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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

Final piperaquine population pharmacokinetic-pharmacodynamic model in patients with P. vivax malaria. KTR is the transit absorption rate constant (KTR = (n + 1)/mean absorption transit time), CL is the elimination clearance, VC is the apparent central volume of distribution, VP is the apparent peripheral volume of distribution, Q is the intercompartment clearance, and F is the relative oral bioavailability.
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fig1: Final piperaquine population pharmacokinetic-pharmacodynamic model in patients with P. vivax malaria. KTR is the transit absorption rate constant (KTR = (n + 1)/mean absorption transit time), CL is the elimination clearance, VC is the apparent central volume of distribution, VP is the apparent peripheral volume of distribution, Q is the intercompartment clearance, and F is the relative oral bioavailability.

Mentions: The initial structural base models were parameterized as elimination clearance (CL/F), intercompartment clearance(s) (Q/F), apparent volume of distribution of the central compartment (VC/F), apparent volume of distribution of the peripheral compartment(s) (VP/F), and absorption rate constant. Several absorption, distribution, and covariate models were fitted to the data to construct the best performing model. Piperaquine pharmacokinetics in patients with P. vivax malaria were best described by a three-compartment distribution model (Figure 1). A three-compartment disposition model resulted in a significant improvement in model fit compared with a two-compartment model (difference in objective function value (ΔOFV) of 108) with no additional benefit of an additional peripheral compartment (ΔOFV = 0.57). A transit-compartment model with a fixed number of transit compartments (n = 3, transit rate constant was set to be identical to absorption rate constant) described the absorption phase better than all other absorption models (ΔOFV > 54.2). A relative bioavailability parameter (i.e., fixed to 100% for the population) was implemented to allow quantification of the interindividual variability in the absorption of piperaquine and resulted in a significant improvement in the model fit (ΔOFV = 81.8).


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)

Final piperaquine population pharmacokinetic-pharmacodynamic model in patients with P. vivax malaria. KTR is the transit absorption rate constant (KTR = (n + 1)/mean absorption transit time), CL is the elimination clearance, VC is the apparent central volume of distribution, VP is the apparent peripheral volume of distribution, Q is the intercompartment clearance, and F is the relative oral bioavailability.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: Final piperaquine population pharmacokinetic-pharmacodynamic model in patients with P. vivax malaria. KTR is the transit absorption rate constant (KTR = (n + 1)/mean absorption transit time), CL is the elimination clearance, VC is the apparent central volume of distribution, VP is the apparent peripheral volume of distribution, Q is the intercompartment clearance, and F is the relative oral bioavailability.
Mentions: The initial structural base models were parameterized as elimination clearance (CL/F), intercompartment clearance(s) (Q/F), apparent volume of distribution of the central compartment (VC/F), apparent volume of distribution of the peripheral compartment(s) (VP/F), and absorption rate constant. Several absorption, distribution, and covariate models were fitted to the data to construct the best performing model. Piperaquine pharmacokinetics in patients with P. vivax malaria were best described by a three-compartment distribution model (Figure 1). A three-compartment disposition model resulted in a significant improvement in model fit compared with a two-compartment model (difference in objective function value (ΔOFV) of 108) with no additional benefit of an additional peripheral compartment (ΔOFV = 0.57). A transit-compartment model with a fixed number of transit compartments (n = 3, transit rate constant was set to be identical to absorption rate constant) described the absorption phase better than all other absorption models (ΔOFV > 54.2). A relative bioavailability parameter (i.e., fixed to 100% for the population) was implemented to allow quantification of the interindividual variability in the absorption of piperaquine and resulted in a significant improvement in the model fit (ΔOFV = 81.8).

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