Table 1.

Population PK and PK/PD models of partners drugs in vulnerable population after malaria treatment with ACTs

Country, year	Population	No. of participants	PK covariate(s) found	Drug exposure target used for dose optimization	PK/PD relationship from study data	Dosing recommendations
Lumefantrine
Multi‐country (meta‐analysis), 2018 15	Adults and children including pregnant women	4,122	Lumefantrine bioavailability decreased when parasitemia was detected and there was dose‐limiting absorption	Day 7 LUM concentrations from non‐pregnant adults for dose optimization	Insufficient power for recrudescent infection to identify population specific associations	Twice daily dosing for 5 days would improve day 7 LUM levels for children
Uganda, 2016 30	Children 6 months to 2 years	105	CL allometrically increased with weight, lower age had lower relative bioavailability	A day 7 LUM capillary concentration < 200 ng/mL	A day 7 LUM concentration < 200 increased hazard of 28‐day recurrent parasitemia by 3‐fold	Children < 2 had suboptimal concentrations (median 7‐day of 216) but new regimens were not recommended
Tanzania, 2014 64	Pregnant and nonpregnant women	55	34% Lower bioavailability and 78% higher clearance during pregnancy	Literature derived LUM targets used (50, 175, 280, 600 ng/mL) for day 7 simulations.	Four‐fold increased odds of recurrent malaria in pregnant women after AL	6 doses over 5 days predicted to decrease the number of individuals below the LUM targets
Tanzania, 2013 27	Adults, pregnant women, and children (1–78 years)	143	CL allometrically increased with weight	Literature derived LUM targets used (50, 175, 280, 600 ng/mL) for day 7	Not evaluated	6 doses over 5 days predicted to decrease the number of individuals below the LUM targets
Papua New Guinean, 2011 29	Children 5 to 10 years	13	Weight effect on CL, lower LUM exposure was observed in small children (15–35 kg)	Not evaluated	Lower average LUM AUC among children with recurrent infection children	Not evaluated
Mali & Niger, 2019 73	Children age 5‐59 months with and without severe acute malnutrition	397	Malnutrition measured by MUAC lowered LUM bioavailability by 25.4% per decrease in MUAC Age (maturation effect) and weight (allometric scaling) increased CL	LUM AUC, day 7 concentration and Cmax values reported in non‐SAM children	SAM children had reduced LUM exposure and increased risk of new infections	6 doses over 5 days or 9 doses over 3 days predicted to result in equivalent exposure in non‐SAM and SAM children
Multi‐country (meta‐analysis) 2007 54	Nonpregnant adults HIV‐malaria co‐infected, malaria‐infected and HIV‐infected	793	CL allometrically increased with weight Lopinavir/ritonavir: 50.1% slower clearance 67.2% increased bioavailability 47.6% reduction in absorption rate Efavirenz: 89.9% increased clearance	Literature derived LUM target of 200 ng/mL for day 7 simulations.	Not evaluated	Extending treatment over 5 or 6 days was predicted to increase lumefantrine exposure for patients on efavirenz No changed need for lopinavir/ritonavir
Tanzania, 2015 53	HIV‐malaria co‐infected adults	269	Efavirenz 58% lower bioavailability Nevirapine: 32% increased bioavailability	Literature derived LUM target of 280 ng/mL for day 7 simulations.	Not evaluated	6 doses over 5 days predicted to decrease the number of individuals below the LUM targets for efavirenz patients
Uganda, 2015 51	HIV‐infected adults	89	Efavirenz 72.6% increased clearance Lopinavir/ritonavir: 62.1% decreased clearance Nevirapine: 24.8% decreased clearance	Literature derived LUM targets used (175, 280, ng/mL) for day 7	Not evaluated	Extending treatment over 7 days was recommended to increase lumefantrine exposure for patients on efavirenz
Piperaquine
Multi‐country (meta‐analysis) 2017 16	Adults and children including pregnant women	728	CL increased by age (maturation effect) and allometrically by weight. Dose‐occasion impacted bioavailability.	Non‐pregnant adult median day 7 PQ concentrations	Not evaluated	Increased dose and increased bands for weight‐band dosing of children < 25 kg
Uganda, 2015 23	Children 6 months to 2 years	107	CL increase by age (maturation effect) and allometrically by weight. There was lower exposure in low weight for age children.	Literature derived 57 ng/mL capillary PQ concentration on day 7	Not evaluated	1.5‐2 times dosing for each weight band from 6 months to 2 years, but recommended further QT evaluation of these regimens
Cambodia, 2013 27	Adults and children (7–53 years)	60	CL allometrically increased with weight	Not evaluated	Not evaluated	Not evaluated
Burkina Faso, 2012 10	Children 2 to 10 years	236	CL allometrically increased with weight, despite increased weight‐normalized PQ dose, young children had lower day 7 PQ concentrations.	Literature derived 30 ng/mL venous transformed to 57 ng/mL capillary PQ concentration on day 7	5.9% increased risk of recurrent malaria for each 1 ng/m decrease in day 7 capillary drug concentrations.	30 mg/kg/day dose in children < 34 kg decreased percentage of children with day 7 PQ concentration < 57 ng/mL from up to 45% to < 20%
Papua New Guinean, 2012 24	Children 5 to 10 years	34	CL allometrically increased with weight	Not evaluated	Lower PQ average AUC among children with recurrent infection (n = 8 children)	No model‐based changes recommended
Cambodia, 2004 25	Children 2 to 10 years and adults > 16 years	85	Separate models for adults and children, clearance 2 times higher for children compared with adults.	Not evaluated	Underpowered (high cure rates) to detect associations.	No model‐based changes recommended.

ACT, artemisinin‐based combination therapy; AL, artemether‐lumefantrine; AUC, area under the curve; CL, clearance; C_max, peak concentration; LUM, lumefantrine; MUAC, mid‐upper arm circumference; PD, pharmacodynamic; PK, pharmacokinetic; PQ, piperaquine; SAM, severe acute malnutrition.