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Population Pharmacokinetics and Antimalarial Pharmacodynamics of Piperaquine in Patients With Plasmodium vivax Malaria in Thailand.

Tarning J, Thana P, Phyo AP, Lwin KM, Hanpithakpong W, Ashley EA, Day NP, Nosten F, White NJ - CPT Pharmacometrics Syst Pharmacol (2014)

Bottom Line: Piperaquine pharmacokinetics were described well by a three-compartment distribution model.The results suggest that a large proportion of the first relapses were suppressed completely by residual piperaquine concentrations and that recurrences resulted mainly from emergence of the second or third relapse or from reinfection.This suggests a significant reduction in P. vivax morbidity when using dihydroartemisinin-piperaquine compared with other antimalarial drugs with shorter terminal postprophylactic effects.

View Article: PubMed Central - PubMed

Affiliation: 1] Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand [2] Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, UK.

ABSTRACT
Dihydroartemisinin-piperaquine is an effective drug in the treatment of Plasmodium falciparum and P. vivax malaria. The objective of this study was to evaluate the population pharmacokinetics and pharmacodynamics of piperaquine in patients with P. vivax malaria in Thailand after a standard regimen of dihydroartemisinin-piperaquine to determine whether residual piperaquine prevents or delays the emergence of P. vivax relapse. Sparse blood samples were collected from 116 patients. Piperaquine pharmacokinetics were described well by a three-compartment distribution model. Relapsing P. vivax malaria was accommodated by a constant baseline hazard (8.94 relapses/year) with the addition of a surge function in a fixed 3-week interval and a protective piperaquine effect. The results suggest that a large proportion of the first relapses were suppressed completely by residual piperaquine concentrations and that recurrences resulted mainly from emergence of the second or third relapse or from reinfection. This suggests a significant reduction in P. vivax morbidity when using dihydroartemisinin-piperaquine compared with other antimalarial drugs with shorter terminal postprophylactic effects.

No MeSH data available.


Related in: MedlinePlus

Visual predictive check of the final time-to-event model describing piperaquine pharmacodynamics in P. vivax malaria. Gray area represents the 95% prediction interval of the time to recurrent infections from 500 simulations. Solid line represents the observed Kaplan–Meier plot for (a) patients in the pharmacokinetic and pharmacodynamic cohort (62 patients, Table 1) and (b) all patients in the efficacy study (241 patients, Table 1).
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fig3: Visual predictive check of the final time-to-event model describing piperaquine pharmacodynamics in P. vivax malaria. Gray area represents the 95% prediction interval of the time to recurrent infections from 500 simulations. Solid line represents the observed Kaplan–Meier plot for (a) patients in the pharmacokinetic and pharmacodynamic cohort (62 patients, Table 1) and (b) all patients in the efficacy study (241 patients, Table 1).

Mentions: Piperaquine inhibits asexual parasite multiplication but has no effect on liver-stage parasites. The influence of piperaquine exposure on the risk of recurrent P. vivax malaria was investigated in 62 patients for whom both pharmacokinetic and pharmacodynamic data were available. However, efficacy data were available from all the 241 patients included in the study. Pharmacodynamic parameters were evaluated using an interval-censoring time-to-event model,18 implemented with the Laplacian estimation method. The pharmacokinetic parameter and variability estimates were fixed to that of the final pharmacokinetic model and used in the pharmacokinetic-pharmacodynamic model. P. vivax malaria in tropical regions commonly displays frequent relapses which emerge at three-week intervals when the infections are treated with rapidly eliminated antimalarials.19 A multiple surge function was, therefore, implemented to characterize this periodicity in the risk of recurrent malaria. The constant hazard function with a periodically increased risk of relapses described the data well. Piperaquine had a significant (ΔOFV = 20.3) protective effect on the risk of recurrent malaria infections with a required in vivo venous piperaquine concentration of 6.92 ng/ml for a 50% relative reduction in baseline hazard (PC50). Sex was selected as a significant covariate (P < 0.05) on baseline hazard in the forward selection step, but it was removed during the backward elimination resulting in a covariate-free pharmacodynamic model. Final pharmacodynamic parameters were well estimated with high precision (Table 2) and simulation-based diagnostics showed good agreement between simulated and observed recurrent malaria infections (Figure 3).


Population Pharmacokinetics and Antimalarial Pharmacodynamics of Piperaquine in Patients With Plasmodium vivax Malaria in Thailand.

Tarning J, Thana P, Phyo AP, Lwin KM, Hanpithakpong W, Ashley EA, Day NP, Nosten F, White NJ - CPT Pharmacometrics Syst Pharmacol (2014)

Visual predictive check of the final time-to-event model describing piperaquine pharmacodynamics in P. vivax malaria. Gray area represents the 95% prediction interval of the time to recurrent infections from 500 simulations. Solid line represents the observed Kaplan–Meier plot for (a) patients in the pharmacokinetic and pharmacodynamic cohort (62 patients, Table 1) and (b) all patients in the efficacy study (241 patients, Table 1).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150927&req=5

fig3: Visual predictive check of the final time-to-event model describing piperaquine pharmacodynamics in P. vivax malaria. Gray area represents the 95% prediction interval of the time to recurrent infections from 500 simulations. Solid line represents the observed Kaplan–Meier plot for (a) patients in the pharmacokinetic and pharmacodynamic cohort (62 patients, Table 1) and (b) all patients in the efficacy study (241 patients, Table 1).
Mentions: Piperaquine inhibits asexual parasite multiplication but has no effect on liver-stage parasites. The influence of piperaquine exposure on the risk of recurrent P. vivax malaria was investigated in 62 patients for whom both pharmacokinetic and pharmacodynamic data were available. However, efficacy data were available from all the 241 patients included in the study. Pharmacodynamic parameters were evaluated using an interval-censoring time-to-event model,18 implemented with the Laplacian estimation method. The pharmacokinetic parameter and variability estimates were fixed to that of the final pharmacokinetic model and used in the pharmacokinetic-pharmacodynamic model. P. vivax malaria in tropical regions commonly displays frequent relapses which emerge at three-week intervals when the infections are treated with rapidly eliminated antimalarials.19 A multiple surge function was, therefore, implemented to characterize this periodicity in the risk of recurrent malaria. The constant hazard function with a periodically increased risk of relapses described the data well. Piperaquine had a significant (ΔOFV = 20.3) protective effect on the risk of recurrent malaria infections with a required in vivo venous piperaquine concentration of 6.92 ng/ml for a 50% relative reduction in baseline hazard (PC50). Sex was selected as a significant covariate (P < 0.05) on baseline hazard in the forward selection step, but it was removed during the backward elimination resulting in a covariate-free pharmacodynamic model. Final pharmacodynamic parameters were well estimated with high precision (Table 2) and simulation-based diagnostics showed good agreement between simulated and observed recurrent malaria infections (Figure 3).

Bottom Line: Piperaquine pharmacokinetics were described well by a three-compartment distribution model.The results suggest that a large proportion of the first relapses were suppressed completely by residual piperaquine concentrations and that recurrences resulted mainly from emergence of the second or third relapse or from reinfection.This suggests a significant reduction in P. vivax morbidity when using dihydroartemisinin-piperaquine compared with other antimalarial drugs with shorter terminal postprophylactic effects.

View Article: PubMed Central - PubMed

Affiliation: 1] Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand [2] Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, UK.

ABSTRACT
Dihydroartemisinin-piperaquine is an effective drug in the treatment of Plasmodium falciparum and P. vivax malaria. The objective of this study was to evaluate the population pharmacokinetics and pharmacodynamics of piperaquine in patients with P. vivax malaria in Thailand after a standard regimen of dihydroartemisinin-piperaquine to determine whether residual piperaquine prevents or delays the emergence of P. vivax relapse. Sparse blood samples were collected from 116 patients. Piperaquine pharmacokinetics were described well by a three-compartment distribution model. Relapsing P. vivax malaria was accommodated by a constant baseline hazard (8.94 relapses/year) with the addition of a surge function in a fixed 3-week interval and a protective piperaquine effect. The results suggest that a large proportion of the first relapses were suppressed completely by residual piperaquine concentrations and that recurrences resulted mainly from emergence of the second or third relapse or from reinfection. This suggests a significant reduction in P. vivax morbidity when using dihydroartemisinin-piperaquine compared with other antimalarial drugs with shorter terminal postprophylactic effects.

No MeSH data available.


Related in: MedlinePlus