A Model for Estimating Total Parasite Load in Falciparum Malaria Patients

Gravenor, Mike B.; Lloyd, Alun L.; Kremsner, Peter G.; Missinou, Michel A.; English, Mike; Marsh, Kevin; Kwiatkowski, Dominic P.

doi:10.1006/jtbi.2002.3030

Cited by 44 publications

(58 citation statements)

References 16 publications

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“…Developmental stage differences within and between species may also contribute to errors in the nucleic acid-based quantification of parasitemia. Gravenor et al (9) have estimated that more than 70% of P. falciparuminfected erythrocytes can be sequestered away from the blood volume sampled for diagnosis. In contrast, schizonts of P. vivax, P. malariae, and P. ovale (which contain 10 to 20 merozoites) are not considered to sequester and may contribute to estimation of levels of parasitemia higher than those observed by microscopy.…”

Section: Discussionmentioning

confidence: 99%

Development of a Multiplex PCR-Ligase Detection Reaction Assay for Diagnosis of Infection by the Four Parasite Species Causing Malaria in Humans

et al. 2004

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The diagnosis of infections caused by Plasmodium species is critical for understanding the nature of malarial disease, treatment efficacy, malaria control, and public health. The demands of field-based epidemiological studies of malaria will require faster and more sensitive diagnostic methods as new antimalarial drugs and vaccines are explored. We have developed a multiplex PCR-ligase detection reaction (LDR) assay that allows the simultaneous diagnosis of infection by all four parasite species causing malaria in humans. This assay exhibits sensitivity and specificity equal to those of other PCR-based assays, identifying all four human malaria parasite species at levels of parasitemias equal to 1 parasitized erythrocyte/l of blood. The multiplex PCR-LDR assay goes beyond other PCR-based assays by reducing technical procedures and by detecting intraindividual differences in species-specific levels of parasitemia. Application of the multiplex PCR-LDR assay will provide the sensitivity and specificity expected of PCR-based diagnostic assays and will contribute new insight regarding relationships between the human malaria parasite species and the human host in future epidemiological studies.PCR diagnosis of malaria species infections exhibits sensitivity and specificity superior to those of blood smear microscopy, which is considered the "gold standard," and antigencapture rapid diagnostic tests (RDTs) (22, 32). Additional practical strengths of the PCR include the ability to evaluate samples that have been archived as whole blood or on microscope slides (25) under various conditions for years and compatibility with the widely used 96-well plate, automation-ready formats.The superior sensitivity of the PCR has greatly expanded the capability to understand malaria parasite parasitism beyond the limits of blood smear microscopy. In clinical settings equipped with appropriate instrumentation, PCR-based diagnostic strategies enable Plasmodium species identification, despite parasitemias at levels below blood smear sensitivity limits. The results obtained by these more sensitive assays are often useful in making specific treatment decisions to kill species (Plasmodium vivax and P. ovale) that are capable of establishing dormant liver stages and subsequent malarial relapses. In many epidemiological studies, evidence of low-level infection consistently reported through PCR detection of subpatent infections suggests that the prevalence of malaria parasite infection is higher than that estimated by evaluation of blood smears (2,3,17,20,29,33). Similar observations of this nature have suggested that infection by all four parasite species causing malaria in humans is not uncommon in some regions where malaria is endemic (20,29) and that the prevalence of P. malariae and P. ovale is higher than that estimated previously (20,29,33

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Section: Discussionmentioning

confidence: 99%

Development of a Multiplex PCR-Ligase Detection Reaction Assay for Diagnosis of Infection by the Four Parasite Species Causing Malaria in Humans

et al. 2004

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“…Instead, the authors stated that the killing rate constants encompassed both host immunity and the effects of the anti-malarial therapies. The authors, in another publication (22), also expanded the above model to have 48 parasite compartments of an average age of 1 h (P 1 (t), P 2 (t), … P 48 (t)). The model comprised of four parameters: a single transition rate for moving between the 48 compartments and two killing rate constants for different groupings of the parasite compartments (selected based on in vitro data regarding the killing action of the anti-malarial) and PMF.…”

Section: Within-host Anti-malarial Pharmacokinetic-pharmacodynamic Momentioning

confidence: 99%

“…Gravenor et al (22) PD modeling of parasite data from children with falciparum malaria who received quinine…”

Section: Statistical Approaches For Estimation Of the Biological Paramentioning

confidence: 99%

“…These models can be incorporated in population-level analyses to predict the selection and spread of drug resistance (8). A variety of within-host PK-PD models have been described for falciparum malaria, and there is a wide variation in the number of biological parameters describing the parasite life cycle and PD effect of the anti-malarial treatment (5)(6)(7)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). The accuracy of these models in predicting the change in parasite burden following treatment depends on many factors.…”

Section: Introductionmentioning

confidence: 99%

“…Some of these mechanistic PK-PD models have been fitted formally to patient parasite-time profiles to obtain parameter estimates (10,11,14,16,17,21,22), whereas others have simply selected parameter values that generate parasitetime profiles that accord well with the profiles from clinical studies (5)(6)(7)9,12,13,15,(18)(19)(20). Both of these approaches are dependent on empirical data defining the dynamics of the parasite burden.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Making the Most of Clinical Data: Reviewing the Role of Pharmacokinetic-Pharmacodynamic Models of Anti-malarial Drugs

Simpson

Zaloumis

Livera

et al. 2014

AAPS J

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Abstract. Mechanistic within-host models integrating blood anti-malarial drug concentrations with the parasite-time profile provide a valuable decision tool for determining dosing regimens for anti-malarial treatments, as well as a formative component of population-level drug resistance models. We reviewed published anti-malarial pharmacokinetic-pharmacodynamic models to identify the challenges for these complex models where parameter estimation from clinical field data is limited. The inclusion of key pharmacodynamic processes in the mechanistic structure adopted varies considerably. These include the life cycle of the parasite within the red blood cell, the action of the anti-malarial on a specific stage of the life cycle, and the reduction in parasite growth associated with immunity. With regard to estimation of the pharmacodynamic parameters, the majority of studies simply compared descriptive summaries of the simulated outputs to published observations of host and parasite responses from clinical studies. Few studies formally estimated the pharmacodynamic parameters within a rigorous statistical framework using observed individual patient data. We recommend three steps in the development and evaluation of these models. Firstly, exploration through simulation to assess how the different parameters influence the parasite dynamics. Secondly, application of a simulation-estimation approach to determine whether the model parameters can be estimated with reasonable precision based on sampling designs that mimic clinical efficacy studies. Thirdly, fitting the mechanistic model to the clinical data within a Bayesian framework. We propose that authors present the model both schematically and in equation form and give a detailed description of each parameter, including a biological interpretation of the parameter estimates.

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The Role of Clinical Pharmacology in Chemotherapy of Multidrug‐Resistant Plasmodium falciparum

Karbwang

Na‐Bangchang

2020

The Journal of Clinical Pharma

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Malaria remains one of the major global public health problems due to the emergence and spread of multidrug‐resistant Plasmodium falciparum. In recent years, clinical pharmacology has significantly contributed to the optimal dosing regimens of antimalarial drugs. The application of pharmacometric modeling and simulation has assisted in the accurate characterization of pharmacokinetic‐pharmacodynamic relationships and the optimization of the dosage regimens of existing antimalarial drugs, including new antimalarial candidates for multidrug‐resistant P falciparum in different populations.

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A Model for Estimating Total Parasite Load in Falciparum Malaria Patients

Cited by 44 publications

References 16 publications

Development of a Multiplex PCR-Ligase Detection Reaction Assay for Diagnosis of Infection by the Four Parasite Species Causing Malaria in Humans

Development of a Multiplex PCR-Ligase Detection Reaction Assay for Diagnosis of Infection by the Four Parasite Species Causing Malaria in Humans

Making the Most of Clinical Data: Reviewing the Role of Pharmacokinetic-Pharmacodynamic Models of Anti-malarial Drugs

The Role of Clinical Pharmacology in Chemotherapy of Multidrug‐Resistant Plasmodium falciparum

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