Table 2.
Primary study outcomes per compound
| Author (year) | Country (time period) | Population | Drug (dose) | Number of women | Result |
|---|---|---|---|---|---|
| Artemether | |||||
| Tarning (2013) | Uganda (Oct 2006 –May 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 2008–Sept 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 2004–Aug 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 2008–March 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 2008–Jan 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 2008–March 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 2007–Nov 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 2007–Nov 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 2000–July 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 2008–Jan 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 2008–March 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 2008–Dec 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 2008–Sept 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 2007–Nov 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 2007–Nov 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 2008–Dec 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 2000–July 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 2004–Aug 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 2008–Sept 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 2006–May 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 2006–May 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 2004–Aug 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 2004–Aug 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 2007–May 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 2007–May 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 2008–Jan 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 1986–June 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 2006–July 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 (1999–2000) | 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 2007–Feb 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 2007–Feb 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 2008–Dec 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 2008–Dec 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) |