Drugs 2005; 65 (1): 75-87REVIEW ARTICLE 0012-6667/05/0001-0075/$39.95/0

2005 Adis Data Information BV. All rights reserved.

PiperaquineA Resurgent Antimalarial Drug

Timothy M.E. Davis, Te-Yu Hung, Ing-Kye Sim, Harin A. Karunajeewa andKenneth F. Ilett

Medicine Unit Fremantle and Pharmacology Unit Nedlands, School of Medicine andPharmacology, University of Western Australia, Crawley, Western Australia, Australia

ContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 751. Historical Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 762. Chemical Structure and Physicochemical Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 763. Pharmacodynamic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77

3.1 In Vitro Antimalarial Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 773.2 Parasite Resistance to Piperaquine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 783.3 Animal Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 793.4 Clinical Studies in Humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 793.5 Piperaquine as a Part of Artemisinin-Based Combination Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . 80

4. Pharmacokinetic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 814.1 Animal Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 814.2 Clinical Studies in Humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81

5. Toxicity and Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 825.1 Animal Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 825.2 Clinical Studies in Humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84

6. Conclusion and Current Status of Piperaquine as an Antimalarial Drug . . . . . . . . . . . . . . . . . . . . . . . . . 84

Piperaquine is a bisquinoline antimalarial drug that was first synthesised in theAbstract1960s, and used extensively in China and Indochina as prophylaxis and treatmentduring the next 20 years. A number of Chinese research groups documented that itwas at least as effective as, and better tolerated than, chloroquine against falcipar-um and vivax malaria, but no pharmacokinetic characterisation was undertaken.With the development of piperaquine-resistant strains of Plasmodium falciparumand the emergence of the artemisinin derivatives, its use declined during the1980s.

However, during the next decade, piperaquine was rediscovered by Chinesescientists as one of a number of compounds suitable for combination with anartemisinin derivative. The rationale for such artemisinin combination therapies(ACTs) was to provide an inexpensive, short-course treatment regimen with ahigh cure rate and good tolerability that would reduce transmission and protectagainst the development of parasite resistance. This approach has now beenendorsed by the WHO.

Piperaquine-based ACT began as China-Vietnam 4 (CV4: dihydroartemis-inin [DHA], trimethoprim, piperaquine phosphate and primaquine phosphate),

76 Davis et al.

which was followed by CV8 (the same components as CV4 but in increasedquantities), Artecom (in which primaquine was omitted) and Artekin orDuo-Cotecxin (DHA and piperaquine phosphate only). Recent Indochinesestudies have confirmed the excellent clinical efficacy of piperaquine-DHA combi-nations (28-day cure rates >95%), and have demonstrated that currently recom-mended regimens are not associated with significant cardiotoxicity or otheradverse effects.

The pharmacokinetic properties of piperaquine have also been characterisedrecently, revealing that it is a highly lipid-soluble drug with a large volume ofdistribution at steady state/bioavailability, long elimination half-life and a clear-ance that is markedly higher in children than in adults. The tolerability, efficacy,pharmacokinetic profile and low cost of piperaquine make it a promising partnerdrug for use as part of an ACT.

1. Historical Background nam[4,5] and introduced into the Vietnamese Nation-al Malaria Control Programme in 2000. However,there were three concerns with CV8. First, the rolePiperaquine is a bisquinoline antimalarial drugof trimethoprim was questionable since, like otherthat was synthesised independently by both theantibacterial agents, it does not have prompt andShanghai Pharmaceutical Industry Research Insti-potent antimalarial activity. Secondly, there is a hightute in China and Rhone Poulenc in France in therate of glucose-6-phosphate dehydrogenase defi-1960s.[1] Because of its relative potency and tolera-ciency amongst Asian populations, especially in eth-bility, it superseded chloroquine as the antimalarialnic minorities in countries such as Vietnam.[6] Redrecommended by the Chinese National Malariacell haemolysis, sometimes fatal, can occur in thisControl Programme in 1978, and the equivalent ofsituation if primaquine is given. Thirdly, the dose of140 million adult treatment doses were subsequentlyDHA in the original formulation of CV8 (10mgmanufactured and distributed.[2] With the develop-per tablet) resulted in a total dose that was muchment of piperaquine-resistant strains of Plasmodiumlower than recommended when DHA alone is usedfalciparum and the appearance of the artemisininfor the initial treatment of acute malaria (80mg overderivatives, piperaquine use diminished in the2 days vs 480mg over 7 days).1980s.

The most recent changes to CV8 have seenIn 1990, Chinese scientists ‘rediscovered’ piper-primaquine excluded (Artecom)[7] and, more re-aquine as one of a number of components of short-cently, both primaquine and also trimethoprim ex-course artemisinin-based combination therapies for-cluded (Artekin 2, which was renamed asmulated to achieve a high cure rate without signif-Artekin).[2,8] In the case of Artecom, Artekin

icant adverse effects. The first of these was China-and the most recent formulations of CV8, the DHAVietnam 4 (CV4)1, which contained dihy-content of each tablet has been increased to a totaldroartemisinin (DHA), trimethoprim, piperaquinedose of 256mg over 2–3 days.phosphate and primaquine phosphate.[2] Initial

small-scale, nonrandomised trials in China and In- 2. Chemical Structure anddochina led to the reformulation of CV4 as Physicochemical PropertiesCV8,[3] which was the same drug combination asCV4 but with different quantities of the compon- Piperaquine is available as the base (C29 H32 Cl2ents. CV8 was evaluated in further trials in Viet- N6; 4,4′-(1,3-propaneiyldi-4,1-piperazinediyl)bis[7-

1 The use of trade names is for product identification purposes only and does not imply endorsement.

2005 Adis Data Information BV. All rights reserved. Drugs 2005; 65 (1)

Piperaquine in Malaria 77

CI

N

N

N N

N

N

CI

4 H3PO4

Fig. 1. Chemical structure of piperaquine phosphate (1,3-bis[1-(7-chloro-4′-quinolyl)-4′-piperazinyl] phosphate).

chloro]quinoline; molecular weight 535.51) and al- quine and 13 other bisquinolines from an N,N-so as its water soluble tetra-phosphate salt, pipera- bis(7-chloroquinolin-4-yl) alkanediamines seriesquine phosphate (figure 1; C29 H32 Cl2 N6. 4 against chloroquine-resistant P. falciparum strainsH3PO4; molecular weight 927.48; Rhone Poulenc in vitro and P. berghei strains in mice. Piperaquine13228). Piperaquine base is a pale white to yellow and 12 of the 13 other bisquinolines showed a signif-crystalline powder with a melting point of icantly lower resistance index in vitro than chloro-212–213°C[9] and UV absorption peaks at 225, 239 quine, and good in vivo activity against P. berghei inand 340nm.[10] It is a basic compound (dissociation mice without significant toxicity. The theory thatconstant [pKa] = 8.92) that is only sparingly soluble steric inhibition of transporter-mediated drug effluxin water at neutral and alkaline pH, but has high mechanisms protects piperaquine from chloroquinelipid solubility (log10P = 6.16).[11] Piperaquine phos- resistance is also supported by the activity of otherphate is a white to pale yellow crystalline power, bulky aminoquinoline compounds (including tetra-readily soluble in water, slightly bitter, sensitive to and trisquinolines) against chloroquine-resistantlight and has a melting point 246–252°C.[12] Al- parasite strains.[23]

though commercially available in China and listed A study using electron microscopy showed dif-in the Chinese Pharmacopoeia,[13] piperaquine phos- fering morphological changes in the trophozoites ofphate is not yet included in Western pharmaco- piperaquine-sensitive and piperaquine-resistantpoeias. A synthetic 7-hydroxylated derivative of P. berghei ANKA strains.[24] Clumps of pigmentpiperaquine (4-(7-chloro-4-quinolinyl)-α-[[4-(7- were seen inside the food vacuole of the pipera-chloro-4-quinolinyl)-1-piperazinyl]methyl]-1-pip- quine-sensitive strains (also seen in sensitive para-erazineethanol;C29 H32 Cl2 N6O; molecular weight sites treated with chloroquine). Hence, these data551.51) and its tetra-phosphate salt (C29 H32 Cl2 suggest that the food vacuole is also the site ofN6O. 4 H3PO4; molecular weight 943.46) have also action of piperaquine.[25] A recent study in micebeen synthesised,[14] and shown to have antimalarial infected with P. berghei ANKA strain and treatedactivity in vitro and in animals and humans.[15-18]

with DHA and/or piperaquine phosphate, showedsimilar findings in intraerythrocytic trophozoites

3. Pharmacodynamic Profile and gametocytes. Food vacuole membranes and mi-tochondria became swollen, and multilamellatewhirls and abnormal pigment grains were seen with-3.1In Vitro Antimalarial Activityin an hour of exposure.[26] Since piperaquine con-

Bisquinolines as a class have received renewed tains the 7-chloro-4-aminoquinoline structure foundinterest in the last decade, with numerous studies in all 4-aminoquinoline drugs, it is likely that pipera-showing good antimalarial activity against chloro- quine and aminoquinolines such as chloroquinequine-resistant Plasmodium strains.[19-21] The bulky have similar targets. Evidence suggesting the inhibi-bisquinoline structure may be important for activity tion of the heme-digestion pathway in the parasiteagainst chloroquine-resistant strains, and may act by food vacuole is most convincing.[22] Haemoglobin,inhibiting the transporters that efflux chloroquine an essential source of nutrient for the parasite, isfrom the parasite food vacuole.[21,22] In 1992, Ven- normally cleaved into the toxic globin and ferricnerstrom et al.[21] examined the activity of pipera- heme (ferriprotoporphyrin IX) and is then detoxified

2005 Adis Data Information BV. All rights reserved. Drugs 2005; 65 (1)

78 Davis et al.

Table I. Concentration that produces 50% inhibition (IC50) values for piperaquine and chloroquine from in vitro resistance studies

Origin of Plasmodium falciparum strain Piperaquine IC50 (nmol/L) Chloroquine IC50 (nmol/L) Reference

South Yunnan, China 320 125 33

Southeast Yunnan, China 228 136 33

Yunnan Province, China 240 60 34

China 320 119 35

Laos 167 114 35

South Yunnan, China 243 125 36

Hainan Island, China 1720 910 37

Chloroquine-sensitive FCC-1/HN 59, 58a 81, 64a 31

Chloroquine-resistant Cambodian I 61, 89a 563, 220a 31

Chloroquine-sensitive P. falciparum 8.3 8.9 21

Chloroquine-resistant P. falciparum 16 100 21

Madagascar 26 70 38

Chloroquine-sensitive P. falciparum, Cameroon 36 42 39

Chloroquine-resistant P. falciparum, Cameroon 41 201 39

a Values are means of two separate studies.

by polymerisation or biocrystallisation to form lected from southern China increased subsequentlyin areas where piperaquine was used widely.[31,33-37]structures known as ‘haemozin’ or malarial pig-

ment.[27] Chloroquine, a highly lipophilic diprotic There are conflicting views in the literature onbase, enters the food vacuole by traversing the mem- cross-resistance between piperaquine and other anti-

malarials, in particular chloroquine and artemisininbrane in its unprotonated form before becomingderivatives.[16,22,31,40-42] In two piperaquine-resistanttrapped in the acidic environment within the vacu-strains developed in vitro by increasing drug pres-ole. It is hypothesised to act by either directly bind-sure (P. berghei ANKA and K173 PR strains),ing to ferriprotoporphyrin IX and/or by inhibitingcross-resistance was found between piperaquine andenzymatic polymerisation of haemozin.[22,28-30] Thehydroxy-piperaquine, artesunate, artemisinin andtertiary nitrogens are possible sites of protonation onmefloquine. In other strains, cross-resistance be-piperaquine and may allow the drug to act in atween piperaquine and pyronaridine was reported tosimilar way to chloroquine.be moderate. Studies showing cross-resistance be-tween piperaquine and primaquine are inconclusive,

3.2 Parasite Resistance to Piperaquine with one reporting complete lack of cross-resistancewhile another showed minimal cross-resis-

Table I summarises in vitro parasite sensitivity tance.[40,41] A recent study of bisquinolines bydata for piperaquine and chloroquine. The 50% in- Basco and Ringwald[39] found that piperaquine washibitory concentration (IC50) of parasite isolates highly active against P. falciparum, with a meanfrom China suggests that widespread unregulated IC50 of 39 nmol/L (range 8–78 nmol/L), and wasuse of piperaquine as a monotherapy in China since also equally active against chloroquine-sensitivethe late 1970s has played a significant role in the and -resistant strains from Cameroon.development of parasite resistance. Although meth- The presence of cross-resistance between pipera-odological differences in the in vitro test methods quine and chloroquine is supported by other in vitromake comparisons between studies difficult, IC50 studies of isolates collected from the Chinese prov-values from Chinese isolates during the early 1980s inces of Yunnan and Hainan and the China-Laoswere comparable with those of wild strains from border.[33,35-37] Yang et al.[35] reported that >95% ofMadagascar where piperaquine had not been chloroquine-resistant P. falciparum exhibited cross-used.[31,32] However, the IC50 values of isolates col- resistance to piperaquine and amodiaquine. How-

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Piperaquine in Malaria 79

ever, there are no clinical or in vitro studies to in some studies are most likely to be related tosuggest the occurrence of cross-resistance between differences in solubility.piperaquine and artemisinin derivatives and/ormefloquine in P. falciparum. In vitro studies that

3.4 Clinical Studies in Humansreport the absence of cross-resistance betweenpiperaquine and chloroquine also report a general

Piperaquine phosphate was first used for humanlack of cross-resistance with other 4-aminoqui-antimalarial prophylaxis in China in 1979. Morenolines, including amodiaquine.[22,31,32]

than 20 000 residents in six provinces were givenTo our knowledge, there are no published studiespiperaquine alone or as piperaquine phosphate in theassessing in vitro the possibility of an interaction‘preventive tablet number 3’ (equivalent to pipera-between piperaquine and artemisinin derivatives.quine base 150mg with sulfadoxine 50mg).[1,45] InSignificant synergism of the combination wouldHainan province, >3000 residents were givenhelp to overcome parasite resistance to either com-600mg of piperaquine base or four tablets of ‘pre-ponent. In the case of chloroquine, there is evidenceventive tablet number 3’ (piperaquine base 600mgof mild antagonism with the artemisinin drugs,[43]

plus sulfadoxine 200mg) each month. Malaria inci-but the clinical relevance of this is questionable.dence steadily decreased from 2.8% to 1.4% over 3months, while untreated residents recorded an inci-

3.3 Animal Studies dence ranging from 5.8% to 10.3%.[46] These resultsare consistent with another study that used three orfour tablets of ‘preventive tablet number 3’ (pipera-Studies in mice infected with chloroquine-sensi-quine base 450–600mg plus sulfadoxinetive or -resistant strains of P. berghei found pipera-150–200mg). Malaria incidence over 28 days wasquine and piperaquine phosphate to have differentsignificantly different between 973 treated residentspotencies in prophylactic and therapeutic roles. The(0.13–2.8%) and 7608 untreated controlsdoses of piperaquine and piperaquine phosphate re-(9.8–23.2%).[1,47]quired to suppress infections were found to be sig-

nificantly different (piperaquine base 87 ± 4 mg/kg After 1979, piperaquine replaced chloroquine asand piperaquine phosphate equivalent to 65 ± 3mg first-line treatment of chloroquine-resistant P. falci-of base/kg; p < 0.01).[42] In the same study, in vivo parum in China. Hence, piperaquine was often usedcurative doses of piperaquine and piperaquine phos- as a comparison arm in studies evaluating efficacyphate against chloroquine-sensitive and -resistant of new drugs and/or formulations (table II).[16,48-52]

P. berghei strains were also determined. ED50 (dose The doses in the standard clinical regimen mostlyproducing a 50% effective response) values were varied between the equivalent of piperaquine base5.0 ± 0.2 mg/kg (piperaquine base) and 4.5 ± 1.5–3.0g given in divided doses over 2 or 3 days.[48]

0.1 mg/kg (base equivalent of piperaquine phospha- Trials utilising dosages in this range had recrudes-te) in chloroquine-sensitive strains, and 22.3 ± cence rates ranging from 0% to 37%, and one trial1.2 mg/kg and 19.1 ± 0.8 mg/kg (piperaquine base that used a lower dose equivalent to piperaquineand base equivalent of piperaquine phosphate, re- base (0.75g) had a recrudescent rate of 80%. Withspectively) in chloroquine-resistant strains. These doses of piperaquine base 1.5 or 1.8g, mean feverdata suggest low-level cross-resistance between clearance time ranged from 17 to 36 hours and meanpiperaquine and chloroquine.[42] Another study also parasite clearance times from 61 to 105 hours. It isshowed piperaquine phosphate to be more potent important to note that some studies reporting feverthan piperaquine base in protecting rodents from P. and parasite clearance time values outside of theseberghei malaria over 45 days (50 and 200 mg/ ranges used lower than usual dosages.[49] However,kg).[44] In our view, the differences in potency be- these studies should be interpreted cautiously astween piperaquine and piperaquine phosphate seen sample sizes varied widely (n = 5–56), and the doc-

2005 Adis Data Information BV. All rights reserved. Drugs 2005; 65 (1)

80 Davis et al.

Table II. Clinical efficacy of piperaquine (base) monotherapy in humans

No. of Total dose FCT (h) PCT (h) Follow-up Recrudescence Resistance Referencepatients (g) [mean ± SD] [mean ± SD] (d) (%)

51 1.5 17 ± 6 105 ± 17 28 37 10 RI; 11 RII; 13 RIII 52

5 0.75 46 ± 53 122 ± 48 28 80 2 RI/RII; 1 RIII 50

53 1.5 36 ± 21 70 ± 21 28 13 7 RI 49

53 1.5 28 ± 22 100 ± 20 28 17 7RI; 2RII 51

15 1.8 NA 60 ± 10 28 27 NA 48

15 3.0 NA 61 ± 19 28 20 NA 48

3 1.5 24–48 48–72 0 NA NA 53

43 1.8 <72 34–48 (n = 24) 7 0 0% 158–72 (n = 19)

FCT = fever clearance time; NA = not applicable; PCT = parasite clearance time; RI = prompt and sustained asexual parasite clearance today 7 but reappearance before day 28; RII = >75% fall in asexual parasitaemia by 48h but not clearance, plus persistent parasitaemia onday 7; RIII = <25% fall in asexual parasitaemia by 48h, plus persistent parasitaemia on day 7.

umentation of patient randomisation and follow-up comparable with that of artesunate, which is mostprocedures was limited. often used in combination with mefloquine.[3,61]

The efficacy of piperaquine has also been evalu- CV8 was the first DHA and piperaquine phos-ated in the treatment of vivax malaria.[54] In a study phate combination to be incorporated into nationalof 280 patients, a total dose of piperaquine phospha- treatment recommendations in Vietnam. There arete (1.5g over 2 days) was compared with a combina- plans for extensive postmarketing surveillance.[3] Intion of chloroquine base (1.2g) and primaquine central and southern Vietnam, a 3-day regimen is(30mg). The authors concluded that the two regi- used as the first-line treatment and local journalsmens had similar efficacy. have reported a 28-day cure rate of at least

96%.[4,5,62,63] A recently published study has shown3.5 Piperaquine as a Part of it to be as effective as atovaquone-proguanil forArtemisinin-Based Combination Therapy treatment of uncomplicated malaria (28-day cure

rates 94% and 95% for CV8 [n = 84] and atova-While the widespread introduction of the potentquone/proguanil [n = 81], respectively).[64] Withartemisinin derivatives has proved to be highly suc-good tolerability and low cost,[65] the combinationcessful, it is imperative that they be used in conjunc-has advantages over artesunate-mefloquine, whichtion with a second antimalarial drug in order tois the usual ACT used in Vietnam.[66] Nevertheless,prevent the high recrudescence rates seen withdata on the pharmacokinetics and efficacy of theshort-course therapy.[55,56] This therapeutic strategyproduct are limited and safety in pregnancy, lacta-is termed artemisinin combination therapy (ACT)tion and young children are lacking. Artecom,and has been widely advocated as the most appropri-which contains piperaquine phosphate, DHA andate strategy for antimalarial treatment.[57-59] How-trimethoprim, is currently registered in China andever, the choice of a partner drug depends primarilyVietnam[67] but has had limited use. It has beenon cost, tolerability and pre-existing drug resistance.superseded by Artekin and Duo-Cotecxin.Piperaquine rates well on all three of these issues

and, therefore, appears to be an excellent partner The first published report of the efficacy ofdrug for ACT.[2,8,60] Artekin in humans was of a study of 106 Cambodi-

an patients (76 children and 30 adults) with uncom-Combinations of piperaquine phosphate withplicated falciparum malaria.[8] The study showedDHA produced and marketed by Chinese andexcellent efficacy using a four-dose regimen (meanVietnamese pharmaceutical companies are sum-total doses according to age were DHA 6.6–10.1marised in table III. Although DHA has had limitedmg/kg and piperaquine phosphate 52.9–81.2 mg/kg)clinical use as monotherapy, its oral absorption is

2005 Adis Data Information BV. All rights reserved. Drugs 2005; 65 (1)

Piperaquine in Malaria 81

delivered over 32 hours, with 98.6% and 92.3% reintroducing piperaquine as a candidate anti-28-day cure rates in children and adults, respective- malarial agent,[3] and in an animal toxicology studyly.[8] A subsequent study using the same regimen in by Sheng et al.,[70] its t1/2 in dogs was quoted as 9.4a further 62 Cambodian patients (32 adults, includ- days, but details of how this figure was derived wereing ten with P. vivax, and 30 children with P. not given in either publication.falciparum) performed in an area of high chloro-

4.2 Clinical Studies in Humansquine resistance demonstrated 100% 28-day curerates in all groups.[68] The findings of these two

The first pharmacokinetic data of piperaquine instudies were subsequently confirmed in a large,humans were published by Hung et al.[71] from stud-randomised trial of Artekin, Artecom andies in Cambodian children and adults with uncom-artesunate-mefloquine.[2] The 56-day cure rate wasplicated P. falciparum and P. vivax malaria treated98.7% in 166 patients treated with Artekin usingwith Artekin 2 tablets containing DHA 40mg andsimilar dosages to those in the first report[8] adminis-piperaquine phosphate 320mg or Artekin 2 gran-tered over 48 hours. Artecom also proved to beules for dissolution in water (DHA 15mg, pipera-highly effective in this study, with a 56-day cure ratequine phosphate 120mg per sachet; used in youngerof 97.4% in a group of 157 patients. The 56-day curechildren). Four equal doses were administered at 0,rate for artesunate-mefloquine was 98.7%6, 24 and 32 hours with mean total doses of pipera-quine base of 32–35 mg/kg. Using a population4. Pharmacokinetic Profilepharmacokinetic approach, a two-compartmentopen model with first-order absorption, with or

4.1 Animal Studieswithout a lag time, was fitted to the data. Simulated

A study in 1979 using 14C-labelled piperaquine concentration-time plots (using the population para-phosphate found that absorption from the gut in meters reported by Hung et al.[71]), for both adultsmice was rapid with a high systemic availability and children with malaria are shown in figure 2.(80–90%).[69] During the 1-month observation Absorption was slow, with mean absorption half-period, piperaquine accumulated preferentially in times (t1/2,abs) of 9.1 and 9.3 hours in adults andthe liver, kidney and spleen and the calculated half- children, respectively. The mean terminal elimina-life (t1/2) was 9 days. However, these studies mea- tion half-life (t1/2,z) was long in both adults (543sured total 14C and the results are of limited value as hours) and children (324 hours), while the meanradiolabeled metabolites may also have been pre- volume of distribution at steady state/bioavailabilitysent, which contributed differentially to the total 14C (Vss/F) was very large in adults (574 L/kg) andmeasurements over time.[69] A preliminary investi- children (614 L/kg). Clearance/bioavailability (CL/gation using solvent extraction and paper chroma- F) was approximately twice as high in childrentography on urine from two mice fed 14C-pipera- (1.85 L/h/kg) compared with adults (0.9 L/h/kg). Itquine found no evidence for the presence of radio- is of interest that the Artekin formulations used inlabeled metabolites.[69] In a WHO report these studies achieved plasma piperaquine concen-

Table III. Contents of piperaquine phosphate and other ingredients in combination antimalarial tablets

Trade name Piperaquine phosphate (mg) Dihydroartemisinin (mg) Trimethoprim (mg) Primaquine (mg)

CV-8a 320 32 90 5

Artecoma 320 32 90 0

Artekinb, Duo-Cotecxinc 320 40 0 0

a Central Pharmaceutical Factory 26, Ho Chi Minh City, Vietnam; Tonghe Pharmaceutical Co. Ltd, Chongqing, PR China (http://www.artecom.com.cn).

b Holleykin Pharmaceutical Co. Ltd, Guangzhou, PR China.

c Beijing Holley-Cotec Pharmaceuticals Co. Ltd, Beijing, PR China (http://www.cotecxin.com).

2005 Adis Data Information BV. All rights reserved. Drugs 2005; 65 (1)

82 Davis et al.

The metabolism of piperaquine in humans hasnot been studied in detail. Hung et al.[9] found noevidence for conversion to 7-hydroxy piperaquine,while a recent study of piperaquine oral bioavaila-bility in volunteers reported that a minor unidenti-fied putative metabolite peak in plasma (high-per-formance liquid chromotography [HPLC] retentiontime 11.5 minutes versus 4.8 minutes for pipera-quine) from some individuals.[73] Lindegardh etal.[72,74] have also documented the presence of apossible metabolite that appears in blood samplestaken about 2 hours after oral piperaquine adminis-tration and is detected as a small peak with a longerHPLC retention time than piperaquine. Chro-matograms published by Lindegardh et al.[74] sug-gest that there may be a more polar metabolite aswell. Since piperaquine has no primary functional

Time (days)

1

10

100

300

423528211470

Pip

eraq

uine

(µg

/L)

Fig. 2. Simulated piperaquine concentration-time profiles in adults(solid line), and children (dotted line) following oral piperaquinedoses at 0, 6, 24 and 32 hours (total dose 32 mg/kg as base).Profiles are based on the population pharmacokinetic model andmean pharmacokinetic parameters for patients with falciparum orvivax malaria, as reported by Hung et al.[71]

groups that could form phase 2 polar metabolites, itseems likely that a phase 1 oxidative process some-trations that were generally above reported IC50where on the ring structures may be a necessaryvalues for piperaquine (4.4 and 8.6 mg/L in sensi-prerequisite step for production of this putative me-tive and resistant P. falciparum strains, respective-tabolite.ly).[21]

Similar pharmacokinetic characteristics are seenPiperaquine concentrates moderately in redwith other highly lipid-soluble antimalarials. Forblood cells with a mean red blood cell : plasma ratioexample, Vdss/F is large and t1/2,z relatively long forof 1.5 at 46% haematocrit and over the plasmachloroquine (115 L/kg, 3–14 days, respectively),[75]

concentration range 50–500 µg/L.[9] Plasma proteinhalofantrine (125 L/kg; 1–3 days)[76] and meflo-binding of piperaquine has not been measured di-quine (19 L/kg; 17 days).[77] Administration of

rectly but is estimated to be around 97%.[9] Linde-mefloquine,[77] atovaquone[78] or halofantrine[76]

gardh[72] has shown that piperaquine concentrationswith a fatty meal has also been shown to significant-

in EDTA and heparinised plasma are equivalent,ly increase the area under the respective plasma

while serum concentrations prepared from the sameconcentration-time curves. The high molecular

blood are approximately 58% higher.[72] This mayweight of piperaquine, together with its pharmaco-

be because the clotting process releases drug con- kinetic properties suggests that it may undergo en-centrated in leucocytes and/or thrombocytes.[72]

terohepatic recycling. Interestingly, Chen et al.[69]

A recent crossover study in healthy Caucasian have presented radiolabeled distribution and excre-volunteers compared the bioavailability of pipera- tion data that they interpreted as supporting enter-quine tablets (piperaquine phosphate 500mg = ohepatic recycling as the main pathway for pipera-piperaquine base 289mg) fasting and after a quine excretion in mice.standard high-fat breakfast.[73] After the high-fatmeal, both maximum serum concentration and area 5. Toxicity and Tolerabilityunder the concentration-time curve from 0 to lasttimepoint increased significantly (p < 0.016), by 5.1 Animal Studies172% and 134%, respectively, suggesting that theabsorption of piperaquine may be facilitated by the Sheng et al.[70] determined the LD50 (dose that ispresence of fat in the diet. lethal to 50% of animals tested) and ED50 for

2005 Adis Data Information BV. All rights reserved. Drugs 2005; 65 (1)

Piperaquine in Malaria 83

chloroquine and piperaquine in mice. On a molar The chronic toxicity of piperaquine phosphatebasis, the data suggest that piperaquine is less toxic was also investigated by Sheng et al.[70] in twothan chloroquine, with the putative therapeutic in- studies in dogs and one in monkeys. In the firstdex for piperaquine being over five times greater study in dogs, piperaquine was given at a dose ofthan that for chloroquine (table IV).[70] In dogs ad- 100 mg/kg weekly for 14 weeks. Serum ALT, aministered piperaquine phosphate 100 or 200 mg/kg sensitive indicator of hepatocellular damage, wasorally (n = 9 and 4, respectively), vomiting occurred consistently elevated in one of four treated dogs andin 67–75% and tremor in 11–25%, while one of four occasionally raised in the other three, but theseanimals died after the 200 mg/kg dose.[70] Acute abnormalities resolved rapidly after cessation of thetoxicity was also investigated in 13 monkeys admin- drug. Blood urea nitrogen was not altered by pipera-istered doses of piperaquine phosphate ranging from quine treatment.25 to 200 mg/kg. Tremor was absent and there were In a second study,[70] weekly haematological andno deaths, while vomiting was frequently seen at the blood chemistry studies were performed in six dogs100 and 200 mg/kg doses.[70]

during and after piperaquine 6 mg/kg weekly for 6In rabbits, acute cardiovascular toxicity of piper- months. Hepatotoxicity was the main feature, with

aquine phosphate was compared with that of chloro- raised serum ALT levels in two dogs. Minor revers-quine phosphate by determining the cumulative in- ible depression of total white blood cell and neutro-travenous doses that caused a fall in blood pressure phil counts was also observed. These latter changesor electrocardiographic abnormalities.[70] In general, were not attributed to bone marrow depression.piperaquine had a significantly better cardiovascular There were no urinary abnormalities and histopatho-toxicity profile than chloroquine. The dose needed logical examinations of kidney sections were alsoto produce a 40mm Hg lowering of blood pressure normal at the end of the study. By contrast, his-was 2.6 times higher for piperaquine (42 mg/kg) topathological examination of the liver at study endthan chloroquine (16 mg/kg). Prolongation of the showed changes in all animals. There were areas ofelectrocardiographic PR interval and QRS duration cell proliferation and fibrosis as well as phagocyteswas commonly observed (70% and 40% of rabbits and Kupffer cells with brown inclusions. Thesefor piperaquine, and 100% and 100% of rabbits for changes were less evident 3 months after the dosingchloroquine, respectively), but the cumulative dose was ceased and were also less evident for the sameof piperaquine associated with this toxicity dose administered over a 2-week period.(50–56 mg/kg) was about 5-fold higher than that for In the study in monkeys,[70] piperaquine was giv-chloroquine (9–11 mg/kg). Atrioventricular block en as 25 mg/kg weekly for 3 months or 50 mg/kgwas present in 100% of rabbits after a cumulative every 2 weeks for 5 months. Histopathologicalchloroquine dose of 19 mg/kg, whereas only two changes in the liver at the end of these periods wereanimals showed this effect with piperaquine at a less evident than in the dog experiments. As in dogs,cumulative dose of 50 mg/kg. ST segment depres- there was a mild reversible depression of total whitesion was seen in 90% of rabbits with piperaquine cell and neutrophil counts but no suppression of(35 mg/kg) but was not seen with chloroquine. bone marrow.

Consistent with studies in dogs and monkeys, astudy of liver ultrastructure in mice treated acutelywith piperaquine phosphate 1000 mg/kg andsulfadoxine 100 mg/kg revealed immediate (4 hoursafter dosing) evidence of damage to hepatic mito-chondria, and both smooth and rough endoplasmicreticulum.[79] These changes gradually decreasedover time and 2–3 months later most cells were

Table IV. LD50 (dose that is lethal to 50% of animals tested), ED50

(dose that produces a 50% effective response) and therapeuticindex of piperaquine phosphate and chloroquine phosphate in mice

Drug LD50 ED50 Therapeutic(µmol/kg) (µmol/kg) index

Piperaquine 1184 4.3 275phosphate

Chloroquine 849 20 42phosphate

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84 Davis et al.

normal, although some hepatocytes still contained drugs such as chloroquine in these patient groupsfatty inclusions. suggests that piperaquine is also likely to be safely

used, use of piperaquine during pregnancy and lac-In vitro, piperaquine phosphate had no mutagenictation cannot be recommended at this time.effects in the Ames test, chromosome analysis as-

says or in sister chromatid exchange rates.[70] The6. Conclusion and Current Status ofoffspring of pregnant mice administered pipera-Piperaquine as an Antimalarial Drugquine phosphate 40–360 mg/kg for 6 days, starting

at day 9–14 of gestation, showed no evidence ofPiperaquine is an aminoquinoline antimalarialembryotoxicity or teratogenicity.[70]

with a favourable safety and toxicity profile. It iseffective against P. vivax and P. falciparum, includ-5.2 Clinical Studies in Humansing strains of P. falciparum resistant to chloroquine.However, when used extensively as monotherapy,Overall, studies have shown piperaquine mono-parasite resistance to piperaquine can develop. Itstherapy to be well tolerated with few patients report-tolerability, effectiveness, pharmacokinetic profileing adverse events.[2,48,50-52] The situation is similarand low cost make it a promising partner drug forin studies of piperaquine administered as part ofuse as part of short-course ACT. Co-formulations ofACT.[2,8,64] Common minor complaints have includ-piperaquine with DHA (Artekin and Duo-ed mild headache, dizziness, nausea, abdominal painCotecxin) have proved highly effective, well toler-and vomiting, although these symptoms are oftenated and are available at a cost as low as $US1.00/difficult to distinguish from symptoms resultingadult treatment course (2004 value).[2] This makesfrom malaria itself.[48,50-52,71] In early Chinese stud-them potentially affordable to many countries whereies, no haematological, biochemical, cardiac or hep-the burden of disease due to malaria is greatest.atic abnormalities were described, but it is unclearIndeed, piperaquine is part of national anti-malarialwhether they were specifically assessed.[48,50-52]

drug policy as monotherapy (China) or ACT (CV8Given the toxicity profile described in animalin Vietnam), while Artekin (Duo-Cotecxin) isstudies of piperaquine[70] and the pattern of toxicitycurrently registered in a number of South-East Asianobserved in humans from other closely chemicallycountries.related aminoquinoline antimalarial drugs, the most

It has been recommended that ACT incorporate aimportant potential toxicity of piperaquine wouldshort t1/2 artemisinin derivative and an effective part-relate to effects on cardiac conduction, blood pres-ner drug with a relatively long t1/2 (>4 days).[2] Al-sure regulation and on glucose metabolism. How-though long t1/2 antimalarial agents such as chloro-ever, a detailed safety and tolerability evaluationquine are particularly likely to induce resistance inperformed by Karunajeewa et al.[68] in 62 Cambodi-P. falciparum, there is evidence that ACT can pro-ans (including 32 adults and 30 children) with un-tect against this. In a study from Thailand, the addi-complicated malaria showed no significant electro-tion of artesunate to mefloquine halted the progres-cardiographic changes (including the corrected QTsion of established mefloquine resistance;[80] how-interval), changes in plasma glucose or posturalever, this study was from a low transmission area. Inhypotension following treatment with Artekin atareas of high transmission, such as found in sub-the manufacturer’s recommended doses. ConcurrentSaharan Africa, the frequency of malaria infectionpharmacokinetic data from these patients suggestand low blood piperaquine concentrations in the tailthat peak piperaquine concentrations of <800 µg/Lof the elimination phase could, through selection ofare not associated with clinically significant cardi-resistant parasite strains, limit the lifespan of treat-otoxicity. There are no published data relating to thements such as Artekin.safety of piperaquine in pregnancy, lactation or chil-

dren younger than 2 years. Although extensive ex- The raw material piperaquine is not presentlyperience with other closely related aminoquinoline manufactured to Good Manufacturing Practice

2005 Adis Data Information BV. All rights reserved. Drugs 2005; 65 (1)

Piperaquine in Malaria 85

China: World Health Organization Regional Office For the(GMP) standards, and no piperaquine-containingWestern Pacific. Manila: World Health Organization, 2002:

preparations are registered with the US FDA or 41-5211. Piperaquine. SciFinder Scholar. Columbus (OH): Americansimilar international drug regulatory bodies.

Chemical Society, 2004Artemisinin derivatives have been in a similar posi-12. Hung TY. Pharmacokinetics of piperaquine in humans [B Med

tion and yet are widely used throughout the tropics. Sci Thesis]. Crawley (WA): University of Western Australia,2002Although this does not justify the development of

13. The State Pharmacopoeia Commission of The People’s Repub-non-GMP piperaquine-based ACT, it is not surpris- lic of China. Pharmacopoeia of the People’s Republic ofChina. Beijing: Chemical Industry Press, 2000ing that formulations such as Artekin have been

14. Xu D, Shen N, Li Y, et al. Studies on the antimalarial drugdeveloped and distributed in the same way. How-hydroxypiperaquine and its phosphate. J Med Coll PLA 1988;

ever, it is encouraging to note that the Medicines for 3: 5-1215. Li J, Huang W. Effects of artesunate, pyronaridine, and hydrox-Malaria Venture organisation is actively involved in

ypiperaquine on chloroquine-sensitive and chloroquine-resis-the development of piperaquine-based ACT whichtant isolates of Plasmodium falciparum in vitro [in Chinese].

includes production of product to GMP stan- Zhongguo Yao Li Xue Bao 1988; 9: 83-616. Chen L. Recent studies on antimalarial efficacy of piperaquinedards.[81]

and hydroxypiperaquine. Chin Med J 1991; 104: 161-317. Xu D, Shen N, Yin M, et al. New antimalarial and antisilicosis

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