Piperaquine A Resurgent Antimalarial Drug
Abstract
Piperaquine is a bisquinoline antimalarial drug that was first synthesised in the 1960s, and used extensively in China and Indochina as prophylaxis and treatment during the next 20 years. A number of Chinese research groups documented that it was 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 falciparum and the emergence of the artemisinin derivatives, its use declined during the 1980s.
However, during the next decade, piperaquine was rediscovered by Chinese scientists as one of a number of compounds suitable for combination with an artemisinin derivative. The rationale for such artemisinin combination therapies (ACTs) was to provide an inexpensive, short-course treatment regimen with a high cure rate and good tolerability that would reduce transmission and protect against the development of parasite resistance. This approach has now been endorsed by the WHO.
Piperaquine-based ACT began as China-Vietnam 4 (CV4: dihydroartemis- inin [DHA], trimethoprim, piperaquine phosphate and primaquine phosphate),which was followed by CV8 (the same components as CV4 but in increased quantities), Artecom (in which primaquine was omitted) and Artekin or Duo-Cotecxin (DHA and piperaquine phosphate only). Recent Indochinese studies 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 other adverse effects.
The pharmacokinetic properties of piperaquine have also been characterised recently, revealing that it is a highly lipid-soluble drug with a large volume of distribution 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 partner drug 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,Piperaquine is a bisquinoline antimalarial drug that was synthesised independently by both the Shanghai Pharmaceutical Industry Research Insti- tute in China and Rhone Poulenc in France in the 1960s.[1] Because of its relative potency and tolera- bility, it superseded chloroquine as the antimalarial recommended by the Chinese National Malaria Control Programme in 1978, and the equivalent of 140 million adult treatment doses were subsequently manufactured and distributed.[2] With the develop- ment of piperaquine-resistant strains of Plasmodium falciparum and the appearance of the artemisinin derivatives, piperaquine use diminished in the 1980s.
In 1990, Chinese scientists ‘rediscovered’ piper- aquine as one of a number of components of short- course artemisinin-based combination therapies for- mulated to achieve a high cure rate without signif- icant adverse effects. The first of these was China- Vietnam 4 (CV4)1, which contained dihy- droartemisinin (DHA), trimethoprim, piperaquine phosphate and primaquine phosphate.[2] Initial there were three concerns with CV8. First, the role of trimethoprim was questionable since, like other antibacterial agents, it does not have prompt and potent antimalarial activity. Secondly, there is a high rate of glucose-6-phosphate dehydrogenase defi- ciency amongst Asian populations, especially in eth- nic minorities in countries such as Vietnam.[6] Red cell haemolysis, sometimes fatal, can occur in this situation if primaquine is given. Thirdly, the dose of DHA in the original formulation of CV8 (10mg per tablet) resulted in a total dose that was much lower than recommended when DHA alone is used for the initial treatment of acute malaria (80mg over 2 days vs 480mg over 7 days).
The most recent changes to CV8 have seen primaquine excluded (Artecom)[7] and, more re- cently, both primaquine and also trimethoprim ex- cluded (Artekin 2, which was renamed as Artekin).[2,8] In the case of Artecom, Artekin and the most recent formulations of CV8, the DHA content of each tablet has been increased to a total dose of 256mg over 2–3 days.small-scale, nonrandomised trials in China and In- 2. Chemical Structure and dochina led to the reformulation of CV4 as Physicochemical Properties CV8,[3] which was the same drug combination as
CV4 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-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 series quine phosphate (figure 1; C29 H32 Cl2 N6. 4 against chloroquine-resistant P. falciparum strains H3PO4; molecular weight 927.48; Rhone Poulenc in vitro and P. berghei strains in mice. Piperaquine 13228). 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- 212–213C[9] and UV absorption peaks at 225, 239 quine, and good in vivo activity against P. berghei in and 340nm.[10] It is a basic compound (dissociation mice without significant toxicity. The theory that constant [pKa] = 8.92) that is only sparingly soluble steric inhibition of transporter-mediated drug efflux in water at neutral and alkaline pH, but has high mechanisms protects piperaquine from chloroquine lipid solubility (log10P = 6.16).[11] Piperaquine phos- resistance is also supported by the activity of other phate 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-resistant light and has a melting point 246–252C.[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 of phate is not yet included in Western pharmaco- piperaquine-sensitive and piperaquine-resistant poeias. A synthetic 7-hydroxylated derivative of P. berghei ANKA strains.[24] Clumps of pigment piperaquine (4-(7-chloro-4-quinolinyl)--[[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 data 551.51) and its tetra-phosphate salt (C29 H32 Cl2 suggest that the food vacuole is also the site of N6O. 4 H3PO4; molecular weight 943.46) have also action of piperaquine.[25] A recent study in mice been synthesised,[14] and shown to have antimalarial infected with P. berghei ANKA strain and treated activity in vitro and in animals and humans.[15-18] with DHA and/or piperaquine phosphate, showed similar findings in intraerythrocytic trophozoites.
Fig. 1. Chemical structure of piperaquine phosphate (1,3-bis[1-(7-chloro-4-quinolyl)-4-piperazinyl] phosphate).
3. Pharmacodynamic Profile and gametocytes. Food vacuole membranes and mitochondria became swollen, and multilamellate
3.1 In Vitro Antimalarial Activity
Bisquinolines as a class have received renewed tains the 7-chloro-4-aminoquinoline structure found interest 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 chloroquine quine-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 parasite against 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, is from the parasite food vacuole.[21,22] In 1992, Ven- normally cleaved into the toxic globin and ferric nerstrom et al.[21] examined the activity of pipera- heme (ferriprotoporphyrin IX) and is then detoxifiedby polymerisation or biocrystallisation to form lected from southern China increased subsequently structures known as ‘haemozin’ or malarial pig- in areas where piperaquine was used widely.[31,33-37]
3.2 Parasite Resistance to Piperaquine with one reporting complete lack of cross-resistance
while another showed minimal cross-resis- Table I summarises in vitro parasite sensitivity tance.[40,41] A recent study of bisquinolines by data for piperaquine and chloroquine. The 50% in- Basco and Ringwald[39] found that piperaquine was hibitory concentration (IC50) of parasite isolates highly active against P. falciparum, with a mean from China suggests that widespread unregulated IC50 of 39 nmol/L (range 8–78 nmol/L), and was use of piperaquine as a monotherapy in China since also equally active against chloroquine-sensitive the 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 vitro make 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-Laos were comparable with those of wild strains from border.[33,35-37] Yang et al.[35] reported that >95% of Madagascar 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. However, there are no clinical or in vitro studies to in some studies are most likely to be related to suggest the occurrence of cross-resistance between differences in solubility.
To our knowledge, there are no published studies assessing in vitro the possibility of an interaction between piperaquine and artemisinin derivatives. Significant synergism of the combination would help to overcome parasite resistance to either com- ponent. In the case of chloroquine, there is evidence of mild antagonism with the artemisinin drugs,[43] but the clinical relevance of this is questionable.
Piperaquine phosphate was first used for human antimalarial prophylaxis in China in 1979. More than 20 000 residents in six provinces were given piperaquine alone or as piperaquine phosphate in the ‘preventive tablet number 3’ (equivalent to pipera- quine base 150mg with sulfadoxine 50mg).[1,45] In Hainan province, >3000 residents were given 600mg of piperaquine base or four tablets of ‘pre- ventive tablet number 3’ (piperaquine base 600mg plus sulfadoxine 200mg) each month. Malaria inci- dence steadily decreased from 2.8% to 1.4% over 3 months, while untreated residents recorded an inci-
3.3 Animal Studies dence ranging from 5.8% to 10.3%.[46] These results are consistent with another study that used three or
Studies in mice infected with chloroquine-sensi- tive or -resistant strains of P. berghei found pipera- quine and piperaquine phosphate to have different potencies in prophylactic and therapeutic roles. The doses of piperaquine and piperaquine phosphate re- quired to suppress infections were found to be significantly different (piperaquine base 87 4 mg/kg After 1979, piperaquine replaced chloroquine as and 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 used curative doses of piperaquine and piperaquine phos- as a comparison arm in studies evaluating efficacy phate against chloroquine-sensitive and -resistant of new drugs and/or formulations (table II).[16,48-52]
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 national of 280 patients, a total dose of piperaquine phospha- treatment recommendations in Vietnam. There are te (1.5g over 2 days) was compared with a combina- plans for extensive postmarketing surveillance.[3] In tion 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 journals mens had similar efficacy. have reported a 28-day cure rate of at least 96%.[4,5,62,63] A recently published study has shown
3.5 Piperaquine as a Part of it to be as effective as atovaquone-proguanil for
Artemisinin-Based Combination Therapy treatment of uncomplicated malaria (28-day cure While the widespread introduction of the potent artemisinin derivatives has proved to be highly suc- cessful, it is imperative that they be used in conjunc- tion with a second antimalarial drug in order to prevent the high recrudescence rates seen with short-course therapy.[55,56] This therapeutic strategy is termed artemisinin combination therapy (ACT) and has been widely advocated as the most appropri- ate strategy for antimalarial treatment.[57-59] How- ever, the choice of a partner drug depends primarily on cost, tolerability and pre-existing drug resistance. Piperaquine rates well on all three of these issues rates 94% and 95% for CV8 [n = 84] and atova- quone/proguanil [n = 81], respectively).[64] With good tolerability and low cost,[65] the combination has advantages over artesunate-mefloquine, which is the usual ACT used in Vietnam.[66] Nevertheless, data on the pharmacokinetics and efficacy of the product are limited and safety in pregnancy, lacta- tion and young children are lacking. Artecom, which contains piperaquine phosphate, DHA and trimethoprim, is currently registered in China and Vietnam[67] but has had limited use. It has been superseded by Artekin and Duo-Cotecxin.and, therefore, appears to be an excellent partner The first published report of the efficacy of drug for ACT.[2,8,60] Artekin in humans was of a study of 106 Cambodi-
Combinations of piperaquine phosphate with DHA produced and marketed by Chinese and Vietnamese pharmaceutical companies are sum- marised in table III. Although DHA has had limited clinical use as monotherapy, its oral absorption is an patients (76 children and 30 adults) with uncom- plicated falciparum malaria.[8] The study showed excellent efficacy using a four-dose regimen (mean total doses according to age were DHA 6.6–10.1 mg/kg and piperaquine phosphate 52.9–81.2 mg/kg) 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 study ly.[8] A subsequent study using the same regimen in by Sheng et al.,[70] its t1/2 in dogs was quoted as 9.4 a further 62 Cambodian patients (32 adults, includ- days, but details of how this figure was derived were ing ten with P. vivax, and 30 children with P. not given in either publication.
4. Pharmacokinetic Profile
4.1 Animal Studies
4.2 Clinical Studies in Humans
The first pharmacokinetic data of piperaquine in humans were published by Hung et al.[71] from stud- ies in Cambodian children and adults with uncom- plicated P. falciparum and P. vivax malaria treated with Artekin 2 tablets containing DHA 40mg and piperaquine phosphate 320mg or Artekin 2 gran- ules for dissolution in water (DHA 15mg, pipera- quine phosphate 120mg per sachet; used in younger children). Four equal doses were administered at 0, 6, 24 and 32 hours with mean total doses of pipera- quine base of 32–35 mg/kg. Using a population pharmacokinetic approach, a two-compartment open model with first-order absorption, with or without a lag time, was fitted to the data.
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 adults mice 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 and the 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 (543 sured total 14C and the results are of limited value as hours) and children (324 hours), while the mean radiolabeled metabolites may also have been pre- volume of distribution at steady state/bioavailability sent, which contributed differentially to the total 14C (Vss/F) was very large in adults (574 L/kg) and measurements 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 children tography on urine from two mice fed 14C-pipera- (1.85 L/h/kg) compared with adults (0.9 L/h/kg). It quine found no evidence for the presence of radio- is of interest that the Artekin formulations used in labeled metabolites.[69] In a WHO report these studies achieved plasma piperaquine concentration and is detected as a small peak with a longer HPLC retention time than piperaquine. Chro- matograms published by Lindega˚rdh et al.[74] sug- gest that there may be a more polar metabolite as well. Since piperaquine has no primary functional groups that could form phase 2 polar metabolites, it seems likely that a phase 1 oxidative process some- where on the ring structures may be a necessary prerequisite step for production of this putative me- tabolite.
Similar pharmacokinetic characteristics are seen with other highly lipid-soluble antimalarials. For example, Vdss/F is large and t1/2,z relatively long for chloroquine (115 L/kg, 3–14 days, respectively),[75] halofantrine (125 L/kg; 1–3 days)[76] and meflo- quine (19 L/kg; 17 days).[77] Administration of mefloquine,[77] atovaquone[78] or halofantrine[76] with a fatty meal has also been shown to significant- ly increase the area under the respective plasma concentration-time curves. The high molecular weight of piperaquine, together with its pharmaco- kinetic properties suggests that it may undergo en- terohepatic recycling. Interestingly, Chen et al.[69]
In vitro, piperaquine phosphate had no mutagenic effects in the Ames test, chromosome analysis as- says or in sister chromatid exchange rates.[70] The offspring of pregnant mice administered pipera- quine phosphate 40–360 mg/kg for 6 days, starting at day 9–14 of gestation, showed no evidence of embryotoxicity or teratogenicity.[70]
5.2 Clinical Studies in Humans
Overall, studies have shown piperaquine mono- therapy to be well tolerated with few patients report- ing adverse events.[2,48,50-52] The situation is similar in studies of piperaquine administered as part of ACT.[2,8,64] Common minor complaints have includ- ed mild headache, dizziness, nausea, abdominal pain and vomiting, although these symptoms are often difficult to distinguish from symptoms resulting from malaria itself.[48,50-52,71] In early Chinese stud- ies, no haematological, biochemical, cardiac or hep- atic abnormalities were described, but it is unclear whether they were specifically assessed.[48,50-52]
Given the toxicity profile described in animal studies of piperaquine[70] and the pattern of toxicity observed in humans from other closely chemically related aminoquinoline antimalarial drugs, the most important potential toxicity of piperaquine would relate to effects on cardiac conduction, blood pres- sure regulation and on glucose metabolism. How- ever, a detailed safety and tolerability evaluation performed by Karunajeewa et al.[68] in 62 Cambodi- ans (including 32 adults and 30 children) with un- complicated malaria showed no significant electro- cardiographic changes (including the corrected QT interval), changes in plasma glucose or postural hypotension following treatment with Artekin at the manufacturer’s recommended doses. Concurrent pharmacokinetic data from these patients suggest that peak piperaquine concentrations of <800 g/L are not associated with clinically significant cardi- otoxicity. There are no published data relating to the safety of piperaquine in pregnancy, lactation or used, use of piperaquine during pregnancy and lac- tation cannot be recommended at this time.
6. Conclusion and Current Status of Piperaquine as an Antimalarial Drug
Piperaquine is an aminoquinoline antimalarial with a favourable safety and toxicity profile. It is effective against P. vivax and P. falciparum, includ- ing strains of P. falciparum resistant to chloroquine. However, when used extensively as monotherapy, parasite resistance to piperaquine can develop. Its tolerability, effectiveness, pharmacokinetic profile and low cost make it a promising partner drug for use as part of short-course ACT. Co-formulations of piperaquine with DHA (Artekin and Duo- Cotecxin) have proved highly effective, well toler- ated and are available at a cost as low as $US1.00/ adult treatment course (2004 value).[2] This makes them potentially affordable to many countries where the burden of disease due to malaria is greatest. Indeed, piperaquine is part of national anti-malarial drug policy as monotherapy (China) or ACT (CV8 in Vietnam), while Artekin (Duo-Cotecxin) is currently registered in a number of South-East Asian countries.
It has been recommended that ACT incorporate a short t1/2 artemisinin derivative and an effective part- ner drug with a relatively long t1/2 (>4 days).[2] Al- though long t1/2 antimalarial agents such as chloro- quine are particularly likely to induce resistance in P. falciparum, there is evidence that ACT can pro- tect against this. In a study from Thailand, the addi- tion of artesunate to mefloquine halted the progres- sion of established mefloquine resistance;[80] how- ever, this study was from a low transmission area. In areas of high transmission, such as found in sub- Saharan Africa, the frequency of malaria infection and low blood piperaquine concentrations in the tail of the elimination phase could, through selection of resistant parasite strains, limit the lifespan of treat- ments such as Artekin.