Utilisation des derives de l'artemisinine pendant la grossesse
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Transcript of 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
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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Cmax et AUC: -50%
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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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Dihydroartemisinin pk in pregnancy
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