 15% (450/4,474)CHLOROQUINE 18% (13/72)QUININE 25% (31/124)ARTEMISININ 32% (32/100)

P=0.3

Outcome of pregnancy according week treatment

EGA (weeks) artemisinin

11-129-107-85-63-40-2

Num

ber

of w

omen

with

pre

gnan

cy o

utco

me

40

30

20

10

0

DELIVERED

ABORTED

% Abortions

<6.0 wks= 35.0%(7/20)

6.0 - <13 wks= 31.3%

(35/80)

P=0.792

1st trimester pregnancy outcomes

• 68 DELIVERED; no stillbirths

• EGA 39.6 [32.5-42.5] wks:10.3% (7/68) premature

• Mean birth weight 2762 [1,380-3,900] grams23.5 % (12/51) low birth weight

• 2 congenital abnormalities: syndactyly, dermoidcyst

Pharmacocinétique

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parameter DHA ATVQ ProguanilCmax 9 2.7 1.3 LOWERAUC 4 4.6 1.6 IN PW

Vd/F 2.3 2.2 1.1 LOWER Cl/F 2.7 2.8 1.6 IN NON-PW

McGready et al., Eur J Clin Pharmacol 2003; 59: 553-537

McGready et al., Eur J Clin Pharmacol 2003; 59: 545-552

McGready et al., Eur J Clin Pharmacol 2005; in press

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For A and P: increase in Vd can be pregnancy related and / or related to decrease oral bioavailability (lower fraction of drug absorbed)

• Proguanil– One compartment– Water soluble, 75%

bound– Metabolism: CYP2C19

(hormonal changes)– Vd increases with GA– Faster clearance– PW: lower Cmax and

AUC

• Atovaquone– One compartment– Lipophilic, 99% bound– Variable absorption,

increased by fats– Excretion: bile, faeces– Cl and Vd increased

with parasitaemia (disease effect)

– Vd increased with GA– Longer half life

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T1/2: 49 h vs 77 h

Problems with existing data

• Too few, many drugs not studied (SP…).• No adequate comparators• Different analytical methods• Do not systematically address the effect of

malaria (disease), protein binding, changes in oral bioavailability

What is needed?

• Data on CQ, Q, SP, AQ, Dapsone(Lapdap), Lumefantrine, Artesunate, Piperaquine

• Relative impacts of disease, pregnancy and food

• Standardization of methods and assays• Studies: optimization of dose for treatment

(and IPT)

Summary artemisinins in pregnancy

• WHO Guidelines:ARTEMISININS can be used in pregnancySevere malaria: life savingUncomplicated malaria when there is no suitable alternative e.g drug resistance with surveillance.

• Urgent need to optimize the treatment of malaria in pregnancy

• ACT Candidate drugs: coartemether and artekin

Lancet 2005;366:717 –25. SEAQUAMAT group*

Atovaquone and proguanil pk in pregnancy

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