Efficacy and safety of dihydroartemisinin-piperaquine

Chloroquine (CQ) is an important antimalarial drug for the treatment of special patient groups and as a comparator for preclinical testing of new drugs. Pharmacokinetic data for CQ in animal models are limited; thus, we conducted a three-part investigation, comprising (i) pharmacodynamic studies of CQ and CQ plus dihydroartemisinin (DHA) in Plasmodium berghei-infected mice, (ii) pharmacokinetic studies of CQ in healthy and malaria-infected mice, and (iii) interspecies allometric scaling for CQ from 6 animal and 12 human studies. The single-dose pharmacodynamic study (10 to 50 mg CQ/kg of body weight) showed dose-related reduction in parasitemia (5-to >500-fold) and a nadir 2 days after the dose. Multiple-dose regimens (total dose, 50 mg/kg CQ) demonstrated a lower nadir and longer survival time than did the same single dose. The CQ-DHA combination provided an additive effect compared to each drug alone. The elimination half-life (t 1/2 ), clearance (CL), and volume of distribution (V) of CQ were 46.6 h, 9.9 liters/h/kg, and 667 liters/kg, respectively, in healthy mice and 99.3 h, 7.9 liters/h/kg, and 1,122 liters/kg, respectively, in malaria-infected mice. The allometric equations for CQ in healthy mammals (CL ‫؍‬ 3.86 ؋ W 0.56 , V ‫؍‬ 230 ؋ W 0.94 , and t 1/2 ‫؍‬ 123 ؋ W 0.2 ) were similar to those for malaria-infected groups. CQ showed a delayed dose-response relationship in the murine malaria model and additive efficacy when combined with DHA. The biphasic pharmacokinetic profiles of CQ are similar across mammalian species, and scaling of specific parameters is plausible for preclinical investigations.Chloroquine (CQ) was introduced 50 years ago as an alternative to quinine (25,70). It became the drug of choice for both prophylaxis and treatment of malaria, but resistance has caused a decline in the contemporary clinical use of chloroquine (25,35,40,70,72). Nevertheless, CQ remains one of the most important antimalarial drugs, especially in the treatment of vivax malaria and special patient groups, such as children and pregnant women (32,37,48,51,73), not least because it is inexpensive and well tolerated and has a rapid onset of action. Recent studies have clarified the mechanism of CQ resistance and shown that clinical efficacy of CQ may return at least a decade after it has been withdrawn from use, prompting suggestions that CQ could reemerge as an important therapeutic option for malaria, most likely in combination with artemisinin compounds or chemosensitizing agents (25,28,36,42,45,70).Notwithstanding its clinical status, CQ has a prominent role as a comparator for in vitro and in vivo preclinical testing of new antimalarial drugs (54,56,68,74). Remarkably, there is a paucity of pharmacokinetic and pharmacodynamic data for CQ in preclinical animal models, particularly in murine malaria models (4,11,29).The pharmacokinetic parameters for CQ exhibit wide interindividual variation, although limitations in study design and analytical procedures have been contributing factors (18,64,65). Recent clinical stud...

Section: Discussionsupporting

confidence: 68%

Pharmacokinetics, Pharmacodynamics, and Allometric Scaling of Chloroquine in a Murine Malaria Model

Moore

Page‐Sharp

Stoney

et al. 2011

“…On the basis of the findings of our study, it is feasible that the reemergence of PQ-resistant strains of P. falciparum could occur as a result of the presence of residual PQ following ACT, because antimalarials with long t 1/2 s are considered to be more likely to select for drug resistance (4,22,33). However, to our knowledge, there are no clinical reports of resistance to PQ as a result of PQ-based ACT, which may reflect the high success rates associated with this regimen (1,2,5,11,12,20,24,28,30).…”

Section: Discussionmentioning

confidence: 99%

“…While this combination is now considered the first-line antimalarial treatment in some Southeast Asian countries, the long t 1/2 of PQ raises concerns about adverse effects and drug resistance (6,10,20,22). Detailed preclinical pharmacodynamic data for PQ, alone or in combination with artemisinin drugs, would complement clinical studies, especially when there is interest in the therapeutic impact of persistent, low PQ concentrations.…”

mentioning

confidence: 99%

Piperaquine Pharmacodynamics and Parasite Viability in a Murine Malaria Model

Moore

Ilett²,

Page‐Sharp³

et al. 2009

Piperaquine (PQ) is an important partner drug in antimalarial combination treatments, but the long half-life of PQ raises concerns about drug resistance. Our aim was to investigate the extended antimalarial effect of PQ in a study of drug efficacy, reinoculation outcomes, and parasite viability after the administration of a single dose of PQ in the murine malaria model. Initially, male Swiss mice were inoculated with Plasmodium berghei and at 64 h after parasite inoculation were given PQ phosphate at 90 mg/kg of body weight intraperitoneally. Parasite viability, drug efficacy, reinoculation responses, and parasite resistance were determined at 25, 40, 60, 90, and 130 days after drug administration. At each time point, six mice were reinoculated with 10 7 P. berghei parasites and blood was harvested from another four mice for viability passage into naïve mice (n ‫؍‬ 5 for each blood sample) and from another two mice for determination of the plasma PQ concentration. The efficacy study demonstrated that the residual PQ concentrations did not suppress the infection after 25 days. Viable parasites were present up to 90 days after PQ dosing, although only 50% and 25% of the passaged parasites remained viable at 60 and 90 days postdosing, respectively. Viable parasites passaged into the naïve hosts were generally resistant to PQ when they were exposed to the drug for a second time. PQ was found to have a substantial antimalarial effect in this model, and the effect appears to be sufficient for a host immunological response to be established, resulting in the long-term survival of P. berghei-infected mice.Piperaquine (PQ) is a bisquinoline antimalarial drug used in contemporary artemisinin combination treatment (ACT) strategies as a partner to dihydroartemisinin (1, 4). In order to prevent drug resistance and early parasite recrudescence associated with the short-acting artemisinin drugs, ACT partner drugs should be long-acting schizonticides with half-lives (t 1/2 s) exceeding 4 days, or two asexual parasite life cycles (10,21). Recent pharmacokinetic studies have demonstrated that PQ has biphasic elimination and a long terminal t 1/2 of 12 to 28 days in humans (10,15,31,32).Several clinical trials of the PQ-dihydroartemisinin combination have shown that it has a high degree of efficacy and good tolerability for the treatment of Plasmodium falciparum infections (1,2,5,7,11,12,17). While this combination is now considered the first-line antimalarial treatment in some Southeast Asian countries, the long t 1/2 of PQ raises concerns about adverse effects and drug resistance (6,10,20,22). Detailed preclinical pharmacodynamic data for PQ, alone or in combination with artemisinin drugs, would complement clinical studies, especially when there is interest in the therapeutic impact of persistent, low PQ concentrations.We have recently demonstrated that PQ has a biphasic elimination profile in mice and has a terminal elimination t 1/2 in malaria parasite-infected and healthy mice of 18 days and 16 days, respectively (18). The ph...

“…In 2008, an international meeting of malaria experts was held to determine the most appropriate treatment for areas where artemisinin resistance to P. falciparum had emerged (6). Dihydroartemisinin-piperaquine (DP) was selected because it had previously demonstrated high efficacy in Cambodia (7)(8)(9) and elsewhere in Southeast Asia (10). The treatment's coformulation gave it an added advantage over ASMQ, which, at the time, was only available as a co-package of the two medicines.…”

mentioning

confidence: 99%

Efficacy of Dihydroartemisinin-Piperaquine for Treatment of Uncomplicated Plasmodium falciparum and Plasmodium vivax in Cambodia, 2008 to 2010

Leang

Barrette

Bouth³

et al. 2013

163

175

We describe here the results of antimalarial therapeutic efficacy studies conducted in Cambodia from 2008 to 2010. A total of 15 studies in four sentinel sites were conducted using dihydroartemisinin-piperaquine (DP) for the treatment of Plasmodium falciparum infection and chloroquine (CQ) and DP for the treatment of P. vivax infection. All studies were performed according to the standard World Health Organization protocol for the assessment of antimalarial treatment efficacy. Among the studies of DP for the treatment of P. falciparum, an increase in treatment failure was observed in the western provinces. In 2010, the PCRcorrected treatment failure rates for DP on day 42 were 25% (95% confidence interval [CI] ‫؍‬ 10 to 51%) in Pailin and 10.7% (95% CI ‫؍‬ 4 to 23%) in Pursat, while the therapeutic efficacy of DP remained high (100%) in Ratanakiri and Preah Vihear provinces, located in northern and eastern Cambodia. For the studies of P. vivax, the day 28 uncorrected treatment failure rate among patients treated with CQ ranged from 4.4 to 17.4%; DP remained 100% effective in all sites. Further study is required to investigate suspected P. falciparum resistance to piperaquine in western Cambodia; the results of in vitro and molecular studies were not found to support the therapeutic efficacy findings. The emergence of artemisinin resistance in this region has likely put additional pressure on piperaquine. Although DP appears to be an appropriate new first-line treatment for P. vivax in Cambodia, alternative treatments are urgently needed for P. falciparum-infected patients in western Cambodia.