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Table 1 Overview and summary of included studies

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

Author (year) Country
(time period)
Type of study Study population Drug (dose) Number of women Pharmacokinetic analytic methodology Pharmacokinetic variables Remarks
Benjamin (2015) [56] Papua New Guinea (not reported) Clinical trial Pregnant women with an EGA >14 weeks without severe malaria or other significant comorbidities and age-matched non-pregnant women without severe malaria and significant comorbidities DHA-PPQ (7/58 mg/kg q.d. for 3 days)
OR
PPQ (1280 mg p.o. q.d. for 3 days) + SP (25 mg/kg once with first dose of PPQ)
32 pregnant women
33 non-pregnant women
Compartmental CL/F, Vc/F, Vp/F, t1/2, AUC0-∞  
Valea (2014) [33] Burkina Faso (Sept 2008Jan 2009) Clinical trial Pregnant women in second and third trimester of pregnancy with uncomplicated Plasmodium falciparum mono-infection and matched non-pregnant women with P. falciparum infection Mefloquine + Artesunate (8/3.6 mg/kg q.d. for 3 days) 24 pregnant women
24 non-pregnant women
Non-compartmental analysis Total dose, Cmax, Cmax/dose, Tmax, CL/F, V/F, t1/2, AUC0-last, AUC0-∞, AUC-∞/dose  
Tarning (2013) [37] 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 the 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
Non-compartmental 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) [38]
Nested in larger efficacy/safety study by Piola (2010) [19]
Adam (2012) [55] Sudan (Aug 2007Feb 2008) Clinical trial Pregnant women in 2nd and 3th 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
Non-compartmental 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) [53]
Hoglund (2012) [53] Sudan (Aug 2007Feb 2008) Clinical trial Pregnant women in 2nd and 3rd 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) [55]
McGready (2012) [51] Thailand (April 2008March 2008) 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
Non-compartmental analysis Total dose, Cmax, Cmax/dose, Tmax, CL/F, V/F, t1/2, AUC0-∞, AUC0-∞/dose  
Tarning (2012-1) [34] 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) [10]
Tarning (2012-2) [36] 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) [19]
Tarning (2012-3) [38] Thailand (Oct 2007May 2008) Clinical trial Pregnant women in second and third trimesters of pregnancy with acute P. vivax mono-infection 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) [40]
Morris (2011) [46] 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) [41]
Onyamboko (2011) [41] 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
Non-compartmental analysis Total dose, Cmax, Tmax, CL/F, V/F, t1/2, AUC0-∞ Based on the same clinical study as Morris (2011) [46]
Rijken (2011-1) [40] Thailand (Oct 2007May 2008) Clinical trial Pregnant women in second and third trimesters of pregnancy with acute P. vivax mono-infection 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
Non-compartmental 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) [38]
Rijken (2011-2) [39] 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
Non-compartmental 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 [34]
Nyunt (2010) [42] 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  
Piola (2010) [19] 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 Non-compartmental analysis Day 7 concentration Based on the same clinical study as Tarning (2012-2) [36] and Tarning (2013) [37]
Karunajeewa (2009) [52] Papua New Guinee (Feb 2006July 2006) Clinical trial Pregnant women in second or third trimester of pregnancy without severe malaria (n = 17: P. falciparum/P. vivax/P. 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-∞  
Tarning (2009) [35] 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) [18]
McGready (2008) [18] 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 Non-compartmental analysis Day 7 concentration Based on the same clinical study as McGready (2006-2) [49] and Tarning (2009) [35]
Green (2007) [54] Kenya (19992000) Clinical trial Primi- and secondi gravid 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-∞  
McGready (2006-1) [47] 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 Non-compartmental and compartmental analysis Total dose, Cmax, Tmax, CL/F, V/F, t1/2, AUC48-72  
McGready (2006-2) [49] 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 Non-compartmental and compartmental analysis Total dose, Cmax, Tmax, CL/F, V/F, t1/2, AUC0-24, AUC 60-84, AUC/dose  
Na Bangchang (2005) [22] Thailand (Nov 2000–April 2001) Clinical trial Pregnant women in third trimester of pregnancy with acute symptomatic P. falciparum mono-infection and Hb > 8 g/dL AP (1000/400 mg p.o. q.d. for 3 days) 26 pregnant women Compartmental analysis Cmax, Tmax, AUC0-∞, PG-CG ratio  
McGready (2003-1) [23] Thailand (not reported) Clinical trial Pregnant women in second or third trimester of pregnancy with recrudescent multi-drug resistant 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) + 300 ml chocolate milk (8 % fat) 24 pregnant women Non-compartmental and compartmental analysis Cmax, Tmax, CL/F, V/F, AUC0-∞, AUC48-∞  
McGready (2003-2) [24] Thailand (not reported) Clinical trial Healthy pregnant women with an EGA > 35 weeks and same women post partum (>2 months) Proguanil (200 mg p.o. once) 45 pregnant women
45 postpartum women
Non-compartmental analysis Total dose, Cmax (plasma and urine), 6 h concentration (plasma and urine)  
Na Bangchang (1994) [44] 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  
Wangboonskul (1993) [32] Thailand (not reported) Clinical trial Pregnant women in third trimester of pregnancy without P. falciparum malaria and same women post partum (>2 months) without P. falciparum malaria and healthy adult male volunteers without P. falciparum malariaa Proguanil (200 mg p.o. once) 10 pregnant women
4 postpartum women
9 male patientsa
Compartmental analysis Cmax, Tmax, CL/F, t1/2, AUC  
Nosten (1990) [43] 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  
  1. q.d. once a day, b.i.d. twice a day, t.i.d. three times a day, p.o. per os (oral), i.v. intravenous, AL artemether-lumefantrine, DHA-PPQ dihydroartemisinin-piperaquine, SP sulfadoxine-pyrimethamine, AP atovaquone-proguanil, PG proguanil, CG cycloguanil, C max maximum concentration after administration, T max time to maximum concentration after administration, CL/F oral clearance, V/F apparent volume of distribution, Vc/F central volume of distribution, Vp/F peripheral volume of distribution, T 1/2 half-life, AUC area under the curve (exposure), Hb haemoglobin, Ht haematocrit
  2. aData for male subjects were included from a previous study for comparison [60]