Pharmacodynamics of Doxycycline in a Murine Malaria Model

Batty, Kevin T.; Law, Angela S. F.; Stirling, Verity; Moore, Brioni R.

doi:10.1128/aac.00529-07

Cited by 13 publications

(13 citation statements)

References 20 publications

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“…Control mice that were initially uninfected and untreated (group 3) and then inoculated at each predetermined time (25,40, 60, 90, or 130 days) showed parasite density-time profiles similar to those found in previous studies (3,18,19), with rapidly rising levels of parasitemia being detected until the time of euthanasia (6 to 8 days after inoculation; peripheral level of parasitemia, Ͼ40%; Fig. 2A).…”

Section: Resultssupporting

confidence: 61%

Piperaquine Pharmacodynamics and Parasite Viability in a Murine Malaria Model

Moore

Ilett²,

Page‐Sharp³

et al. 2009

Antimicrob Agents Chemother

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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...

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Section: Resultssupporting

confidence: 61%

Piperaquine Pharmacodynamics and Parasite Viability in a Murine Malaria Model

Moore

Ilett²,

Page‐Sharp³

et al. 2009

Antimicrob Agents Chemother

Self Cite

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“…pharmacology, pharmacokinetics, and pharmaceutical properties of each drug, alone and in combination. Our studies indicate that this murine model can be a valuable preclinical tool in antimalarial drug discovery and therapeutic refinement (8,43). An essential component of in vivo antimalarial efficacy tests is determining the pharmacokinetic properties of the drug(s).…”

Section: Discussionmentioning

confidence: 99%

“…CQ were administered at 24-h intervals (these doses were used to extend survival of the mice). Blood was harvested from groups of mice (n ϭ 5) by cardiac puncture at 4,8,12, and 24 h after the first dose; 24 h after the second, third, and fourth doses; and then 1, 2, 4, 6, 8, 12, and 18 h after the fifth dose and at 5, 5.25, 5.5, 6, 6.5, 7, 8, 10, 15, 21, and 30 days after commencement of the dosage regimen. The blood was processed for CQ and DCQ measurement by HPLC and for peripheral blood films as described above.…”

Section: Maymentioning

confidence: 99%

“…Mice were anesthetized with 50 to 100 mg/kg sodium pentobarbitone 5 to 10 min prior to blood collection. Blood was harvested from groups of mice (n ϭ 5) by cardiac puncture at 10,15,20,30,45,60,75, and 90 min; 2, 2.5, 3,4,5,8,12,18,24,30,36,48, and 56 h; and 3, 4, 5, and 7 days into 1-ml lithium heparin tubes (Vacutainer; Becton Dickinson, Franklin Lakes, NJ) and centrifuged at 3,000 ϫ g for 10 min, and the plasma was separated and stored at Ϫ80°C until analyzed by high-performance liquid chromatography (HPLC) for CQ and DCQ measurement (31). A peripheral blood film was prepared from each mouse prior to CQ dosing and at the time of euthanasia to confirm that the parasitemia data in the pharmacokinetic study mice were consistent with the pharmacodynamic study (data not shown).…”

Section: Maymentioning

confidence: 99%

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

Moore

Page‐Sharp

Stoney

et al. 2011

Antimicrob Agents Chemother

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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...

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“…A modified Thompson method compares the efficacy of a fixed total dose administered via different regimens and is a plausible approach for investigating ACT regimens . A variation of this method comprises a range of doses to mice over a 3 day period, commencing 3 days after inoculation . Well‐designed studies based on this method, with rich PK and PD data, could be used to develop mechanism based PK–PD models of individual and combination drug regimens.…”

Section: Models In Preclinical Evaluationmentioning

confidence: 99%

Modelling the time course of antimalarial parasite killing: a tour of animal and human models, translation and challenges

Patel

Simpson

Batty

et al. 2014

Brit J Clinical Pharma

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Malaria remains a global public health concern and current treatment options are suboptimal in some clinical settings. For effective chemotherapy, antimalarial drug concentrations must be sufficient to remove completely all of the parasites in the infected host. Optimized dosing therefore requires a detailed understanding of the time course of antimalarial response, whilst simultaneously considering the parasite life cycle and host immune elimination. Recently, the World Health Organization (WHO) has recommended the development of mathematical models for understanding better antimalarial drug resistance and management. Other international groups have also suggested that mechanistic pharmacokinetic (PK) and pharmacodynamic (PD) models can support the rationalization of antimalarial dosing strategies. At present, artemisinin-based combination therapy (ACT) is recommended as first line treatment of falciparum malaria for all patient groups. This review summarizes the PK-PD characterization of artemisinin derivatives and other partner drugs from both preclinical studies and human clinical trials. We outline the continuous and discrete time models that have been proposed to describe antimalarial activity on specific stages of the parasite life cycle. The translation of PK-PD predictions from animals to humans is considered, because preclinical studies can provide rich data for detailed mechanism-based modelling. While similar sampling techniques are limited in clinical studies, PK-PD models can be used to optimize the design of experiments to improve estimation of the parameters of interest. Ultimately, we propose that fully developed mechanistic models can simulate and rationalize ACT or other treatment strategies in antimalarial chemotherapy.

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Pharmacodynamics of Doxycycline in a Murine Malaria Model

Cited by 13 publications

References 20 publications

Piperaquine Pharmacodynamics and Parasite Viability in a Murine Malaria Model

Piperaquine Pharmacodynamics and Parasite Viability in a Murine Malaria Model

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

Modelling the time course of antimalarial parasite killing: a tour of animal and human models, translation and challenges

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