Pharmacokinetic considerations in seasonal malaria chemoprevention

Abstract

In the Sahel region, more than 60% of the annual cases of malaria occur during the rainy season (approximately 3–4 months).Children under 5 years of age are the population most vulnerable to malaria infections and they are the recipients of seasonal malaria chemoprevention (SMC).Sulfadoxine-pyrimethamine plus amodiaquine comprise the only World Health Organization (WHO) recommended SMC, but increasing drug resistance threatens its future.Expanding the deployment of SMC to East and South-East Africa is under evaluation. This region has higher levels of drug resistance than the Sahel.Alternative SMCs are needed.A better understanding of the safety, pharmacokinetic and pharmacodynamic properties of potential SMC medicines, and the determinants of preventive efficacy, should guide the choice of drugs, dosing, and dosing intervals. African children under 5 years of age bear the main burden of global malaria mortality. Seasonal malaria chemoprevention (SMC) with sulfadoxine-pyrimethamine (SP) plus amodiaquine (AQ) given monthly during the rainy season is a highly effective malaria intervention for children aged between 3 months and 5 years living in the Sahel region, a region of intense but seasonal malaria transmission. This intervention is now being considered for other regions of Africa where malaria parasites are more drug resistant. Dihydroartemisinin-piperaquine (DP), an artemisinin-based combination therapy (ACT), has proved to be highly effective and well tolerated in intermittent preventive treatment in pregnant women and children. This combination may be a suitable alternative for SMC. Understanding the safety, pharmacokinetic and pharmacodynamic properties of antimalarial combination therapies is crucial in optimising dosing. African children under 5 years of age bear the main burden of global malaria mortality. Seasonal malaria chemoprevention (SMC) with sulfadoxine-pyrimethamine (SP) plus amodiaquine (AQ) given monthly during the rainy season is a highly effective malaria intervention for children aged between 3 months and 5 years living in the Sahel region, a region of intense but seasonal malaria transmission. This intervention is now being considered for other regions of Africa where malaria parasites are more drug resistant. Dihydroartemisinin-piperaquine (DP), an artemisinin-based combination therapy (ACT), has proved to be highly effective and well tolerated in intermittent preventive treatment in pregnant women and children. This combination may be a suitable alternative for SMC. Understanding the safety, pharmacokinetic and pharmacodynamic properties of antimalarial combination therapies is crucial in optimising dosing. Africa has the highest prevalence of malaria in the world. African children under 5 years of age are at highest risk of dying from falciparum malaria. Across the Sahel region, malaria is a highly seasonal disease with more than 60% of annual malaria cases in the region occurring during the 3–4 months rainy season [1.Cairns M. et al.Estimating the potential public health impact of seasonal malaria chemoprevention in African children.Nat. Commun. 2012; 3: 881Crossref PubMed Scopus (111) Google Scholar]. SMC (see Glossary) is defined as the administration of repeated treatment courses of antimalarial drugs during the high-transmission season. The optimal number of consecutive antimalarial treatment courses depends on local epidemiology. SMC aims to prevent malaria illness by maintaining sufficiently high antimalarial drug concentrations in the blood throughout the transmission period. As SMC is administered to healthy children, safety and tolerability are paramount – poorly tolerated medicines, such as artesunate-mefloquine, which has predictable central nervous system (CNS) adverse effects at treatment doses, cannot be used [2.Lee S.J. et al.Adverse effects of mefloquine for the treatment of uncomplicated malaria in Thailand: A pooled analysis of 19, 850 individual patients.PLoS ONE. 2017; 12e0168780Google Scholar]. Sulfadoxine-pyrimethamine plus amodiaquine (SPAQ), administered monthly for SMC to children aged between 3 and 59 months in the Sahel region, has been recommended by the World Health Organisation (WHO) since 2012 [3.World Health Organization WHO Policy Recommendation: Seasonal Malaria Chemoprevention (SMC) for Plasmodium falciparum malaria Control in Highly Seasonal Transmission Areas of the Sahel sub-Region in Africa.https://apps.who.int/iris/handle/10665/337978Date: 2012Google Scholar,4.World Health Organization Seasonal Malaria Chemoprevention with Sulfadoxine-Pyrimethamine Plus Amodiaquine in Children: a Field Guide. WHO, 2013Google Scholar]. Approximately 39 million children under 5 years of age live in these areas of seasonal malaria transmission in Africa, resulting in an estimated 33.7 million malaria episodes and 152 000 deaths from malaria each year. In 2020, 33.5 million of the children living across the Sahel region received at least one dose of SMC [5.World Health Organization World Malaria Report 2021. WHO, 2021Crossref Google Scholar]. Protective efficacy was estimated at 88.2% (95% CI: 78.7–93.8) [6.ACCESS-SMC Partnership Effectiveness of seasonal malaria chemoprevention at scale in west and central Africa: an observational study.Lancet. 2020; 396: 1829-1840Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar]. Eastern and Southern Africa also have seasonal malaria transmission, and SMC is now under evaluation in these regions, which have different population characteristics and higher levels of drug resistance than West Africa. Therefore, different treatment options and target populations for SMC need to be evaluated in these regions. Artemisinin-based combination therapies (ACTs) are under consideration as alternatives for SMC [7.World Health Organization Guidelines for the Treatment of Malaria. WHO, 2015Google Scholar]. The potent artemisinin derivative eliminates most of the malaria parasites in an infection, but the drug is cleared rapidly from the systemic circulation (terminal half-life of 1–2 h). The slowly eliminated antimalarial ACT partner drugs have lower potency (in terms of parasite killing), but they persist at parasiticidal concentrations for a substantially longer period of time (e.g., piperaquine has a terminal half-life of 20–30 days). This ensures cure of any drug-sensitive malaria infection and it also provides a lengthy post-treatment prophylactic effect. Artemether–lumefantrine is less suitable for SMC because of the substantially shorter terminal elimination half-life of lumefantrine (3–4 days), and its more complicated administration of twice-daily dosing given with food [8.Ashley E.A. et al.How much fat is necessary to optimize lumefantrine oral bioavailability?.Tropical Med. Int. Health. 2007; 12: 195-200Crossref PubMed Scopus (120) Google Scholar,9.Kloprogge F. et al.Artemether-lumefantrine dosing for malaria treatment in young children and pregnant women: a pharmacokinetic-pharmacodynamic meta-analysis.PLoS Med. 2018; 15e1002579Crossref PubMed Scopus (38) Google Scholar]. SMC aims to maintain effective antimalarial drug concentrations in the body throughout the high-transmission period to suppress newly acquired infections. Therefore, dosing regimens should be determined by drug-susceptibility of the parasites and the pharmacokinetic properties of the antimalarial drugs (i.e., drug absorption, distribution, metabolism, and elimination). Most antimalarial drugs have been shown to display a nonlinear relationship between bodyweight and exposure, resulting in a higher dose (mg/kg) needed for young children to achieve equivalent drug exposures [10.Tarning J. et al.Population pharmacokinetics and pharmacodynamics of piperaquine in children with uncomplicated falciparum malaria.Clin. Pharmacol. Ther. 2012; 91: 497-505Crossref PubMed Scopus (77) Google Scholar,11.Chotsiri P. et al.Optimal dosing of dihydroartemisinin-piperaquine for seasonal malaria chemoprevention in young children.Nat. Commun. 2019; 10: 480Crossref PubMed Scopus (20) Google Scholar]. Age can also have a profound impact on the exposure to drugs due to the enzyme maturation of drug metabolising enzymes during the first 2 years of of and in Pharmacol. PubMed Scopus Google of body and maturation to in PubMed Scopus Google Scholar]. (see in the which the pharmacokinetic and pharmacodynamic properties in populations (e.g., in young can be a guide to drug dosing. dosing regimens to maintain drug concentrations the concentrations for much of the malaria season in for effective with monthly it is blood concentrations the for the In the the drug levels may be to suppress parasite sufficiently to prevent parasites to concentrations at the of the dosing be to a antimalarial treatment during the and eliminated at the of the transmission infections at the of SMC should also be eliminated by the ACT treatment of repeated ACT as chemoprevention the risk of malaria and resistance antimalarial drug administration the risk of 2017; Full Text Full Text PDF PubMed Scopus Google Scholar]. A infection during SMC occur blood concentrations are pharmacokinetics the parasites have a higher since infections from a infection, the ACT used for the treatment of malaria should the slowly eliminated antimalarial used for SMC. The pharmacokinetic and pharmacodynamic properties of antimalarial are shown in et in target and J. 2017; PubMed Scopus Google Scholar]. The combination therapy for SMC be highly potent antimalarial with different of drugs should have terminal elimination for monthly dosing. different of and (i.e., time effective drug also the individual drugs from resistance resistance as a of which drug This the parasites to in the of drug resistance is more to in with high resistance is substantially less to during prophylactic therapy since the parasite is parasites from the during a with the treatment of malaria parasites in an antimalarial drug administration the risk of 2017; Full Text Full Text PDF PubMed Scopus Google Scholar]. such a and the resistance was to parasite exposure to an drug with a different of these parasites and prevent the newly parasites from a pharmacokinetic and pharmacodynamic of malaria adverse et in target and J. 2017; PubMed Scopus Google of of of of blood blood and to risk for resistance risk for resistance an to used in treatment of from Plasmodium Plasmodium infections (i.e., transmission food food with other – on between exposure at the effective dose and on the of on between exposure at the effective dose and safety – risk in – risk in of a for for under 2 for for under 2 of the under adverse in a The a (i.e., slowly antimalarial sulfadoxine-pyrimethamine amodiaquine and administration at monthly due to terminal elimination of in SMC from the artemisinin derivative to and and provides antimalarial for infections. infections at the of the rainy season are cleared are substantially to than the higher infections and any newly acquired infections are cleared by the drug concentrations the parasites are drug infections from drug as a of absorption, pharmacokinetic with oral are more to have in drug exposure, which to concentrations and infections. The SMC drugs are given to prevent malaria infections and can be at any of the infection (i.e., but antimalarial drugs are of these drugs are for on parasite in the malaria treatment in the pharmacokinetic properties of the of the and has been used as an antimalarial drug for of infection with parasites is of is well tolerated but by resistance resulting from of in the the target and are well oral have terminal elimination of for and for A of is by and et of in and 2 on the of artemisinin-based combination therapies in malaria from and PubMed Scopus Google Scholar]. is eliminated but of the to its terminal elimination is in the to and is The pharmacokinetic properties of and are and of the and with the elimination of and with but they of first of age et properties of and sulfadoxine-pyrimethamine given as intermittent preventive treatment in PubMed Scopus Google Scholar]. This in a and drug exposure in with of and is on body (see in the resulting in a higher in young children with children and This to a nonlinear relationship between drug exposure and bodyweight at target dose As a children need a higher dose with to achieve equivalent The pharmacokinetics are also by resulting in and lower for and in children with children M. et al.Population pharmacokinetic properties of and a pooled analysis to optimal dosing in African children with uncomplicated 2018; Scopus Google Scholar]. administered is well and rapidly its the et of in and 2 on the of artemisinin-based combination therapies in malaria from and PubMed Scopus Google Scholar]. has a terminal elimination half-life of has a terminal half-life of J. et al.Population pharmacokinetic and pharmacodynamic of amodiaquine and in women with Plasmodium malaria during and 2012; PubMed Scopus Google Scholar]. The enzyme is considered for of to a of and is eliminated in the The pharmacokinetic properties of and are by body and also display an enzyme maturation on elimination J. et and population pharmacokinetic properties of amodiaquine used for seasonal malaria chemoprevention in African Pharmacol. Ther. 2020; PubMed Scopus Google Scholar]. In SMC, is as a dose given for consecutive each amodiaquine is as a dose on the first of The of in children months of age is one each of and and in months of age it is of and is between the drugs, and are living with are should and on should This SMC is given for at least to monthly during the rainy season to children aged months Health Organization Seasonal Malaria Chemoprevention with Sulfadoxine-Pyrimethamine Plus Amodiaquine in Children: a Field Guide. WHO, 2013Google Scholar]. is less well tolerated than may be because of its is The risk of depends on the dose of Approximately and of children of and as an intermittent preventive treatment M. et and tolerability for intermittent preventive treatment to prevent malaria in PubMed Scopus Google Scholar]. in a of 000 children as SMC, only of children adverse of which and the most et of seasonal malaria chemoprevention (SMC) with sulfadoxine-pyrimethamine plus amodiaquine to children under years of age by health in from a ONE. Scholar]. from a SMC an which may have been to the SMC drug the and may in but in children years of age et effects of amodiaquine and an individual meta-analysis.PLoS Med. Scopus Google Scholar]. of drugs is because of the dose pooled pharmacokinetic in African children with uncomplicated falciparum malaria an dose in young children is needed to achieve an equivalent drug exposure with children and for and M. et al.Population pharmacokinetic properties of and a pooled analysis to optimal dosing in African children with uncomplicated 2018; Scopus Google et al.Population pharmacokinetics of the antimalarial a pooled analysis to optimize 2018; Scopus Google Scholar]. is to parasite but the period of post-treatment effect. This the of efficacy in the of high levels of are on infections with drug levels to the recommended need the first dose of monthly SMC with is a treatment by of the first dose the monthly A only of children the of months of J. et and population pharmacokinetic properties of amodiaquine used for seasonal malaria chemoprevention in African Pharmacol. Ther. 2020; PubMed Scopus Google Scholar]. A of intermittent preventive treatment in children in more than of children at least one dose of et to intermittent preventive treatment for malaria in A the ONE. 2019; PubMed Scopus Google Scholar]. A observational in African the of from in to (95% CI: in during [6.ACCESS-SMC Partnership Effectiveness of seasonal malaria chemoprevention at scale in west and central Africa: an observational study.Lancet. 2020; 396: 1829-1840Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar]. In 2020, million children in African received as SMC World Malaria Scholar]. The of the SMC at was estimated at 88.2% (95% CI: and the between and was estimated at (95% CI: [6.ACCESS-SMC Partnership Effectiveness of seasonal malaria chemoprevention at scale in west and central Africa: an observational study.Lancet. 2020; 396: 1829-1840Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar]. The combination of is a recommended ACT in the treatment of uncomplicated falciparum malaria. has shown efficacy and safety in the treatment of malaria and has been evaluated as a as it provides a post-treatment prophylactic effect. The antimalarial of the rapidly eliminated in infections during SMC, is has a elimination with a terminal half-life of 20–30 This for monthly dosing, and in of concentrations with repeated (approximately higher concentrations at with the first dosing M. et of an in relationship for piperaquine in malaria Med. PubMed Scopus Google Scholar]. piperaquine in pharmacokinetic resulting in in concentrations at the of each treatment is a highly and a the of piperaquine to which of the high and in exposure used as SMC. The elimination of piperaquine scale with resulting in lower exposures in children with at dosing, a higher dose (mg/kg) is recommended for young children. is eliminated This during the first 2 years of resulting in an of piperaquine in young children. A pharmacokinetic analysis of maturation was at a age of months (95% CI: et al.Population pharmacokinetic properties of piperaquine in falciparum an individual meta-analysis.PLoS Med. 2017; PubMed Scopus Google Scholar]. This in a exposure in at a concentrations (i.e., persist for 3–4 a can be used as in children and pregnant and have shown high antimalarial efficacy of with of et of dihydroartemisinin-piperaquine with sulfadoxine-pyrimethamine plus amodiaquine for seasonal malaria chemoprevention in PubMed Scopus Google et and safety of intermittent preventive treatment in with (SP) and plus piperaquine in of the a J. 2017; PubMed Scopus Google Scholar]. is recommended as a antimalarial treatment in any African is of artemisinin resistance in of East Africa, but malaria parasites to be et of Plasmodium falciparum with parasite in an efficacy Full Text Full Text PDF PubMed Scopus Google Scholar]. resistance has been in the African but is in the of piperaquine the is drug is with has also been shown to be more effective with other preventive efficacy Plasmodium falciparum infections (95% CI: for the monthly dose and (95% CI: for months M. et of an in relationship for piperaquine in malaria Med. PubMed Scopus Google et of monthly dihydroartemisinin-piperaquine chemoprevention in at high risk of 2012; PubMed Scopus Google Scholar]. A more dose of any prophylactic et of intermittent preventive treatment with dihydroartemisinin-piperaquine on malaria in a PubMed Scopus Google Scholar]. a treatment as a by a dose of efficacy by increasing piperaquine safety tolerability by piperaquine concentrations J. et of antimalarial chemoprevention with dosing of 2017; PubMed Scopus Google Scholar]. dosing also be more to (i.e., have less on with monthly dosing. of monthly dosing also need to be is is a alternative SMC and have the efficacy of monthly with efficacy was in children as SMC (i.e., for and for in and for and for in et of dihydroartemisinin-piperaquine with sulfadoxine-pyrimethamine plus amodiaquine for seasonal malaria chemoprevention in PubMed Scopus Google et of piperaquine with sulfadoxine-pyrimethamine for malaria intermittent preventive treatment in ONE. PubMed Scopus Google Scholar]. has been evaluated in children. was better tolerated than as it was with less in young children J. et safety, and tolerability of regimens for of a in ONE. PubMed Scopus Google Scholar]. The SMC should concentrations (i.e., with adverse effects throughout the malaria transmission season. drug regimens are more and but may be administration of and given as antimalarial in was with of and and should be dosing should achieve concentrations during the in at least of the target This of the pharmacokinetic and the terminal blood in different of with (e.g., and on levels of acquired and the P. falciparum drug properties can be evaluated infections (i.e., the in different of This is for in West Africa where preventive efficacy has been in the of of resistance [6.ACCESS-SMC Partnership Effectiveness of seasonal malaria chemoprevention at scale in west and central Africa: an observational study.Lancet. 2020; 396: 1829-1840Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar]. has been to an optimal dosing and efficacy of given as SMC in children P. et al.Optimal dosing of dihydroartemisinin-piperaquine for seasonal malaria chemoprevention in young children.Nat. Commun. 2019; 10: 480Crossref PubMed Scopus (20) Google Scholar]. The most vulnerable age the children under of have the least and the drug levels dosing, are in efficacy A dose throughout age and bodyweight in drug exposure in children due to the nonlinear relationship between drug exposure and Therefore, optimal dosing should be by dosing to bodyweight age to equivalent exposures in of of the efficacy of seasonal malaria chemoprevention are needed but they have been in the years since it was first in which drug and drug are and by are necessary to SMC preventive efficacy and for can be used to SMC regimens for different levels of and the dosing in each bodyweight population and of resistance (i.e., for need to be the SMC to the East and South-East African with seasonal malaria transmission aims to in children under 5 years of the higher levels of drug resistance a for SMC. have in treatment in region in The combination better it was but efficacy in the treatment of malaria and was to J. et safety, and tolerability of regimens for of a in ONE. PubMed Scopus Google et of malaria and efficacy of combination antimalarial therapies years in an of ONE. Scopus Google Scholar]. The preventive efficacy of SMC in East Africa is to be substantially better than the treatment efficacy due to the in parasite with but it be to be In Africa P. falciparum populations have to the in to et of Plasmodium falciparum malaria of in PubMed Scopus Google in these regions in in these regions the of parasites preventive efficacy is be the for these regions. SMC with seasonal malaria (i.e., has been shown to the efficacy of the SMC in West Africa et a potential for an malaria J. 2017; PubMed Scopus Google Scholar]. The antimalarial efficacy, to the and for have been SMC for antimalarial drug In a SMC antimalarial blood concentrations should prevent parasite and transmission of but the most infections [7.World Health Organization Guidelines for the Treatment of Malaria. WHO, 2015Google Scholar]. As the parasite from the are the is also of lower than an is resistance in the and SMC is (i.e., the most parasites can infections in the with the least and drug be the of is a risk of the SMC but should be a time of rapidly transmission – the of infection at time and transmission are This risk is different from with drug elimination treatment of malaria infections antimalarial drug administration the risk of 2017; Full Text Full Text PDF PubMed Scopus Google Scholar]. the with SMC increasing the of drug resistance was of an SMC in Africa, where parasite resistance to was [6.ACCESS-SMC Partnership Effectiveness of seasonal malaria chemoprevention at scale in west and central Africa: an observational study.Lancet. 2020; 396: 1829-1840Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar]. areas have different of population and local epidemiology. The target population and of SMC should be to the epidemiology. the SMC target population to children to years of age in South-East has been et malaria chemoprevention with of malaria in children under years of 5 in A Med. 2019; PubMed Scopus Google Scholar]. the target population for SMC to different regions children 5 years of age and SMC treatment on an understanding of its needed to maintain antimalarial drug concentrations with prophylactic efficacy throughout the season of high malaria transmission. Most have been estimated from in have to and P. et al.Optimal dosing of dihydroartemisinin-piperaquine for seasonal malaria chemoprevention in young children.Nat. Commun. 2019; 10: 480Crossref PubMed Scopus (20) Google J. et antimalarial drug in 2018; PubMed Scopus Google J. et al.Population pharmacokinetics and antimalarial pharmacodynamics of piperaquine in with Plasmodium malaria in Pharmacol. Scopus (20) Google P. et in lower lumefantrine exposure in children with for uncomplicated malaria.Clin. Pharmacol. Ther. 2019; PubMed Scopus Google Scholar]. In intermittent preventive the time of the of a infection in with malaria has been The antimalarial drug concentrations at time have been used to in for piperaquine in different regions and populations P. et al.Optimal dosing of dihydroartemisinin-piperaquine for seasonal malaria chemoprevention in young children.Nat. Commun. 2019; 10: 480Crossref PubMed Scopus (20) Google J. et antimalarial drug in 2018; PubMed Scopus Google Scholar]. be as they on malaria infection with antimalarial also a for the in in the of et malaria and 2018; PubMed Scopus Google et pharmacokinetic and pharmacodynamic of piperaquine in a infection with Plasmodium falciparum PubMed Scopus Google Scholar]. SMC with for children, aged between 3 and 59 living in the Sahel region has been recommended by WHO for a [3.World Health Organization WHO Policy Recommendation: Seasonal Malaria Chemoprevention (SMC) for Plasmodium falciparum malaria Control in Highly Seasonal Transmission Areas of the Sahel sub-Region in Africa.https://apps.who.int/iris/handle/10665/337978Date: 2012Google Scholar]. of SMC between and are for and and SMC in areas of high malaria transmission from local and global in to antimalarial WHO recommended in 2012 resistance and system evaluation should be to the number of infections and from the dose of A WHO Malaria Policy chemoprevention efficacy has been Health Organization Malaria Policy 2021. WHO, and repeated the need for an for the and of SMC. the SMC should be to populations and regions from SMC, as well as the different antimalarial drug regimens be used in different regions. SMC substantially the and in children living in regions. SMC with has been in the Sahel region, but are and resistance the of drug has shown be a alternative drug combination for SMC. antimalarial for SMC is by the high safety for drugs to healthy children. of be by an of the SMC throughout the African regions of seasonal malaria transmission, safety and can be the target age to children years of age be in and to of SMC regimens an where more is the of and SMC regimens be a to children in areas of high malaria transmission but better of SMC (see are the most alternative antimalarial drug for are the optimal drug regimens to efficacy and to and should the efficacy of SMC be is the lower efficacy for is an to the of antimalarial drugs used for SMC, and can in be to the in are the optimal drug regimens to drug resistance and should drug resistance be in an SMC rapidly should drugs be evaluated for SMC, the high tolerability and safety needed to children on a should the individual of newly antimalarial in SMC be SMC be to the East and South-East African regions of seasonal malaria transmission, and SMC regimens should be used in these areas the high levels of SMC be to children between 5 and years of are the most alternative antimalarial drug for are the optimal drug regimens to efficacy and to and should the efficacy of SMC be is the lower efficacy for is an to the of antimalarial drugs used for SMC, and can in be to the in are the optimal drug regimens to drug resistance and should drug resistance be in an SMC rapidly should drugs be evaluated for SMC, the high tolerability and safety needed to children on a should the individual of newly antimalarial in SMC be SMC be to the East and South-East African regions of seasonal malaria transmission, and SMC regimens should be used in these areas the high levels of SMC be to children between 5 and years of to at the by the is also by the and the of the have a public to any from The with the of on pharmacokinetic by a drug is to the drug of is to the and the half-life is to the the recommended treatment for P. falciparum infections. have comprise artesunate-mefloquine, and the of can maintain the as the dosing the time in which drug concentrations in the systemic circulation are by a antimalarial treatment administered at the of of malaria the antimalarial blood with a parasite of the effects with the administration of a the in the of an administered absorption, distribution, metabolism, and a of antimalarial treatment given at monthly to prevent malaria infection during the high-transmission malaria season. the drug at the time a

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