Table 2. Key findings in studies evaluating mother-to-infant transfer of antimalarials, antituberculosis, and drugs for neglected tropical diseases (NTDs).

Author	Study design, Population	Number of mothers (infants)	Dose	Time postpartum		Plasma samples (Breast milk)	PK Analysis	ClinPK Score (%)	Conclusion	Limitations
Piperaquine Moore et al [44].	Design: Randomized controlled trial evaluating pharmacokinetics and pharmacodynamics of dihydroartemisinin- piperaquine versus sulfadoxine pyrimethamine-piperaquine combinations for intermittent presumptive treatment Population: Pregnant and non-pregnant women (age- and community matched) with no evidence of severe malaria	27 (0)	320 mg at 0, 24, and 48 hours Standard treatment regimen	Not stated	Yes (Yes)		Compartmental	18/19 (94.7)	M:P ratio = 0.58 AID = 0.41 μg/kg/day RID = 0.004% Breast milk transfer after maternal treatment but exposure for breastfed infants appears safe.	Milk crematocrit was not estimated: Variability in breast milk concentration not evaluated. No infants enrolled
Primaquine Gilder et al [29].	Design: Observational study evaluation the use of standard radical primaquine regimen in preventing relapse of P. vivax malaria infection Population: Women aged ≥18 years old with a history of P. vivax infection and no prior radical cure, together with their breastfeeding healthy (no P. vivax malaria infection) infants	20 (20)	0.5 mg base/kg to nonfasted women once daily for 14 days Standard treatment	Not stated	Yes (Yes)		Non-compartmental	17/19 (89.5)	M:P ratio = 0.34 (0.12–0.64) on day 0; 0.37 (0.24–0.61) on day 13 AID: 2.98 (1.15–9.10) μg/kg on day 0; 2.58 (1.06–8.22) μg/kg RID: 0.618% (0.231–1.82) on day 0; 0.517% (0.212–1.64) on day 13 Low breast milk transfer, low chances of infant exposure. Treatment should not be withheld in breastfeeding mothers	Breast milk volume estimated rather than measured across study duration No infantpharmacokinetic data
Chloroquine Ogunbona et al [31].	Design: Observational study evaluating lactation pharmacokinetics and safety in breastfeeding infants when used for prophylaxis Population: Volunteer nursing mothers	11 (0)	Single oral dose of 600 mg base chloroquine Standard dose level for chemoprophylaxis	Not stated	Yes (Yes)		Non-compartmental	9/16 (56.3)	M:P ratio = 5.6 (3.8–9.0) AID = 4.4 ± 2.6 mg RID = 0.70% Breast milk concentrations were greater than plasma concentrations. The average M:P ratio at 24 hours was 6.6 ± 2.4. The peak concentration was 4.4 ± 2.6 mg/L	Limited blood/breast milk samples collected No infants enrolled
Chloroquine Edstein et al [32].	Design: Observational study evaluating lactation pharmacokinetics when used for prophylaxis Population: Volunteer non-breastfeeding mothers	3 (0)	Single oral dose of 600 mg base chloroquine	2–5 days postpartum	Yes (Yes)		Non-compartmental	12/18	M:P ratio = 1.96, 2.35, and 4.26 RID (%): 2.2, 2.9, 4.2 Chloroquine was excreted in breast milk at concentrations greater than that found in plasma	Limited blood/breast milk samples collected No infants enrolled
Quinine Phillips et al [40]	Design: Observational study evaluating the pharmacokinetics and breast milk excretion of quinine in pregnant and lactating women with falciparum malaria Population: Lactating mothers	30 (0)	10 or 20 mg/kg of quinine sulfate	Late pregnancy/Early postpartum (Exact time not stated)	Yes (Yes)		Non-compartmental	12/18	In 5 patients treated intravenously, the mean breast milk concentrations was 2.6 mg/L (range: 0.5–3.6) and mean M:P ratio was 0.21 (0.11–0.32) In 25 patients treated orally, the mean concentration was 0.5–8.0 mg/L and 0.31 (0.11–0.53) in 25 women who received oral treatment Estimated daily breast milk excretion less than 2–3 mg/day, RID (%) <1%	No infants enrolled in the study
Mefloquine Edstein et al [39]	Design: Observational study evaluating the breast milk excretion of mefloquine lactating women with falciparum malaria Population: Volunteer lactating mothers	2 (0)	250 mg	2–3 days postpartum	Yes (Yes)		Non-compartmental	14/18	The elimination in breast milk than in plasma The M:P ratio values of 0.16–0.13 after days and 0.27 after 56 days RID of 3.8%.	Limited number of mothers (only 2) No infants included
Clindamycin Steen and Rane [41]	Design: Observational study evaluating the breast milk excretion of clindamycin in women treated for puerperal anaerobic infections. Population: Lactating mother who have just given birth but not breast feeding their infants	5 (0)	150 mg	One week postpartum	Yes (Yes)		Non-compartmental	9/18	Breast milk concentrations at the end of the dosing interval ranged from <0.5 μg/mL–3.1 μg/mL. No correlation between milk and plasma concentrations at the end of the dosing interval, however a strong correlated with the area under the plasma concentration-time curve	No infant included in the study
Bedaquiline Court et al [30].	Design: Observational study of pharmacokinetics in pregnancy and lactation Population: Pregnant women, aged ≥18 years treated for RR-TB, together with their breastfeeding infants	13 (13)	200 mg dosed 3 times a week, after the 2-week loading dose. Standard treatment	13 women (≥28 weeks) and 6 women (6 weeks postpartum)	Yes (Yes)		Compartmental analysis	15/17 (88.2)	M:P ratio = 13.6 (% RSE = 10.1) for bedaquiline and 4.84 (RSE = 5.10) for the metabolite AID = 0.816 mg/kg/day for bedaquiline and 0.07/mg/kg/day for the metabolite RID = 66.9% The drug significantly accumulates in breast milk; breastfed infants receive mg/kg doses equivalent to maternal doses.	Unbound drug concentrations or albumin levels were not measured, possibly leading to low plasma concentrations. High rate of participant loss to follow up limiting sample size. Limited infant pharmacokinetic data, based on only 4 infants.
Isoniazid Singh et al [42].	Design: Observation study of lactation pharmacokinetics for mothers on standard anti tuberculosis treatment Population: Lactating women with tuberculosis, aged 18–28 years	7 (0)	300 mg single dose daily Standard treatment	Not stated	Yes (Yes)		Compartmental	15/19 (78.9)	M:P ratio = 0.89 (95% CI: 0.70–1.1) AID = 89.9 μ/kg/day (95% CI: 65.6–114) RID = 1.2% (95% CI: 0.9, 1.5) The data suggest that isoniazid therapy is safe during breastfeeding	Few mothers included in the study No infants enrolled
Benznidazole Garcia-Boumissen et al [27].	Design: Observational study of lactation pharmacokinetics and the risk of infant exposure Population: Lactating women with chronic Chagas disease aged 20–34 years	10 (10)	5–8 mg/kg/day twice daily for 30 days Standard treatment	Not stated	Yes (Yes)		Non-compartmental	13/17 (76.5)	M:P ratio = 0.52 (0.3–2.79) AID = 0.65 mg/kg/day RID = 12.3% (5.5–17.0) Limited drug exposure in breast milk hence may be compatible with breast feeding	No infant pharmacokinetic data Small number of infants were enrolled hence not possible to accurately evaluate adverse effects in infants
Nifurtimox Moroni et al [28].	Design: Observational study of lactation pharmacokinetics and safety Population: Lactating women with chronic Chagas disease age 17–36 years	10 (10)	8–12 mg/kg/day Standard treatment	Not stated	Yes (Yes)		Non-compartmental	12//18	M:P ratio = 16 (8.75–30.3) AID = 0.50 mg/kg/day (IQR: 0.20–0.69) RID = 6.70 (IQR: 2.35–7.19) Nifurtimox may be compatible with breastfeeding due to limited drug transfer into breast milk, and low overall infant exposure.	No infant pharmacokinetic data Few infants enrolled, hence not possible to accurate evaluate adverse effects
Albendazole Abdel-tawab et al [37].	Design: Observational study of lactation pharmacokinetics and infant exposure Population: Breastfeeding women aged 18–40 years in a lymphatic filariasis control program	33 (0)	400 mg Standard treatment	2 weeks to 6 months	Yes (Yes)		Non-compartmental	13/18 (72.2)	M:P ratio = 0.9 (0.2–6.5) for albendazole and 0.6 (0.1–1.5) for albendazole sulphoxide Albendazole (and the sulphoxide) attains low concentrations in breast milk unlikely to harm the breastfed infant	Limited (only one) maternal plasma concentration measured. No infants enrolled
Praziquantel Bustinduy et al [43].	Design: Randomized controlled trial for evaluating pharmacokinetics and safety of praziquantel in pregnancy Population: Lactating women infected with Schistosomiasis Japonicum	15 (0)	30 mg/kg twice over 4 hours Standard treatment with same overall dose	Not stated	Yes (Yes) 0.028		Compartmental analysis	18/20 (90)	M:P ratio = NE AID = 0.028 mg/kg/day RID = <0.05% Women in early pregnancy had increased clearance and lower exposure. Significantly lower breast milk exposure than the dose required for antischistosomal activity. Breastfeeding should not be stopped or delayed	No infants enrolled
Praziquantel Putter and Held [34]	Design: Randomized trial evaluating lactation pharmacokinetics of praziquantel at various dosing schedules Population: Healthy lactating women	10 (0)	50 mg/kg once (5 women); 20 mg/kg 3 times at 4-hour intervals (5 women) Standard treatment dose	Not stated	Yes (Yes)		Non-compartmental analysis (Exact method not stated)	10/16 (62.5)	The mean plasma exposure was 3.8 times the mean breast milk exposure. AID = 27.9 μg/day RID = 0.0007% Milk does not represent a deep distribution compartment but readily equilibrates with plasma. Equilibration obviously takes place by passive diffusion and not active secretion	No infants enrolled
Clofazimine Venkatesan et al [38].	Design: Observational study of lactation pharmacokinetics and infant exposure to clofazimine as part of multiple drug treatment Population: Female leprosy patients, aged 19–35 years	8 (0)	50 mg daily (5 women); 100 mg on alternate days (2 women); 100 mg daily (1 woman) Standard treatment	Not stated	Yes (Yes)		Non-compartmental	16/17 (94.1)	M:P ratio = 1.4 ± 0.08 at 4–6 hours after last daily dose AID = 0.199 ± 0.013 mg/kg/day RID = 22.11 ± 1.90% In spite significant breast milk exposure (infant ingestion of 0·225 mg/kg/day), discontinuation is not recommended in breastfeeding mothers till further toxicity studies	Plasma data only available at a single time point. No infants enrolled
Ivermectin Ogbuokiri et al [33].	Design: Controlled trial of lactation pharmacokinetics and infant exposure Population: Healthy mothers whose babies died at birth	4 (0)	150 μg/kg Standard treatment for river blindness	Not stated	Yes (Yes)		Non-compartmental	7/16 (43.8)	AID = 2.75 μg/kg RID = 2.75% Given the additional benefits of ivermectin and its tolerably, low levels in breast milk, exclusion of lactating mothers should be discontinued.	No infants included in the study. Mothers were not breastfeeding—did not sample mature milk
Azithromycin Sutton et al [36].	Design: randomized controlled trial evaluating perinatal pharmacokinetics of azithromycin after a single preincision administration Population: Women undergoing planned cesarean delivery at 37 weeks of gestation (or more)	30 (0)	500 mg	At delivery	Yes (Yes)		Compartmental (2-compartment model)	19/21 (90.5)	AID = 340 μg/day RID = 0.07% High and sustained breast milk concentrations obtained after a single dose. Accumulation of the drug in breast milk from simulation-based studies	No infants enrolled
Azithromycin Salman et al [35].	Design: randomized placebo -controlled Phase III trial of a single dose of azithromycin versus placebo for lactation pharmacokinetics and infant safety Population: Women in labor	20 (0)	2 g	Within 1 month postpartum	No (Yes)		Compartmental	16/18 (88.8)	AID = 0.7 mg/kg/day RID = 2.5% Breast milk exposure may exceed the nominal 10% safety limit in a large proportion of neonates even after a single dose	M:P ratio used was not derived from women in this study. More complex (mechanistic models) were not evaluable due to the limited data. No infants enrolled

AID, absolute daily infant dose; M:P, milk-to-plasma ratio; RID, relative infant dose.

The majority of these studies did not measure concentrations of the drugs in infant plasma limiting the characterization of the actual level of exposure in infants.