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Treating malaria in pregnancy in developing countries: priorities in clinical research and drug development Andrew Vallely†, James McCarthy, John Changalucha, Lisa Vallely and Daniel Chandramohan

CONTENTS Current knowledge & practice 4-aminoquinolones Quinoline methanols

Reducing the burden of falciparum malaria in pregnancy is an urgent international public health priority but one that involves considerable challenges. The rapidly declining effectiveness of agents known to be safe in pregnancy, and the limited efficacy, safety and pharmacokinetic data available for many other antimalarial drugs, mean that current options for the treatment of both severe and uncomplicated falciparum malaria in pregnancy are limited. This report summarizes the literature on this subject and recommends drug combinations for evaluation in Phase II/III treatment trials in pregnancy. Expert Rev. Clin. Pharmacol. 1(1), 61–72 (2008)

Antifolates Antibiotics with antimalarial activity Artemisinins Artemisinin-based combination therapy Expert commentary Five-year view Financial & competing interests disclosure Key issues References Affiliations

†

Author for correspondence University of Queensland, Division of International and Indigenous Health, School of Population Health, Herston Road, Herston, Brisbane Qld 4006, Australia Tel.: +61 733 664 970 Mob.: +61 420 822 319 Fax: +61 733 655 599 [email protected] KEYWORDS: efficacy, kinetics, malaria in pregnancy, safety, treatment

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Every year, more than 30 million pregnancies occur in women living in malaria-endemic countries, the majority in sub-Saharan Africa where the most severe form of malaria, due to Plasmodium falciparum, predominates [1,2]. Falciparum malaria can have devastating effects on the health of pregnant mothers and their infants, including maternal death, anemia, intrauterine growth retardation, stillbirth, premature delivery, low birth weight and perinatal mortality [3–7]. These effects vary according to maternal premunition, itself a function of malaria transmission intensity [8]. Parity and other factors, such as HIV co-infection, influence the pattern of malaria-related disease burden [9–13], which is exacerbated by poverty, undernutrition, micronutrient deficiencies and lack of access to healthcare services for the majority of pregnant women at risk in developing countries [6,14]. In areas of high stable falciparum transmission, maternal anemia, heavy placental infection and fetal growth retardation are the primary consequences of malaria in pregnancy (MiP), and this burden is greatest among women in their first or second pregnancies. Approximately 5–10% of severe anemia during pregnancy in malaria-endemic

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areas is attributable to MiP [2]. In areas of low intensity or markedly seasonal transmission, pregnant women of all parities are at high risk of severe malaria, which is associated with severe adverse maternal and fetal outcomes and an increased risk of hypoglycemia, pulmonary edema and mortality compared with nonpregnant adults [15]. Despite this widely recognized burden of MiP, the number of antimalarial drugs proven in large-scale clinical trials to be safe and efficacious in pregnancy is limited because pregnant women have tended to be excluded from clinical trials owing to safety concerns [16,17]. Pharmacokinetic data, such as drug-absorption characteristics, distribution and elimination half-life, are also limited in pregnancy, making the development of optimal dosing regimes difficult [16–18]. Since 2001, the WHO has advocated the use of combination drug therapy for the treatment of falciparum malaria and strongly advised against monotherapy in order to try and decrease the global spread of antimalarial drug resistance and to preserve the effectiveness of available agents [201]. The use of artemisininbased combination therapies (ACTs) has been

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central to the WHO strategy but, until recently, the use of these highly effective combinations at any stage of pregnancy, except in life-threatening situations where alternatives were either unavailable or contraindicated, was strongly cautioned owing to insufficient safety data [19]. Following extensive expert consultation and a systematic review of evidence from observational studies and clinical trials on antimalarial drug safety and efficacy in pregnancy, revised treatment guidelines were issued at the end of 2006 [15]. These recommend quinine plus clindamycin in the first trimester for treating uncomplicated falciparum MiP and, in the second and third trimesters, either an ACT known to be effective locally, quinine plus clindamycin or artesunate plus clindamycin. In severe malaria, where the priority is to start rapidly acting highly effective treatment as soon as possible, the WHO recommends parenteral artesunate or artemether in the second and third trimesters in preference to quinine due to the risk of recurrent hypoglycemia associated with quinine therapy, particularly in mid–late pregnancy [15]. In the first trimester, parenteral artesunate or quinine are recommended: concerns regarding the safety of artemisinins in early pregnancy need to be balanced against the high mortality risk of severe malaria in pregnancy. The WHO guidelines also stress the importance of pharmacovigilance data and information from Phase III efficacy and safety trials to inform future evidence-based prescribing for MiP and to place current recommendations on a firmer footing. Current knowledge & practice

MiP is unique. P. falciparum-infected erythrocytes are sequestered in the placenta following their adherence to placental chondroitin sulfate A (CSA) [20] and hyaluronic acid [21], allowing the placenta to act as a ‘privileged site’ for parasite replication [18]. Changes in cellular-mediated immune responses during pregnancy result in an increased susceptibility to malaria and other infections [22–24] that appears to persist up to 60 days into the postpartum period [25,26]. Physiological changes, such as delayed gastric emptying time, elevated estrogen and cortisol levels, increased intravascular volume and increased body fat content, alter the absorption, distribution and elimination of a variety of antimalarials in pregnancy, including chloroquine, atovaquone, proguanil, cycloguanil, mefloquine, lumefantrine, artemether, artesunate and dihydroartemisinin [27–31]. It is unclear to what extent these factors may alter the pharmacokinetics of other drugs or differentially affect individual component drugs when used in combination. In malaria-endemic countries where antenatal HIV prevalence is high, the increased risk of serious adverse events associated with some antimalarials in women with HIV–malaria coinfection [32] and drug interactions between antimalarial drugs and antiretrovirals used for the prevention of mother-to-child HIV transmission are also important factors to consider [10]. For example, severe skin reactions due to sulfadoxine–pyrimethamine (SP) are more common in women coinfected by malaria and HIV; SP interacts with both nevirapine and zidovudine. Hepatotoxicity due to an interaction between amodiaquine–artesunate and efavirenz was reported recently in five healthy adult volunteers [33].

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In addition to these concerns, many antimalarials are contraindicated in pregnancy owing to their proven toxicity in animal models or documented adverse maternal or fetal outcomes in human subjects (e.g., primaquine, doxycycline, halofantrine and tafenoquine) [34]. 4-aminoquinolones

Chloroquine, a 4-aminoquinolone with a long half-life of more than 25 days, has been used for decades in the prophylaxis and treatment of uncomplicated falciparum malaria in pregnancy and appears to be safe and well tolerated [17]. Widespread P. falciparum resistance now seriously limits its use, even in combination with other antimalarials [32], although it may still have a role in the prophylaxis and case management of vivax MiP [35]. A recent trial in Ghana found that amodiaquine, which is structurally related to chloroquine but has a shorter effective half-life of 9–18 days [36], was effective either alone or in combination with SP in the treatment of uncomplicated falciparum MiP [37]. This trial had a relatively short period of follow-up (up to 6 weeks post- partum) however, which combined with a modest sample size of 225 per arm, means that it was not possible to fully evaluate safety outcomes. Tolerability was also an issue, with significantly more women reporting minor adverse events in the amodiaquine and amodiaquine–SP treatment arms (86 and 90%, respectively) compared with those receiving SP alone (48%) or no antimalarial drugs (34%; p < 0.0001 for all comparisons). Other researchers have questioned the efficacy, safety and tolerability of amodiaquine in pregnancy [17,38,39], while increasing resistance in East Africa [40,41], Guinea-Bissau [42], Afghanistan [43] and Papua New Guinea [44] are also of concern and suggest that amodiaquinecontaining drug combinations for the treatment of falciparum MiP are unlikely to have a long-term future, with the possible exception of artesunate–amodiaquine in West Africa [45,46]. Quinoline methanols

Quinine, a cinchona alkaloid that has been used in the treatment of malaria for over 300 years [47], is a potent, fast-acting blood schizonticide and remains an important drug for the treatment of both uncomplicated and severe MiP [15]. Developmental toxicity studies in rats, rabbits, dogs [48] and primates [49] have, in general, concluded that the drug does not cause congenital abnormalities or fetal toxicity; early concerns regarding auditory nerve toxicity [50] may have been overstated [39]. Quinine is generally considered safe in all trimesters of pregnancy, including the first trimester [51], although experience is limited to 368 published first-trimester exposures [39]. Quinine was not associated with excess birth defects or other adverse perinatal outcomes when used to treat over 700 second- and third-trimester pregnant women in Thailand [52,53]. The pharmacokinetics of quinine and its metabolites were recently described in 16 Sudanese women with uncomplicated falciparum malaria [54]. No significant differences were observed between the eight pregnant and eight nonpregnant subjects in this study (e.g., time to reach maximum plasma concentration following oral

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administration was 1.8 and 2.5 h and elimination half-life was 12.0 and 10.9 h, respectively), suggesting that dose adjustment in pregnancy is unnecessary for quinine. The main concerns related to quinine use in pregnancy are the risk of hypoglycemia, particularly in severe malaria during the second and third trimesters [15], and tinnitus, dizziness and other features of cinchonism that make tolerability and compliance an issue in those treated with oral quinine for uncomplicated disease [55]. The South East Asian Quinine Artesunate Malaria Trial (SEAQUAMAT) trial conducted among 1461 nonpregnant adults and children with severe malaria between 2003 and 2005 found that parenteral artesunate was associated with a significantly lower mortality than quinine and led to the recommendation that artesunate be used as the drug of choice in the treatment of severe malaria in low-transmission areas and in the second and third trimesters of pregnancy in all transmission settings [15,56]. The limited safety data available on artemisinin compounds during the first trimester compared with quinine mean that quinine remains the mainstay for treating severe malaria in early pregnancy [15]. There are concerns, however, that the efficacy of quinine in pregnancy may be declining, particularly in South East Asia [55,57,58]. Mefloquine is a 4-quinolinemethanol derivative with a chemical structure related to quinine and an elimination half-life of 2–4 weeks in healthy, nonpregnant adult volunteers [59]. The pharmacokinetics of mefloquine have been described in nine pregnant women in Thailand with uncomplicated falciparum malaria [30]. These data suggest that pregnant women may require higher doses per kilogram body weight than nonpregnant subjects and that further research on dose optimization is required. In animal toxicity studies, mefloquine was teratogenic in mice and rats at a dose of 100 mg/kg/day and in rabbits at 80 mg/kg/day; at high doses (160 mg/kg/day), mefloquine was also embryotoxic in rabbits [59]. Placental perfusion studies suggest that mefloquine is able to cross the human placenta and enter the fetal circulation [60] but some researchers have suggested that the results of such studies be interpreted with caution [61]. In human populations, randomized, controlled trials, observational studies and postmarketing surveillance strongly support the view that mefloquine is safe, effective and well tolerated for the prophylaxis and treatment of pregnancy-associated malaria [16], although many researchers still have reservations regarding safety [17], following reports from Thailand in the 1990s of an increased risk of stillbirth in women taking mefloquine during pregnancy [62–64]. Mefloquine has been used alone for prophylaxis in the preconception period and in all trimesters of pregnancy [64–68] and in the treatment of chloroquine- and multidrug-resistant falciparum MiP, both as monotherapy [58,62,69–71] and in combination with other antimalarials, including the artemisinins [58,72–74]. Antifolates

SP has been used extensively for intermittent preventive treatment of MiP (IPTp) [16,18] and in the treatment of uncomplicated falciparum malaria in children, pregnant and nonpregnant adults in the past; however, increasing parasite resistance

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in the last 30–40 years means that this combination is now ineffective in many malaria-endemic countries, particularly in Eastern and Southern Africa [40,75–80,202], South East Asia [81,82], South America [83,84] and the Pacific [44]. Remarkably, and in contrast to the artemisinins and a variety of other drugs, there are no published data on the pharmacokinetics of sulfadoxine or pyrimethamine in pregnancy, either alone or in combination [85]. Some authors have suggested that SP be combined with artemisinins or with cheaper and more readily available alternatives, such as chloroquine or amodiaquine [86], to maintain its effectiveness. Combinations such as amodiaquine–SP may represent an interim approach prior to the implementation of ACTs in some settings [36], such as West Africa [87,88], but evidence of the safety and efficacy of amodiaquine–SP in pregnant women is limited [37]. Proguanil has been used extensively for malaria chemoprophylaxis in travellers, including pregnant women in all trimesters, and is probably one of the safest antimalarials currently available [34,66,89–91]. The elimination half-life of proguanil is 12–21 h in healthy adult volunteers and approximately 40–60% of the drug is eliminated by urinary excretion [92]. The pharmacokinetics of proguanil and its active metabolite, cycloguanil, are significantly altered in healthy women taking oral contraception or in the third trimester of pregnancy [93] and in pregnant women with uncomplicated falciparum malaria compared with healthy adult volunteers [27]. Atovaquone has an elimination half-life of 2–3 days in healthy volunteers and a different molecular target to proguanil, although both agents inhibit parasite pyrimidine biosynthesis [92]. The pharmacokinetics of atovaquone are also significantly altered during pregnancy [94]. Proguanil in fixed-dose combination with atovaquone (Malarone®) has been used for the treatment of uncomplicated falciparum malaria in adults and children and also appears safe, effective and well tolerated during pregnancy, although there are very few data on first-trimester exposure [27]. In animal toxicity studies, there were no adverse maternal or fetal outcomes observed in pregnant rats, although the combination was associated with reduced fetal birthweight and viability in rabbits [39,92]. The most serious limitation to the use of this combination in pregnancy is cost: atovaquone–proguanil is currently beyond the reach of the vast majority of malaria-endemic countries. An additional consideration is whether the current fixed-dose combination is sufficient for the treatment of uncomplicated falciparum malaria in late pregnancy owing to the lower plasma concentrations, increased oral clearance and apparent volume of distribution of atovaquone and proguanil observed following oral administration compared with healthy subjects and patients with acute malaria [94]. Atovaquone–proguanil doses may need to be increased by up to 50% in the third trimester and in women taking oral contraception [93,94]. Chlorproguanil has a similar mode of action and pharmacokinetic profile to proguanil and has been used primarily in fixeddose coformulation with dapsone, an antifolate antibiotic used

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in the treatment of leprosy, which has an elimination half-life of 31 h [91]. The combination (Lapdap®) has been shown to be safe and effective in the treatment of uncomplicated malaria in children [78,95,96] and pregnant women [97], although safety concerns in areas of high glucose-6-phosphate dehydrogenase (G6PD) deficiency remain [91]. A recent review reported results from 924 dapsone exposures during pregnancy but concluded that data are insufficient to conduct a quantitative risk–benefit analysis [98]. In addition, unlike proguanil and its active metabolites [93,94], the pharmacokinetics of chlorproguanil and dapsone have not been described in pregnancy. Given the pharmacokinetics data on proguanil, it is likely that the dose of chlorproguanil will need to be increased in late pregnancy to ensure adequate efficacy, but the narrow therapeutic window of dapsone [91] means this is not possible using the current fixed-dose coformulation of Lapdap [39]. Large-scale treatment trials are currently underway among pregnant women with uncomplicated falciparum malaria in Tanzania [203] and Mali [204]. Antibiotics with antimalarial activity

A number of antibiotics have shown promising antimalarial activity both in vitro [99,100] and in clinical trials, particularly when used in combination with a rapidly acting partner, such as quinine, artesunate or artemether [52,101–104]. Given the increasing parasite resistance to other classes of drugs and the considerable experience of antibiotic use in pregnancy [105], this approach may represent a new avenue for drug development; however, there are several constraints and potential risks associated with this approach, the most obvious being that several antibiotics, such as tetracycline and doxycycline, are known to be toxic in pregnancy and are therefore contraindicated [34,39]. All antibiotics with demonstrated antimalarial properties, such as clindamyicn, azithromycin, rifampicin, ciprofloxacin and the tetracyclines, are slow-acting antimalarials and have poor efficacy unless partnered with a potent, rapidly acting agent, such as an artemisinin or quinine [17]. Antibiotics may therefore represent suitable adjuncts in the treatment of uncomplicated falciparum malaria but are unlikely to have a role in the treatment of severe MiP. Finally, there is a risk that widespread use of antibiotic-containing drug combinations for treating MiP could accelerate the emergence and spread of antimicrobial resistance. Clindamycin is a lincosamide antibiotic related to lincomycin, it has an elimination half-life of approximately 2–3 h in healthy adults [106] and appears to exert its biological effect by inhibiting normal parasite apicoplast growth [100]. No pharmacokinetic data are available in pregnant women with malaria [17]. In a recent systematic review, clindamycin was safe and effective in treating genital infections in the second trimester and was associated with a lower risk of preterm births compared with placebo [107]. An open, randomized, comparison study among 129 second- and third-trimester women with acute uncomplicated falciparum malaria in Thailand showed evidence of a significant synergistic effect when clindamycin was added to quinine, and this combination was also safe and

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efficacious compared with artesunate alone [52]. Current WHO treatment guidelines recommend clindamycin be partnered with quinine as first-line treatment for uncomplicated falciparum malaria in the first trimester and with either artesunate or quinine later in pregnancy [15]. Clindamycin has also been investigated in combination with fosmidomycin (a drug originally developed as an antibiotic in the 1980s [108]) for the treatment of multidrug-resistant malaria in nonpregnant adults in Gabon and Thailand [104] and in children with uncomplicated falciparum malaria in Gabon [109], but showed poor efficacy at 28 days. The safety, efficacy and pharmacokinetics of fosmidomycin have not been established in pregnancy. Azithromycin is a macrolide antibiotic derived from erythromycin that has an elimination half-life of 68 h in healthy human volunteers and is excreted largely unchanged in the bile following hepatic clearance [110]. In pregnancy, the placenta appears to act as an effective barrier to fetal exposure [111]. Azithromycin has been used extensively to treat sexually transmitted and vaginal infections during pregnancy in total treatment doses of up to 1–2 g and is considered a safe alternative in pregnant women who are allergic to β-lactam antibiotics [112–114]. Azithromycin has shown activity against P. falciparum in vitro [99,115], in the murine malaria model [116] and in randomized, controlled treatment trials in children and nonpregnant adults with uncomplicated falciparum malaria in Thailand [101,103]. The 28-day cure rate of artesunate plus azithromycin was 56% in a study by Krudsood et al. [101] but a more recent Phase II trial reported 90% 28-day efficacy in the azithromycin plus artesunate group (750 and 100 mg twice daily, respectively, for 3 days) and in the azithromycin plus quinine group (500 mg and 10 mg/kg three-times daily, respectively, for 3 days) [103]. Treatment trials among pregnant women have yet to be conducted and may be inappropriate given the uncertain efficacy of azithromycin-containing formulations. Artemisinins

Artemisinin compounds are derived from sweet wormwood (Artemisia annua), a herb used in traditional Chinese medicine for over 2000 years [117,118]. All are potent, rapid-acting blood schizonticides that act by inhibiting parasite sarcoplasmic–endoplasmic reticulum calcium ATPase and have very short elimination half-lives of approximately 40 min to several hours [119]. The pharmacokinetics of dihydroartemisinin, the principal active metabolite of artesunate and artemether and an important drug in its own right, have recently been described in 24 second- and third-trimester pregnant women treated for uncomplicated falciparum malaria in Thailand [28]. There is still considerable debate regarding the safety of artemisinins in pregnancy, especially during the first trimester [15–17,19,39,55]. All are associated with embryotoxicity in the rat and rabbit where embryolethality, late fetal resorption, and abnormal development of the cardiovascular system, axial skeleton and limbs have been reported [19,117]. The mechanism of developmental toxicity is unclear. In rats, the yolk sac appears

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highly susceptible to artemisinins [120], but recent studies in primates, which showed high rates of fetal loss, indicate that other mechanisms must be involved in higher mammals [121]. Published data from clinical trials in humans are limited to approximately 864 women exposed during the second and third trimester and 158 first-trimester exposures [16], but no study to date has been designed to capture excess early pregnancy loss, the most important human safety issue to investigate based on animal toxicity data. The lack of information in this area underpins the recent decision by the WHO to recommend that ACTs continue to be restricted to the second and third trimesters of pregnancy (except in life-threatening situations where the priority is to commence treatment for severe malaria with a rapidly effective drug as quickly as possible) and that pharmacovigilance programs be expanded to build a sufficient evidence base to inform future policy [15,19]. There are no published studies describing the safety of parenteral artemisinins for the treatment of severe MiP but, following the compelling results of the aforementioned SEAQUAMAT trial [56], and the recognition that, unlike quinine, artemisinin therapy is not associated with hyperinsulinemia and hypoglycemia when used to treat severe MiP, the WHO now recommends artemether and artesunate as first-line drugs for severe malaria in the second and third trimester [15]. In the first trimester, where uncertainty regarding the developmental toxicity of the artemisinins remains and where quinine therapy is less likely to be complicated by hypoglycemia, parenteral quinine remains the drug of choice. Artemisinin-based combination therapy

Artemether–lumefantrine (Coartem®/Riamet®) is a fixed-dose ACT available at subsidized cost to malaria-endemic countries since 2001 following a special pricing agreement between the WHO and Novartis [201]. Artemether–lumefantrine is now the first-line treatment for uncomplicated falciparum malaria in adults and children in 19 countries in sub-Saharan Africa and 56 countries worldwide [201]. Lumefantrine has a longer half-life than artemether (2–3 days vs 2 h) and interferes with the conversion of heme to hemozoin within the parasite acid food vacuole [117]. Doses as high as 1000 mg/kg were not associated with teratogenicity, maternal, embryo or fetal toxicity in rats or rabbits [117]. There are no published human safety data on lumefantrine in pregnancy. The pharmacokinetics of artemether and lumefantrine were recently described in 13 second- and thirdtrimester pregnant women with uncomplicated falciparum malaria in Thailand [29]. Compared with nonpregnant adults with acute malaria, pregnant women in this study demonstrated lower plasma concentrations of artemether, dihydroartemisinin and lumefantrine, and eliminated lumefantrine more rapidly. These findings suggest dose-optimization studies are required to determine optimal dosing regimes for treatment in pregnancy. Efficacy and safety trials of artemether–lumefantrine for IPTp are currently underway in Uganda and Ghana [205,206]. A trial comparing quinine and artemther–lumefantrine for the treatment of uncomplicated falciparum malaria in the second and third trimester has started recruitment in Uganda [207].

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Artesunate–amodiaquine has recently become available offpatent in a fixed-dose coformulation that is expected to cost less than US$1.00 per adult treatment course [122]. The combination has yet to be evaluated for treating MiP but had comparable efficacy and safety with artesunate–mefloquine, artemether–lumefantrine and amodiaquine–SP for treating uncomplicated falciparum malaria in children and nonpregnant adults in Senegal [45], and encouraging results have been reported in children aged under 5 years in Ghana [46] and Tanzania [123]. However, a recent study from Indonesia suggests that dihydroartemisinin–piperaquine may be more effective and better tolerated in the treatment of multidrug-resistant P. falciparum and Plasmodium vivax malaria [124]. Given the poor tolerability of amodiaquine in pregnancy, it is unclear what future role this combination may have, even if proven to be efficacious and safe in pregnancy. Mefloquine in combination with artemether or artesunate appears to be safe and efficacious in treating uncomplicated falciparum malaria in the second and third trimesters of pregnancy [72–74]. Artesunate–mefloquine is being developed in fixed-dose coformulation by the Drugs for Neglected Diseases Initiative (DNDi) and is expected to become available in late 2007 at a cost of approximately US$2.00 per adult treatment course [208]. Artesunate–atovaquone–proguanil was more effective and better tolerated than quinine for treating uncomplicated falciparum malaria in the second and third trimester in Thailand [57,94,125] but is expensive and may best be reserved for refractory cases. Chlorproguanil–dapsone–artesunate (CDA; Lapdap plus artesunate) is under development [209] with a multicenter treatment trial recently completed in children and adolescents in Africa [210]; however, no trials are currently planned in pregnant women. Dihyroartemisinin–piperaquine (DP; Artekin©/Eurartekin©) is a fixed-dose ACT being developed through an international public–private partnership between: Holleykin Pharmaceutical, China; Sigma-Tau Industries, Italy; the University of Oxford, UK; and the Medicines for Malaria Venture (MMV) [211]. Dihydroartemisinin is a derivative of artemisinin with an elimination half-life of 40–60 min [119]. Piperaquine is a 4-aminoquinoline with a long half-life of 3–4 weeks [119], developed in China in the 1960s [126]. Piperaquine resistance emerged in the mid1990s, stimulating the search for a suitable partner drug for coformulation. DP has been used extensively in China, Vietnam, Cambodia and other parts of South East Asia and is safe, effective and well tolerated for treating uncomplicated, multidrug-resistant falciparum malaria in children and adults [127–130]. Encouraging results have also been reported recently from a treatment trial among children in Uganda [131] and the results of two recently completed trials in Indonesia [212] and Peru [213] are expected in 2008. To date, no treatment trials have been undertaken among pregnant women with uncomplicated falciparum malaria, which may reflect the lack of published data on the safety and pharmacokinetics of piperaquine in pregnancy.

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Dihydroartemisinin–mefloquine appears safe and efficacious in the treatment of uncomplicated falciparum malaria in children in Nigeria [132] and adults in Thailand [133], but there are no data on this combination in pregnancy or any apparent plans to develop this combination in fixed-dose coformulation, despite evidence of the safety of mefloquine in pregnancy compared with piperaquine. Pyronaridine, an acridine derivative structurally related to quinacrine, has been used in China since the 1970s and has been shown to be efficacious and safe in 40 adults [134] and 44 children [135] in West Africa for treating uncomplicated falciparum malaria. More recently, pyronaridine has been used with dihydroartemisinin for the treatment of multidrug-resistant falciparum malaria [136]. A fixed-dose coformulation with artesunate (PANDA) [137] is being developed and results of a Phase II trial among children in Gabon are expected in 2007 [214]. There are no published safety data on pyronaridine use in pregnancy but the drug does not appear to be embryotoxic in rats [138]. Expert commentary

Given the evidence available, which drugs and drug combinations should be prioritized for pharmacokinetic studies and investigation in efficacy and safety trials for the treatment of uncomplicated and severe MiP? There is some evidence that combining potent short-acting artemisinins with longer acting agents is likely to delay the emergence of resistance to the slowly eliminated component [118]. Conversely, some authors advise combining drugs with similar elimination half-lives due to the risk of resistance emerging to the longer acting drug owing to its persistence alone at subtherapeutic levels once the rapidly eliminated drug has been excreted [32]. This is of most concern in high-transmission settings, where there is a good chance of reexposure to malaria during the convalescent period [36]. For this reason, the effectiveness of combinations such as artesunate–mefloquine may decline more rapidly than anticipated in highly endemic sub-Saharan Africa, despite the excellent results observed with this combination for treating multidrug-resistant malaria in lower transmission settings in South East Asia [36]. Others have stressed the importance of not combining artemisinins with drugs that are already failing, such as chloroquine, amodiaquine or SP, in many settings, due to the risk of reduced efficacy of the combination [139]. Combining drugs that have different molecular targets is also preferable to reduce the risk of resistance [32,119]. Acceptability, cost, availability, the possibility of a fixed-dose formulation and a simple dosing regimen are other important considerations [140], while reducing inappropriate treatment through improved diagnostics is also vital [141]. ACTs for the treatment of uncomplicated falciparum malaria in pregnancy

There are insufficient human safety data to recommend that any ACT enters clinical trials among women in the first trimester of pregnancy. In the second and third trimesters however, the balance of evidence suggests that artemisinins are safe and

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should be used as first-line agents in the case management of uncomplicated and severe MiP [15]. Given the subsidized cost arrangements, the availability of a fixed-dose coformulation that has already been introduced as first-line treatment in children and nonpregnant adults in many malaria-endemic countries, and the use of partner drugs with different molecular targets, artemether–lumefantrine (Coartem/Riamet) represents a promising new option for the treatment of uncomplicated falciparum malaria in the second and third trimesters. Results of the ongoing Phase III clinical trial in pregnant women in Uganda are therefore eagerly awaited [215]. Dihydroartemisinin–piperaquine (Artekin) is relatively inexpensive (∼US$1.00 for an adult treatment course, which is comparable to Coartem) [142], combines a very short-acting artemisinin with a longer acting partner with a different mode of action and is available in a fixed-dose coformulation. The lack of safety data on piperaquine suggests that the combination enter Phase II trials in second- and third-trimester women rather than proceeding directly to Phase III. Mefloquine is a long-acting agent with a similar elimination half-life to piperaquine (∼2–4 weeks) [119], but also has a proven safety record in pregnancy and a fixed-dose coformulation with artesunate will soon become available, although cost will likely limit widespread use, at least initially [143]. Artesunate–mefloquine therefore appears a promising candidate for evaluation in Phase III trials for the treatment of uncomplicated falciparum malaria in the second and third trimesters of pregnancy. Other ACTs that should be considered for evaluation in Phase III clinical treatment trials in the second and third trimester include: clindamycin or azithromycin in combination with artesunate or dihydroartemisinin; CDA; and dihydroartemisinin plus mefloquine. Artesunate–azithromycin has shown promising efficacy in the treatment of uncomplicated falciparum malaria in Thai adults [103] and both drugs are considered safe when administered alone in the second and third trimester. Prior to large-scale Phase II/III efficacy and safety trials, the pharmacokinetics of both drugs when administered in combination must be established in pregnant women and dose-optimization studies must be conducted. Non-ACTs for uncomplicated falciparum MiP

The safety of mefloquine and azithromycin in all trimesters of pregnancy is now reasonably well established and this combination would pair drugs with similar elimination half-lives and different molecular targets. This combination is also likely to have additional health benefits by reducing maternal and perinatal infections, which may offset cost concerns. Sexually transmitted infections are common in women of childbearing age in Africa and may go undiagnosed and untreated during pregnancy [144]. For example, azithromycin is effective for treating chlamydia infection during pregnancy [112], which is associated with increased risk of stillbirth, prematurity and low birth weight [145,146]. Mefloquine–azithromycin could represent a safe and effective combination but the efficacy of azithromycin is still questionable and has never been established in pregnancy. Until

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these issues are resolved, this combination cannot be considered for evaluation in Phase II/III treatment trials. Cost and the lack of a fixed dose coformulation are additional disadvantages. Severe MiP

In addition to concerns regarding the suitability of various combinations for uncomplicated falciparum malaria, several important questions remain with regards to the treatment of severe MiP. The safety of parenteral artesunate and artemether in the first trimester has yet to be established and the pharmacokinetics of these agents following parenteral administration in women with severe malaria in the second and third trimester has not been described. These are urgent research and surveillance priorities in the development of alternatives to quinine-based treatment regimens for severe disease in pregnancy [55]. Five-year view

Increased international commitment to support the development of new drug combinations in fixed-dose coformulations; the conduction of large-scale clinical trials to assess

safety, efficacy and optimal dosing in pregnancy, and the establishment of rigorous systems for Phase IV trials and other forms of pharmacovigilance in resource-poor malariaendemic countries are a public health priority in the next 5 years if the burden of maternal and child health due to malaria is to be lessened. Rigorous multicenter Phase II/III clinical trials to evaluate the safety and efficacy of antimalarials for the treatment of uncomplicated and severe MiP remain an urgent international research and public health priority. Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Key issues • Malaria in pregnancy can have devastating consequences for the health of pregnant women and their infants in all transmission settings. • The pharmacokinetics and optimal dosing regimens of many antimalarials currently in use are unknown in pregnant women. Research to establish the pharmacokinetics and optimal dosing regimens of candidate antimalarial drugs and drug combinations for use in pregnancy are urgently required. • Establishing the safety of antimalarial drugs in the first trimester is a priority. • This lack of information makes it difficult to decide which antimalarials are likely to be effective in treating pregnancy-associated malaria and which combinations should be prioritized for investigation in Phase II/III clinical trials. • Artemether–lumefantrine, dihydroartemisinin–piperaquine, artesunate–mefloquine, artesunate–azithromyicn and azithromycin–mefloquine currently appear to be the best candidates for Phase II/III treatment trials in highly endemic countries. References 1

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A multi-centre, randomised, double-blind, double dummy study comparing the efficacy and safety of chlorproguanil-dapsoneartesunate versus artemether-lumefantrine in the treatment of acute uncomplicated Plasmodium falciparum malaria in children and adolescents in Africa www.clinicaltrials.gov/ct/show/ NCT00344006?order=1

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A Randomized trial to compare the efficacy of artekin and amodiaquine plus artesunate for the treatment of acute falciparum and vivax malaria in Timika, Papua www.clinicaltrials.gov/ct/show/ NCT00157885?order=1

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Efficacy and safety of dihydroartemisinin/piperaquine (Artekin®) for the treatment of uncomplicated malaria in Peru www.clinicaltrials.gov/ct/show/ NCT00373607?order=3

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Pyronaridine and artesunate (3:1) in children with acute uncomplicated Plasmodium falciparum malaria www.clinicaltrials.gov/ct/show/ NCT00331136?order=39

Quinine vs artemether/lumefantrine in uncomplicated malaria during pregnancy www.clinicaltrials.gov/ct/show/ NCT00495508?order=23

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Andrew Vallely Senior Lecturer, Tropical & Infectious Diseases, University of Queensland, Division of International and Indigenous Health, School of Population Health, Herston Road, Herston, Brisbane Qld 4006, Australia Tel.: +61 733 664 970 Mob.: +61 420 822 319 Fax: +61 733 655 599 [email protected]

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James McCarthy School of Population Health, Brisbane Qld 4006; Queensland Institute of Medical Research, University of Queensland, Brisbane Qld 4029, Australia [email protected]

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John Changalucha National Institute for Medical Research, Mwanza Centre, PO Box 1462, Mwanza, Tanzania [email protected]

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Lisa Vallely University of Queensland, School of Population Health, Brisbane Qld 4006, Australia [email protected]

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Daniel Chandramohan London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK [email protected]

Expert Rev. Clin. Pharmacol. 1(1), (2008)