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Quantifying the pharmacology of antimalarial drug combination therapy

View Article: PubMed Central - PubMed

ABSTRACT

Most current antimalarial drugs are combinations of an artemisinin plus a‘partner’ drug from another class, and are known asartemisinin-based combination therapies (ACTs). They are the frontline drugs intreating human malaria infections. They also have a public-health role as anessential component of recent, comprehensive scale-ups of malaria interventions andcontainment efforts conceived as part of longer term malaria elimination efforts.Recent reports that resistance has arisen to artemisinins has caused considerableconcern. We investigate the likely impact of artemisinin resistance by quantifyingthe contribution artemisinins make to the overall therapeutic capacity of ACTs. Weachieve this using a simple, easily understood, algebraic approach and by moresophisticated pharmacokinetic/pharmacodynamic analyses of drug action; the twoapproaches gave consistent results. Surprisingly, the artemisinin componenttypically makes a negligible contribution (≪0.0001%) to the therapeuticcapacity of the most widely used ACTs and only starts to make a significantcontribution to therapeutic outcome once resistance has started to evolve to thepartner drugs. The main threat to antimalarial drug effectiveness and control comesfrom resistance evolving to the partner drugs. We therefore argue that public healthpolicies be re-focussed to maximise the likely long-term effectiveness of thepartner drugs.

No MeSH data available.


Boxplots of drugs’ therapeutic capacity quantified asPRRtot.(a) Individual drugs used in ACTs. (b) The contribution ofartemisinin to overall ACT therapeutic capacity in a variety of ACTs; thisis measured as the ratio artemisinin PRRtot: partner drugPRRtot. Note that in all plots the upper“whisker” of the boxplot lies immediately above the box andis difficult to distinguish. We identify the 5th and95th centiles of the data by horizontal red lines. [Thebox delimits the second and third quartiles of the data (i.e. theinter-quartile range, IQR) with the horizontal line in that box representingthe median value; the whiskers are the upper/lower quartile valuesplus/minus 1.5 times the IQR. Data points that lie outside the whiskers areregarded as outliers and are plotted individually. Note that the upperwhiskers all lie virtually on top of the interquartile box due to thelogarithmic scaling of the Y-axis]. Abbreviations:ACT = artemisinin combination therapy,AQ = amodiaquine, AR = artemether,AS = artesunate, DHA = dihydroartemisinin,LF = lumefantrine, MQ = mefloquine,PPQ = piperaquine,SP = sulfadoxine-pyrimethamine; Subscripts:b.i.d = twice daily dosing, R = resistance,q.d. = once daily dosing.
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f1: Boxplots of drugs’ therapeutic capacity quantified asPRRtot.(a) Individual drugs used in ACTs. (b) The contribution ofartemisinin to overall ACT therapeutic capacity in a variety of ACTs; thisis measured as the ratio artemisinin PRRtot: partner drugPRRtot. Note that in all plots the upper“whisker” of the boxplot lies immediately above the box andis difficult to distinguish. We identify the 5th and95th centiles of the data by horizontal red lines. [Thebox delimits the second and third quartiles of the data (i.e. theinter-quartile range, IQR) with the horizontal line in that box representingthe median value; the whiskers are the upper/lower quartile valuesplus/minus 1.5 times the IQR. Data points that lie outside the whiskers areregarded as outliers and are plotted individually. Note that the upperwhiskers all lie virtually on top of the interquartile box due to thelogarithmic scaling of the Y-axis]. Abbreviations:ACT = artemisinin combination therapy,AQ = amodiaquine, AR = artemether,AS = artesunate, DHA = dihydroartemisinin,LF = lumefantrine, MQ = mefloquine,PPQ = piperaquine,SP = sulfadoxine-pyrimethamine; Subscripts:b.i.d = twice daily dosing, R = resistance,q.d. = once daily dosing.

Mentions: An intuitive, ‘simple’ approach, and a more sophisticatedpharmacokinetic/pharmacodynamic (PKPD) modelling approach, can be used to quantifythe therapeutic capacity of antimalarial drugs. This is most easily quantified asthe total Parasite Reduction Ratio (PRRtot), of partner drugs andartemisinins used in the current generation of ACTs (see Methods section). Thetherapeutic capacities are given in Table 1. Partner drugshave far more therapeutic capacity than the artemisinins (Table1) so the latter make only an extremely small contribution, typically≪0.0001%, to overall therapeutic capacity of the ACT (Table2). The PKPD method simulates 1,000 individual patients which allows theinter-patient variation in PRRtot to be incorporated (Fig.1a). These results show that the contribution of the artemisinins tototal ACT therapeutic capacity is typically negligible when parasites are sensitiveto the partner drug. The average contribution of artemisinins to ACTs based on themost widely used partner drugs (amodiaquine, lumefantrine, mefloquine, piperaquine)varies between 10−10.5 and 10−30 thatof its partner drug using the simple method, and between 10−9and 10−46 using the PKPD method. However, incorporating PKand PD variability suggests artemisinin may make a significant contribution in asmall proportion of patients (Fig. 1b), although even if theartemisinin does make a significant contribution, the partner drug may still havesufficient therapeutic capacity to successfully eradicate the infection on its own.It is only when resistance has arisen to the partner drugs that artemisinins startto make a contribution to its ACT therapeutic capacity (Table2). In summary, artemisinins make a negligible contribution to overallACT therapeutic capacity when partner drugs are effective and only start to providesome protection once resistance starts to make the partner drug ineffective.Artemisinins play a role at this point (approximately halving failure rates6) but the long half-lives of partner drugs will further driveresistance eventually leaving artemisinins present as ineffective monotherapies78910.


Quantifying the pharmacology of antimalarial drug combination therapy
Boxplots of drugs’ therapeutic capacity quantified asPRRtot.(a) Individual drugs used in ACTs. (b) The contribution ofartemisinin to overall ACT therapeutic capacity in a variety of ACTs; thisis measured as the ratio artemisinin PRRtot: partner drugPRRtot. Note that in all plots the upper“whisker” of the boxplot lies immediately above the box andis difficult to distinguish. We identify the 5th and95th centiles of the data by horizontal red lines. [Thebox delimits the second and third quartiles of the data (i.e. theinter-quartile range, IQR) with the horizontal line in that box representingthe median value; the whiskers are the upper/lower quartile valuesplus/minus 1.5 times the IQR. Data points that lie outside the whiskers areregarded as outliers and are plotted individually. Note that the upperwhiskers all lie virtually on top of the interquartile box due to thelogarithmic scaling of the Y-axis]. Abbreviations:ACT = artemisinin combination therapy,AQ = amodiaquine, AR = artemether,AS = artesunate, DHA = dihydroartemisinin,LF = lumefantrine, MQ = mefloquine,PPQ = piperaquine,SP = sulfadoxine-pyrimethamine; Subscripts:b.i.d = twice daily dosing, R = resistance,q.d. = once daily dosing.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC5036534&req=5

f1: Boxplots of drugs’ therapeutic capacity quantified asPRRtot.(a) Individual drugs used in ACTs. (b) The contribution ofartemisinin to overall ACT therapeutic capacity in a variety of ACTs; thisis measured as the ratio artemisinin PRRtot: partner drugPRRtot. Note that in all plots the upper“whisker” of the boxplot lies immediately above the box andis difficult to distinguish. We identify the 5th and95th centiles of the data by horizontal red lines. [Thebox delimits the second and third quartiles of the data (i.e. theinter-quartile range, IQR) with the horizontal line in that box representingthe median value; the whiskers are the upper/lower quartile valuesplus/minus 1.5 times the IQR. Data points that lie outside the whiskers areregarded as outliers and are plotted individually. Note that the upperwhiskers all lie virtually on top of the interquartile box due to thelogarithmic scaling of the Y-axis]. Abbreviations:ACT = artemisinin combination therapy,AQ = amodiaquine, AR = artemether,AS = artesunate, DHA = dihydroartemisinin,LF = lumefantrine, MQ = mefloquine,PPQ = piperaquine,SP = sulfadoxine-pyrimethamine; Subscripts:b.i.d = twice daily dosing, R = resistance,q.d. = once daily dosing.
Mentions: An intuitive, ‘simple’ approach, and a more sophisticatedpharmacokinetic/pharmacodynamic (PKPD) modelling approach, can be used to quantifythe therapeutic capacity of antimalarial drugs. This is most easily quantified asthe total Parasite Reduction Ratio (PRRtot), of partner drugs andartemisinins used in the current generation of ACTs (see Methods section). Thetherapeutic capacities are given in Table 1. Partner drugshave far more therapeutic capacity than the artemisinins (Table1) so the latter make only an extremely small contribution, typically≪0.0001%, to overall therapeutic capacity of the ACT (Table2). The PKPD method simulates 1,000 individual patients which allows theinter-patient variation in PRRtot to be incorporated (Fig.1a). These results show that the contribution of the artemisinins tototal ACT therapeutic capacity is typically negligible when parasites are sensitiveto the partner drug. The average contribution of artemisinins to ACTs based on themost widely used partner drugs (amodiaquine, lumefantrine, mefloquine, piperaquine)varies between 10−10.5 and 10−30 thatof its partner drug using the simple method, and between 10−9and 10−46 using the PKPD method. However, incorporating PKand PD variability suggests artemisinin may make a significant contribution in asmall proportion of patients (Fig. 1b), although even if theartemisinin does make a significant contribution, the partner drug may still havesufficient therapeutic capacity to successfully eradicate the infection on its own.It is only when resistance has arisen to the partner drugs that artemisinins startto make a contribution to its ACT therapeutic capacity (Table2). In summary, artemisinins make a negligible contribution to overallACT therapeutic capacity when partner drugs are effective and only start to providesome protection once resistance starts to make the partner drug ineffective.Artemisinins play a role at this point (approximately halving failure rates6) but the long half-lives of partner drugs will further driveresistance eventually leaving artemisinins present as ineffective monotherapies78910.

View Article: PubMed Central - PubMed

ABSTRACT

Most current antimalarial drugs are combinations of an artemisinin plus a‘partner’ drug from another class, and are known asartemisinin-based combination therapies (ACTs). They are the frontline drugs intreating human malaria infections. They also have a public-health role as anessential component of recent, comprehensive scale-ups of malaria interventions andcontainment efforts conceived as part of longer term malaria elimination efforts.Recent reports that resistance has arisen to artemisinins has caused considerableconcern. We investigate the likely impact of artemisinin resistance by quantifyingthe contribution artemisinins make to the overall therapeutic capacity of ACTs. Weachieve this using a simple, easily understood, algebraic approach and by moresophisticated pharmacokinetic/pharmacodynamic analyses of drug action; the twoapproaches gave consistent results. Surprisingly, the artemisinin componenttypically makes a negligible contribution (≪0.0001%) to the therapeuticcapacity of the most widely used ACTs and only starts to make a significantcontribution to therapeutic outcome once resistance has started to evolve to thepartner drugs. The main threat to antimalarial drug effectiveness and control comesfrom resistance evolving to the partner drugs. We therefore argue that public healthpolicies be re-focussed to maximise the likely long-term effectiveness of thepartner drugs.

No MeSH data available.