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Population Pharmacokinetics and Pharmacodynamics of Praziquantel in Ugandan Children with Intestinal Schistosomiasis: Higher Dosages Are Required for Maximal Efficacy

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Population Pharmacokinetics and Pharmacodynamics of Praziquantel in Ugandan Children with Intestinal Schistosomiasis : Higher Dosages Are Required for Maximal Efficacy. / Bustinduy, Amaya L; Waterhouse, David; de Sousa-Figueiredo, Jose C; Roberts, Stephen A.; Atuhaire, Aaron; Van Dam, Govert J; Corstjens, Paul L A M; Scott, Janet T; Stanton, Michelle C; Kabatereine, Narcis B; Ward, Stephen; Hope, William W; Stothard, J Russell.

In: MBio, Vol. 7, No. 4, e00227-16, 09.08.2016.

Research output: Contribution to journalJournal articlepeer-review

Harvard

Bustinduy, AL, Waterhouse, D, de Sousa-Figueiredo, JC, Roberts, SA, Atuhaire, A, Van Dam, GJ, Corstjens, PLAM, Scott, JT, Stanton, MC, Kabatereine, NB, Ward, S, Hope, WW & Stothard, JR 2016, 'Population Pharmacokinetics and Pharmacodynamics of Praziquantel in Ugandan Children with Intestinal Schistosomiasis: Higher Dosages Are Required for Maximal Efficacy', MBio, vol. 7, no. 4, e00227-16. https://doi.org/10.1128/mBio.00227-16

APA

Bustinduy, A. L., Waterhouse, D., de Sousa-Figueiredo, J. C., Roberts, S. A., Atuhaire, A., Van Dam, G. J., Corstjens, P. L. A. M., Scott, J. T., Stanton, M. C., Kabatereine, N. B., Ward, S., Hope, W. W., & Stothard, J. R. (2016). Population Pharmacokinetics and Pharmacodynamics of Praziquantel in Ugandan Children with Intestinal Schistosomiasis: Higher Dosages Are Required for Maximal Efficacy. MBio, 7(4), [e00227-16]. https://doi.org/10.1128/mBio.00227-16

Vancouver

Author

Bustinduy, Amaya L ; Waterhouse, David ; de Sousa-Figueiredo, Jose C ; Roberts, Stephen A. ; Atuhaire, Aaron ; Van Dam, Govert J ; Corstjens, Paul L A M ; Scott, Janet T ; Stanton, Michelle C ; Kabatereine, Narcis B ; Ward, Stephen ; Hope, William W ; Stothard, J Russell. / Population Pharmacokinetics and Pharmacodynamics of Praziquantel in Ugandan Children with Intestinal Schistosomiasis : Higher Dosages Are Required for Maximal Efficacy. In: MBio. 2016 ; Vol. 7, No. 4.

Bibtex

@article{ff19b7cb6e304f3bb078283df8a5550e,
title = "Population Pharmacokinetics and Pharmacodynamics of Praziquantel in Ugandan Children with Intestinal Schistosomiasis: Higher Dosages Are Required for Maximal Efficacy",
abstract = "UNLABELLED: Each year, millions of African children receive praziquantel (PZQ) by mass drug administration (MDA) to treat schistosomiasis at a standard single dose of 40 mg/kg of body weight, a direct extrapolation from studies of adults. A higher dose of 60 mg/kg is also acceptable for refractory cases. We conducted the first PZQ pharmacokinetic (PK) and pharmacodynamic (PD) study in young children comparing dosing. Sixty Ugandan children aged 3 to 8 years old with egg patent Schistosoma mansoni received PZQ at either 40 mg/kg or 60 mg/kg. PK parameters of PZQ racemate and enantiomers (R and S) were quantified. PD outcomes were assessed by standard fecal egg counts and novel schistosome-specific serum (circulating anodic antigen [CAA]) and urine (circulating cathodic antigen [CCA]) antigen assays. Population PK and PD analyses were performed to estimate drug exposure in individual children, and the relationship between drug exposure and parasitological cure was estimated using logistic regression. Monte Carlo simulations were performed to identify better, future dosing regimens. There was marked PK variability between children, but the area under the concentration-time curve (AUC) of PZQ was strongly predictive of the parasitological cure rate (CR). Although no child achieved antigenic cure, which is suggestive of an important residual adult worm burden, higher AUC was associated with greater CAA antigenic decline at 24 days. To optimize the performance of PZQ, analysis of our simulations suggest that higher doses (>60 mg/kg) are needed, particularly in smaller children.IMPORTANCE: Schistosomiasis is a neglected tropical disease, typically associated with chronic morbidity, and its control is a global health priority. Praziquantel (PZQ) is the only available antiparasitic drug and is often given out, as a single oral dose (40 mg/kg), to school-aged children by mass drug administration (MDA) schemes operating within preventive chemotherapy campaigns as endorsed by the World Health Organization (WHO). This current strategy has several limitations. (i) It excludes preschool children who can be patently infected. (ii) It delivers PZQ at a dose directly extrapolated from adult pharmacological studies. To address these problems, we conducted the first pharmacokinetic and pharmacodynamic study of young children within an area of Uganda where Schistosoma mansoni is hyperendemic. Our results demonstrate that a higher dose (>60 mg/kg) is required, especially in smaller children, and draw attention to the need for further optimization of PZQ treatment based on schistosome antigenic assays, which are more sensitive to pharmacodynamic markers.",
keywords = "Animals, Anthelmintics, Antigens, Helminth, Child, Child, Preschool, Feces, Female, Humans, Male, Parasite Egg Count, Praziquantel, Schistosoma mansoni, Schistosomiasis mansoni, Uganda, Journal Article, Research Support, Non-U.S. Gov't",
author = "Bustinduy, {Amaya L} and David Waterhouse and {de Sousa-Figueiredo}, {Jose C} and Roberts, {Stephen A.} and Aaron Atuhaire and {Van Dam}, {Govert J} and Corstjens, {Paul L A M} and Scott, {Janet T} and Stanton, {Michelle C} and Kabatereine, {Narcis B} and Stephen Ward and Hope, {William W} and Stothard, {J Russell}",
note = "Copyright {\textcopyright} 2016 Bustinduy et al.",
year = "2016",
month = aug,
day = "9",
doi = "10.1128/mBio.00227-16",
language = "English",
volume = "7",
journal = "MBio",
issn = "2150-7511",
publisher = "American Society for Microbiology",
number = "4",

}

RIS

TY - JOUR

T1 - Population Pharmacokinetics and Pharmacodynamics of Praziquantel in Ugandan Children with Intestinal Schistosomiasis

T2 - Higher Dosages Are Required for Maximal Efficacy

AU - Bustinduy, Amaya L

AU - Waterhouse, David

AU - de Sousa-Figueiredo, Jose C

AU - Roberts, Stephen A.

AU - Atuhaire, Aaron

AU - Van Dam, Govert J

AU - Corstjens, Paul L A M

AU - Scott, Janet T

AU - Stanton, Michelle C

AU - Kabatereine, Narcis B

AU - Ward, Stephen

AU - Hope, William W

AU - Stothard, J Russell

N1 - Copyright © 2016 Bustinduy et al.

PY - 2016/8/9

Y1 - 2016/8/9

N2 - UNLABELLED: Each year, millions of African children receive praziquantel (PZQ) by mass drug administration (MDA) to treat schistosomiasis at a standard single dose of 40 mg/kg of body weight, a direct extrapolation from studies of adults. A higher dose of 60 mg/kg is also acceptable for refractory cases. We conducted the first PZQ pharmacokinetic (PK) and pharmacodynamic (PD) study in young children comparing dosing. Sixty Ugandan children aged 3 to 8 years old with egg patent Schistosoma mansoni received PZQ at either 40 mg/kg or 60 mg/kg. PK parameters of PZQ racemate and enantiomers (R and S) were quantified. PD outcomes were assessed by standard fecal egg counts and novel schistosome-specific serum (circulating anodic antigen [CAA]) and urine (circulating cathodic antigen [CCA]) antigen assays. Population PK and PD analyses were performed to estimate drug exposure in individual children, and the relationship between drug exposure and parasitological cure was estimated using logistic regression. Monte Carlo simulations were performed to identify better, future dosing regimens. There was marked PK variability between children, but the area under the concentration-time curve (AUC) of PZQ was strongly predictive of the parasitological cure rate (CR). Although no child achieved antigenic cure, which is suggestive of an important residual adult worm burden, higher AUC was associated with greater CAA antigenic decline at 24 days. To optimize the performance of PZQ, analysis of our simulations suggest that higher doses (>60 mg/kg) are needed, particularly in smaller children.IMPORTANCE: Schistosomiasis is a neglected tropical disease, typically associated with chronic morbidity, and its control is a global health priority. Praziquantel (PZQ) is the only available antiparasitic drug and is often given out, as a single oral dose (40 mg/kg), to school-aged children by mass drug administration (MDA) schemes operating within preventive chemotherapy campaigns as endorsed by the World Health Organization (WHO). This current strategy has several limitations. (i) It excludes preschool children who can be patently infected. (ii) It delivers PZQ at a dose directly extrapolated from adult pharmacological studies. To address these problems, we conducted the first pharmacokinetic and pharmacodynamic study of young children within an area of Uganda where Schistosoma mansoni is hyperendemic. Our results demonstrate that a higher dose (>60 mg/kg) is required, especially in smaller children, and draw attention to the need for further optimization of PZQ treatment based on schistosome antigenic assays, which are more sensitive to pharmacodynamic markers.

AB - UNLABELLED: Each year, millions of African children receive praziquantel (PZQ) by mass drug administration (MDA) to treat schistosomiasis at a standard single dose of 40 mg/kg of body weight, a direct extrapolation from studies of adults. A higher dose of 60 mg/kg is also acceptable for refractory cases. We conducted the first PZQ pharmacokinetic (PK) and pharmacodynamic (PD) study in young children comparing dosing. Sixty Ugandan children aged 3 to 8 years old with egg patent Schistosoma mansoni received PZQ at either 40 mg/kg or 60 mg/kg. PK parameters of PZQ racemate and enantiomers (R and S) were quantified. PD outcomes were assessed by standard fecal egg counts and novel schistosome-specific serum (circulating anodic antigen [CAA]) and urine (circulating cathodic antigen [CCA]) antigen assays. Population PK and PD analyses were performed to estimate drug exposure in individual children, and the relationship between drug exposure and parasitological cure was estimated using logistic regression. Monte Carlo simulations were performed to identify better, future dosing regimens. There was marked PK variability between children, but the area under the concentration-time curve (AUC) of PZQ was strongly predictive of the parasitological cure rate (CR). Although no child achieved antigenic cure, which is suggestive of an important residual adult worm burden, higher AUC was associated with greater CAA antigenic decline at 24 days. To optimize the performance of PZQ, analysis of our simulations suggest that higher doses (>60 mg/kg) are needed, particularly in smaller children.IMPORTANCE: Schistosomiasis is a neglected tropical disease, typically associated with chronic morbidity, and its control is a global health priority. Praziquantel (PZQ) is the only available antiparasitic drug and is often given out, as a single oral dose (40 mg/kg), to school-aged children by mass drug administration (MDA) schemes operating within preventive chemotherapy campaigns as endorsed by the World Health Organization (WHO). This current strategy has several limitations. (i) It excludes preschool children who can be patently infected. (ii) It delivers PZQ at a dose directly extrapolated from adult pharmacological studies. To address these problems, we conducted the first pharmacokinetic and pharmacodynamic study of young children within an area of Uganda where Schistosoma mansoni is hyperendemic. Our results demonstrate that a higher dose (>60 mg/kg) is required, especially in smaller children, and draw attention to the need for further optimization of PZQ treatment based on schistosome antigenic assays, which are more sensitive to pharmacodynamic markers.

KW - Animals

KW - Anthelmintics

KW - Antigens, Helminth

KW - Child

KW - Child, Preschool

KW - Feces

KW - Female

KW - Humans

KW - Male

KW - Parasite Egg Count

KW - Praziquantel

KW - Schistosoma mansoni

KW - Schistosomiasis mansoni

KW - Uganda

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1128/mBio.00227-16

DO - 10.1128/mBio.00227-16

M3 - Journal article

C2 - 27507822

VL - 7

JO - MBio

JF - MBio

SN - 2150-7511

IS - 4

M1 - e00227-16

ER -