Utilisation des derives de l'artemisinine pendant la grossesse

37
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

Transcript of Utilisation des derives de l'artemisinine pendant la grossesse

Page 1: Utilisation des derives de l'artemisinine pendant la grossesse

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

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

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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%

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Conséquences de la chimiorésistance

Morbidité

Mortalité

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•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

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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

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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

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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

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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)

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Nouveau-nés et nourrissons

• Age gestationnel• Examen Neurologique

et développent des enfants jusqu’à 1 an

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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

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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.

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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

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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)

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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

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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

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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

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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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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

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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)

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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*

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