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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

Prediction-corrected visual predictive check of the final model describing piperaquine pharmacokinetics in P. vivax malaria. Open circles represent the observed piperaquine concentrations. Solid black line represents the 50th percentile of the observations, and dash lines represent the 5th and 95th percentiles of the observations. Gray areas represent the 95% confidence intervals of the simulated 5th, 50th, and 95th percentiles from 1,000 simulations. The inset shows a prediction-corrected visual predictive check for the first 3 days of piperaquine treatment.
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fig2: Prediction-corrected visual predictive check of the final model describing piperaquine pharmacokinetics in P. vivax malaria. Open circles represent the observed piperaquine concentrations. Solid black line represents the 50th percentile of the observations, and dash lines represent the 5th and 95th percentiles of the observations. Gray areas represent the 95% confidence intervals of the simulated 5th, 50th, and 95th percentiles from 1,000 simulations. The inset shows a prediction-corrected visual predictive check for the first 3 days of piperaquine treatment.

Mentions: The mean parameter estimates from the simultaneous model with both venous and capillary data were also comparable with estimates when capillary and venous data were modeled separately. The final pharmacokinetic model displayed satisfactory goodness-of-fit diagnostics (Supplementary Figure S1 online) with a small epsilon-shrinkage of 15.0%. However, a relatively high η-shrinkage (up to 43.5%) could be seen for certain parameters in the final model because of the sparse data. The numerical and prediction-corrected visual predictive checks resulted in 4.6% (95% CI: 2.7–8.1%) and 3.7% (95% CI: 2.5–8.2%) of piperaquine observations below and above the simulated 90% prediction interval, respectively (Figure 2).


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)

Prediction-corrected visual predictive check of the final model describing piperaquine pharmacokinetics in P. vivax malaria. Open circles represent the observed piperaquine concentrations. Solid black line represents the 50th percentile of the observations, and dash lines represent the 5th and 95th percentiles of the observations. Gray areas represent the 95% confidence intervals of the simulated 5th, 50th, and 95th percentiles from 1,000 simulations. The inset shows a prediction-corrected visual predictive check for the first 3 days of piperaquine treatment.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig2: Prediction-corrected visual predictive check of the final model describing piperaquine pharmacokinetics in P. vivax malaria. Open circles represent the observed piperaquine concentrations. Solid black line represents the 50th percentile of the observations, and dash lines represent the 5th and 95th percentiles of the observations. Gray areas represent the 95% confidence intervals of the simulated 5th, 50th, and 95th percentiles from 1,000 simulations. The inset shows a prediction-corrected visual predictive check for the first 3 days of piperaquine treatment.
Mentions: The mean parameter estimates from the simultaneous model with both venous and capillary data were also comparable with estimates when capillary and venous data were modeled separately. The final pharmacokinetic model displayed satisfactory goodness-of-fit diagnostics (Supplementary Figure S1 online) with a small epsilon-shrinkage of 15.0%. However, a relatively high η-shrinkage (up to 43.5%) could be seen for certain parameters in the final model because of the sparse data. The numerical and prediction-corrected visual predictive checks resulted in 4.6% (95% CI: 2.7–8.1%) and 3.7% (95% CI: 2.5–8.2%) of piperaquine observations below and above the simulated 90% prediction interval, respectively (Figure 2).

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