Skip to main content

Table 2 Primary study outcomes per compound

From: The influence of pregnancy on the pharmacokinetic properties of artemisinin combination therapy (ACT): a systematic review

Author (year) Country (time period) Population Drug (dose) Number of women Result
Artemether
 Tarning (2013) Uganda (Oct 2006May 2009) Pregnant women with uncomplicated P. falciparum infection with an EGA > 13 weeks and non-pregnant women matched for history of fever, temp. >37.5 °C, smoking status and level of parasitaemia AL (80/480 mg p.o. b.i.d. for 3 days) + 200 ml milk tea 21 pregnant women Estimated exposure to artemether and DHA was similar to that previously reported in pregnant Thai patients and lower than reported in adult non-pregnant Thai patients
 Tarning (2012-2) Uganda (March 2008Sept 2008) Pregnant women in second and third trimester of pregnancy (EGA > 13 weeks) with uncomplicated P. falciparum malaria AL (80/480 mg p.o. b.i.d. for 3 days) + 200 ml milk tea 21 pregnant women No statistically significant differences in pharmacokinetic properties between second and third trimester
 McGready (2006-2) Thailand (April 2004Aug 2004) Pregnant women in the second and third trimester of pregnancy with recrudescent uncomplicated multi-drug resistant P. falciparum malaria after 7-day quinine treatment AL (80/480 mg p.o. b.i.d. for 3 days) + 250 ml chocolate milk (7 g fat) 13 pregnant women No significant differences in the pharmacokinetic parameters of artemether and DHA between the second and third trimester. Comparison with data from literature showed a lower AUC and Cmax of artemether compared to male Thai patients and of DHA compared to non-pregnant patients
Author (year) Country (time period) Type of study Population Drug (dose) Number of women Pharmacokinetic analytic methodology Pharmacokinetic variables Remarks
Artesunate
 Kloprogge (2015) Thailand (April 2008March 2009) Clinical trial Pregnant women in second and third trimester of pregnancy (Ht > 25 %) with uncomplicated P. falciparum malaria and the same women post partum (3 months) without malaria Group 1
Artesunate (4 mg/kg) i.v. q.d. on day 0; artesunate (4 mg/kg) p.o q.d. on day 1–6
Group 2
Artesunate (4 mg/kg) p.o. q.d. on day 0; artesunate (4 mg/kg) i.v. q.d. on day 1, artesunate (4 mg/kg) p.o. q.d. on day 2–6)
20 pregnant women
Group 1: 10 women
Group 2: 10 women
14 postpartum women
Compartmental analysis AUC0-12, Cmax, Tmax, t1/2, CL/F, Vd/F Based on the same clinical study as McGready (2012)
 Valea (2014) Burkina Faso (Sept 2008Jan 2009) Clinical trial Pregnant women in second and third trimester of pregnancy with uncomplicated P. falciparum monoinfection and matched non-pregnant women with P. falciparum infection Mefloquine + Artesunate (8/3.6 mg/kg q.d. for 3 days) 24 pregnant women
23 non-pregnant women
Noncompartmental analysis Total dose, Cmax, Cmax/dose, Tmax, CL/F, V/F, t1/2, AUC0-last, AUC0-∞, AUC-∞/dose  
 McGready (2012) Thailand (April 2008March 2009) Clinical trial Pregnant women in second and third trimester of pregnancy (Ht > 25 %) with uncomplicated P. falciparum malaria and the same women post partum (3 months) without malaria Group 1
Artesunate (4 mg/kg) i.v. q.d. on day 0; artesunate (4 mg/kg) p.o q.d. on day 1–6
Group 2
Artesunate (4 mg/kg) p.o. q.d. on day 0; artesunate (4 mg/kg) i.v. q.d. on day 1, artesunate (4 mg/kg) p.o. q.d. on day 2–6)
20 pregnant women
Group 1: 10 women
Group 2: 10 women
14 postpartum women
Noncompartmental analysis Total dose, Cmax, Cmax/dose, Tmax, CL/F, V/F, t1/2, AUC0-∞, AUC0-∞/dose Based on the same clinical study as Kloprogge (2015)
 Morris (2011) DRC (May 2007Nov 2008) Clinical trial Pregnant women in second (22–26 weeks) and third (32–36 weeks) trimester of pregnancy with asymptomatic P. falciparum parasitaemia (200–300,000 p/µL; Ht > 30 %) and same women post partum (3 months) with (n = 2) or without (n = 24) P. falciparum parasitaemia and non-pregnant female volunteers with asymptomatic P. falciparum parasitaemia (200–300,000 p/µL) Artesunate (200 mg) p.o. q.d. on day 0 + SP (1725 mg) p.o. q.d. on day 1 26 pregnant women
26 postpartum women
25 non-pregnant women
Compartmental analysis T1/2, CL/F, V/F Based on the same clinical study as Onyamboko (2011)
  Onyamboko (2011) DRC (May 2007Nov 2008) Clinical trial Pregnant women in second (22–26 weeks) and third (32–36 weeks) trimester of pregnancy with asymptomatic P. falciparum parasitaemia (200–300,000 p/µL; Ht > 30 %) and same women post partum (3 months) with (n = 2) or without (n = 24) P. falciparum parasitaemia and non-pregnant female volunteers with asymptomatic P. falciparum parasitaemia (200–300,000 p/µL) Artesunate (200 mg) p.o. q.d. on day 0 + SP (1725 mg) p.o. q.d. on day 1 26 pregnant women
26 postpartum women
25 non-pregnant women
Noncompartmental analysis Total dose, Cmax, Tmax, CL/F, V/F, t1/2, AUC0-∞ Based on the same clinical study as Morris (2011)
  McGready (2006-1) Thailand (Oct 2000July 2001) Clinical trial Pregnant women in second or third trimester of pregnancy with recrudescent uncomplicated P. falciparum malaria after 7-day quinine treatment and Ht > 25 % Artesunate-AP (4/20/8 mg/kg p.o. q.d. for 3 days) + 200 ml chocolate milk (8 % fat) 24 Noncompartmental and compartmental analysis Total dose, Cmax, Tmax, CL/F, V/F, t1/2, AUC48-72  
Dihydroartemisinin
 Benjamin (2015) Papua New Guinee (…) Clinical trial Pregnant women in second and third trimester of pregnancy (EGA > 14 weeks) and age-matched non-pregnant women with uncomplicated with malaria infection Group 1
DHA-PPQ (7/58 mg/kg p.o. q.d. for 3 days)
Group 2
PPQ (1280 mg p.o. q.d. for 3 days) + SP (25 mg/kg once)
32 pregnant women
33 non-pregnant women
Compartmental analysis MTT, NN, CL/F, Vc/F, Q/F, Vp/F, t1/2, AUC0-∞  
 Valea (2014) Burkina Faso (Sept 2008Jan 2009) Clinical trial Pregnant women in second and third trimester of pregnancy with uncomplicated P. falciparum monoinfection and matched non-pregnant women with P. falciparum infection Mefloquine + Artesunate (8/3.6 mg/kg q.d. for 3 days) 24 pregnant women
23 non-pregnant women
Noncompartmental analysis Total dose, Cmax, Cmax/dose, Tmax, CL/F, V/F, t1/2, AUC0-last, AUC0-∞, AUC-∞/dose  
 McGready (2012) Thailand (April 2008March 2009) Clinical trial Pregnant women in second and third trimester of pregnancy (Ht > 25 %) with uncomplicated P. falciparum malaria and the same women post partum (3 months) without malaria Group 1
Artesunate (4 mg/kg) i.v. q.d. on day 0; artesunate (4 mg/kg) p.o q.d. on day 1–6
Group 2
Artesunate (4 mg/kg) p.o. q.d. on day 0; artesunate (4 mg/kg) i.v. q.d. on day 1, artesunate (4 mg/kg) p.o. q.d. on day 2–6)
20 pregnant women
Group 1: 10 women
Group 2: 10 women
14 postpartum women
Noncompartmental analysis Total dose, Cmax, Cmax/dose, Tmax, CL/F, V/F, t1/2, AUC0-∞, AUC0-∞/dose Based on the same clinical study as Kloprogge (2015)
 Tarning (2012-1) Thailand (June 2008Dec 2008) Clinical trial Pregnant women in second and third trimester of pregnancy (Ht > 25 %) with uncomplicated P. falciparum malaria and matched non-pregnant women with P. falciparum malaria DHA-PPQ (6.4/51.2 mg/kg p.o. q.d. for 3 days) 24 pregnant women
24 non-pregnant women
Compartmental analysis Cmax, Tmax, CL/F, V/F, t1/2, AUC0-24, AUC0-92, day 7 and 28 concentration Based on the same clinical study as Rijken (2011-2)
 Tarning (2012-2) Uganda (March 2008Sept 2008) Clinical trial Pregnant women in second and third trimester of pregnancy (EGA > 13 weeks) with uncomplicated P. falciparum malaria AL (80/480 mg p.o. b.i.d. for 3 days) + 200 ml milk tea 21 pregnant women Compartmental analysis Total dose, Cmax, Tmax, CL/F, V/F, t1/2, AUC60-last, AUC/dose Nested in larger efficacy study by Piola (2010)
 Morris (2011) DRC (May 2007Nov 2008) Clinical trial Pregnant women in second (22–26 weeks) and third (32–36 weeks) trimester of pregnancy with asymptomatic P. falciparum parasitaemia (200–300,000 p/µL; Ht > 30 %) and same women post partum (3 months) with (n = 2) or without (n = 24) P. falciparum parasitaemia and non-pregnant female volunteers with asymptomatic P. falciparum parasitaemia (200–300,000 p/µL) Artesunate (200 mg) p.o. q.d. on day 0 + SP (1725 mg) p.o. q.d. on day 1 26 pregnant women
26 postpartum women
25 non-pregnant women
Compartmental analysis T1/2, CL/F, V/F Based on the same clinical study as Onyamboko (2011)
 Onyamboko (2011) DRC (May 2007Nov 2008) Clinical trial Pregnant women in second (22–26 weeks) and third (32–36 weeks) trimester of pregnancy with asymptomatic P. falciparum parasitaemia (200–300,000 p/µL; Ht > 30 %) and same women post partum (3 months) with (n = 2) or without (n = 24) P. falciparum parasitaemia and non-pregnant female volunteers with asymptomatic P. falciparum parasitaemia (200–300,000 p/µL) Artesunate (200 mg) p.o. q.d. on day 0 + SP (1725 mg) p.o. q.d. on day 1 26 pregnant women
26 postpartum women
25 non-pregnant women
Noncompartmental analysis Total dose, Cmax, Tmax, CL/F, V/F, t1/2, AUC0-∞ Based on the same clinical study as Morris (2011)
 Rijken (2011-2) Thailand (June 2008Dec 2008) Clinical trial Pregnant women in second and third trimester of pregnancy (Ht < 25 %) with uncomplicated P. falciparum malaria and matched non-pregnant women with P. falciparum malaria DHA-PPQ (6.4/51.2 mg/kg p.o. q.d. for 3 days) 24 pregnant women
24 non-pregnant women
Noncompartmental analysis Total dose, Cmax, Cmax/dose, CL/F, V/F, t1/2, AUC0-last, AUC0-∞, AUC0-∞/dose, AUC0-24, AUC24-48, AUC48-72, AUC72-∞, day 7, 14 and 28 concentration Based on the same clinical study as Tarning (2012-1)
 McGready (2006-1) Thailand (Oct 2000July 2001) Clinical trial Pregnant women in second or third trimester of pregnancy with recrudescent uncomplicated P. falciparum malaria after 7-day quinine treatment and Ht > 25 % Artesunate-AP (4/20/8 mg/kg p.o. q.d. for 3 days) + 200 ml chocolate milk (8 % fat) 24 Noncompartmental and compartmental analysis Total dose, Cmax, Tmax, CL/F, V/F, t1/2, AUC48-72  
 McGready (2006-2) Thailand (April 2004Aug 2004) Clinical trial Pregnant women in the second and third trimester of pregnancy with recrudescent uncomplicated multi-drug resistant P. falciparum malaria after 7-day quinine treatment AL (80/480 mg p.o. b.i.d. for 3 days) + 250 ml chocolate milk (7 g fat) 13 pregnant women Noncompartmental and compartmental analysis Total dose, Cmax, Tmax, CL/F, V/F, t1/2, AUC0-24, AUC60-84, AUC/dose  
Lumefantrine
 Kloprogge (2013) Uganda (March 2008Sept 2008) Clinical trial Pregnant women in second and third trimester of pregnancy (EGA > 13 weeks) with uncomplicated P. falciparum malaria AL (80/480 mg p.o. b.i.d. for 3 days) + 200 ml milk tea 115 pregnant women
26 venous samples
89 capillary samples
17 non-pregnant women
(all venous samples)
Compartmental analysis AUC0-∞, Cmax, T1/2, day 7 concentration Nested in larger efficacy/safety study by Piola (2010)
 Tarning (2013) Uganda (Oct 2006May 2009) Clinical trial Pregnant women with uncomplicated P. falciparum infection with an EGA > 13 weeks and non-pregnant women matched for history of fever, temp. >37.5 °C, smoking status and level of parasitaemia AL (80/480 mg p.o. b.i.d. for 3 days) + 200 ml milk tea
OR
Quinine (10 mg/kg p.o. t.i.d. for 7 days)
AL:
21 pregnant women
Lumefantrine:
26 pregnant women
17 non-pregnant women
Quinine:
21 pregnant women
Noncompartmental analysis Total dose, Cmax, Cmax/dose, Tmax, CL/F, V/F, t1/2, AUC0-last, AUC0-∞, AUC-∞/dose, AUC72-last, AUC72-∞, day 7 concentration Results for artemether and dihydroartemisinin are reported by Tarning (2012-2).
Nested in larger efficacy/safety study by Piola (2010)
 Piola (2010) Uganda (Oct 2006May 2009) Clinical trial Pregnant women with uncomplicated P. falciparum infection (<250,000 p/µL) with an EGA > 13 weeks and Hb > 7 g/dL AL (80/480 mg p.o. b.i.d. for 3 days) + 200 ml milk 97 pregnant women Noncompartmental analysis Day 7 concentration Based on the same clinical study as Tarning (2012-2) and Tarning (2013)
 Tarning (2009) Thailand (not reported) Clinical trial Pregnant women in second or third trimester of pregnancy with uncomplicated symptomatic P. falciparum malaria AL (80/480 mg p.o. b.i.d. for 3 days) + 200–250 ml chocolate milk (6-7 g fat) 103 pregnant women Compartmental analysis Total dose, CL/F, V/F, day 7 concentration Nested in larger efficacy/safety study by McGready (2008)
 McGready (2008) Thailand (April 2004Aug 2006) Clinical trial Pregnant women in second or third trimester of pregnancy with acute uncomplicated P. falciparum malaria AL (80/480 mg p.o. b.i.d. for 3 days) + 250 ml chocolate milk (7 g fat) 85 pregnant women Noncompartmental analysis Day 7 concentration Based on the same clinical study as McGready (2006-2) and Tarning (2009)
 McGready (2006-2) Thailand (April 2004Aug 2004) Clinical trial Pregnant women in the second and third trimester of pregnancy with recrudescent uncomplicated multi-drug resistant P. falciparum malaria after 7-day quinine treatment AL (80/480 mg p.o. b.i.d. for 3 days) + 250 ml chocolate milk (7 g fat) 13 pregnant women Noncompartmental and compartmental analysis Total dose, Cmax, Tmax, CL/F, V/F, t1/2, AUC0-24, AUC 60-84, AUC/dose  
Amodiaquine
 Tarning (2012-3) Thailand (Oct 2007May 2008) Clinical trial Pregnant women in second and third trimesters of pregnancy with acute P. vivax monoinfection and same women post partum (84–173 days) with (n = 7) or without (n = 12) P. vivax malaria Amodiaquine (10 mg/kg p.o. q.d. for 3 days) 27 pregnant women
19 postpartum women
Compartmental analysis Cmax, Tmax, t1/2, AUC-last Based on the same clinical study as Rijken (2011-1)
 Rijken (2011-1) Thailand (Oct 2007May 2008) Clinical trial Pregnant women in second and third trimesters of pregnancy with acute P. vivax monoinfection and same women post partum (84–173 days) with (n = 7) or without (n = 12) P. vivax malaria Amodiaquine (10 mg/kg p.o. q.d. for 3 days) 24 pregnant women
18 postpartum women
Noncompartmental analysis Total dose, Cmax, Cmax/dose, Tmax, CL/F, V/F, t1/2, AUC0-last, AUC0-∞, AUC0-∞/dose, day 7 concentration Based on the same clinical study as Tarning (2012-3)
Mefloquine
 Valea (2014) Burkina Faso (Sept 2008Jan 2009) Clinical trial Pregnant women in second and third trimester of pregnancy with uncomplicated P. falciparum monoinfection and matched non-pregnant women with P. falciparum infection Mefloquine + Artesunate (8/3.6 mg/kg q.d. for 3 days) 24 pregnant women
23 non-pregnant women
Noncompartmental analysis Total dose, Cmax, Cmax/dose, Tmax, CL/F, V/F, t1/2, AUC0-last, AUC0-∞, AUC-∞/dose  
 Na Bangchang (1994) Thailand (Sept 1986June 1988) Clinical trial Pregnant women in first (n = 2) and third (n = 7) trimester of pregnancy with P. falciparum parasitaemia and non-pregnant women matched for age with P. falciparum parasitaemia Mefloquine (15 mg/kg) 9 pregnant women
8 non-pregnant women
Compartmental analysis Total dose, Cmax, Tmax, CL/F, V/F, t1/2  
 Nosten (1990) Thailand (not reported) Clinical trial Pregnant women in third trimester of pregnancy Group 1:
Mefloquine (250 mg per week)
Group 2:
Mefloquine (125 mg per week)
20 pregnant women Compartmental analysis Cmax, Tmax, CL/F, t1/2, AUC  
Sulfadoxine-pyrimethamine
 Nyunt (2010) Mali, Mozambique, Sudan and Zambia (not reported) Clinical trial Pregnant women with an EGA 15–36 weeks without P. falciparum parasitaemia (Hb > 8 g/dL) and same women post partum (6–43 weeks) without P. falciparum parasitaemia and with Hb > 8 g/dL (Mali and Zambia)/postpartum women (>6 months) without P. falciparum parasitaemia and with Hb > 8 g/dL (Mozambique and Sudan) and matched non-pregnant women with acute uncomplicated falciparum malaria (Mozambique) SP (1500/75 mg p.o. once) 97 pregnant women
77 postpartum women
Compartmental analysis Total dose, Cmax, CL/F, V/F, t1/2, AUC0-∞, day 7 concentration  
 Karunajeewa (2009) Papua New Guinee (Feb 2006July 2006) Clinical trial Pregnant women in second or third trimester of pregnancy without severe malaria (n = 17: P. falciparum/vivax/malariae parasitaemia; n = 13: no parasitaemia) and matched non-pregnant women (n = 9: falciparum/vivax/malariae parasitaemia; n = 21: no parasitaemia) SP (1500/75 mg p.o. once) + Chloroquine (1350 mg p.o. q.d. for 3 days) 30 pregnant women
30 non-pregnant women
Compartmental analysis CL/F, V/F, t1/2, AUC0-∞  
 Green (2007) Kenya (19992000) Clinical trial Primi- and secundigravid women with uncomplicated singleton pregnancies with EGA 16–28 weeks and Hb > 8 g/dL without symptomatic malaria (n = 11: parasitaemic; n = 22: aparasitaemic) and same women post partum (2-3 months) without symptomatic malaria (n = 1: parasitaemic; n = 10: aparasitaemic) SP (1500/75 mg p.o. once) 33 pregnant women
16 HIV-positive
17 HIV-negative
11 postpartum women
6 HIV-positive
5 HIV-negative
Compartmental analysis CL/F, V/F, t1/2, AUC0-∞  
Piperaquine
 Benjamin (2015) Papua New Guinee (not reported) Clinical trial Pregnant women in second and third trimester of pregnancy (EGA > 14 weeks) and age-matched non-pregnant women with uncomplicated with malaria infection Group 1
DHA-PPQ (7/58 mg/kg p.o. q.d. for 3 days)
Group 2
PPQ (1280 mg p.o. q.d. for 3 days) + SP (25 mg/kg once)
32 pregnant women
33 non-pregnant women
Compartmental analysis MTT, NN, CL/F, Vc/F, Q/F, Vp/F, t1/2, AUC0-∞  
 Adam (2012) Sudan (Aug 2007Feb 2008) Clinical trail Pregnant women in second and third trimester of pregnancy (EGA 15–40 weeks) with uncomplicated P. falciparum malaria and Hb > 7 g/dL. and age- and weight-matched non-pregnant women with uncomplicated P. falciparum malaria DHA-PPQ (2.4/20 mg/kg q.d. for 3 days) 12 pregnant women
12 non-pregnant women
Noncompartmental analysis Total dose, Cmax (after dose 1, 2 and 3), Tmax (after dose 1, 2 and 3), CL/F, V/F, T1/2, AUC0-last, AUC0-∞, AUC-∞/dose, AUC0-24, AUC24-48, AUC48-72, AUC72-∞, day 7 and 14 concentration Based on the same clinical study as Hoglund (2012)
 Hoglund (2012) Sudan (Aug 2007Feb 2008) Clinical trial Pregnant women in second and third trimester of pregnancy (EGA 15–40 weeks) with uncomplicated P. falciparum malaria and Hb > 7 g/dL. and age- and weight-matched non-pregnant women with uncomplicated P. falciparum malaria DHA-PPQ (2.4/20 mg/kg q.d. for 3 days) 12 pregnant women
12 non-pregnant women
Compartmental analysis Cmax, Tmax, t1/2, AUC 48-90, AUC0-90, day 7 and 28 concentration Based on the same clinical study as Adam (2012)
 Tarning (2012-1) Thailand (June 2008Dec 2008) Clinical trial Pregnant women in second and third trimester of pregnancy (Ht > 25 %) with uncomplicated P. falciparum malaria and matched non-pregnant women with P. falciparum malaria DHA-PPQ (6.4/51.2 mg/kg p.o. q.d. for 3 days) 24 pregnant women
24 non-pregnant women
Compartmental analysis Cmax, Tmax, CL/F, V/F, t1/2, AUC0-24, AUC0-92, day 7 and 28 concentration Based on the same clinical study as Rijken (2011-2)
 Rijken (2011-2) Thailand (June 2008Dec 2008) Clinical trial Pregnant women in second and third trimester of pregnancy (Ht < 25 %) with uncomplicated P. falciparum malaria and matched non-pregnant women with P. falciparum malaria DHA-PPQ (6.4/51.2 mg/kg p.o. q.d. for 3 days) 24 pregnant women
24 non-pregnant women
Noncompartmental analysis Total dose, Cmax, Cmax/dose, CL/F, V/F, t1/2, AUC0-last, AUC0-∞, AUC0-∞/dose, AUC0-24, AUC24-48, AUC48-72, AUC72-∞, day 7, 14 and 28 concentration Based on the same clinical study as Tarning (2012-1)