A simultaneous population pharmacokinetic analysis of rifampicin in Malawian adults and children.

Alessandro Schipani; Henry Pertinez; Rachel Mlota; Elizabeth Molyneux; Nuria Lopez; Fraction K. Dzinjalamala; Joep J. Van Oosterhout; Steve Ward; Saye Khoo; Gerry Davies

doi:10.1111/bcp.12848

A simultaneous population pharmacokinetic analysis of rifampicin in Malawian adults and children.

Alessandro Schipani, Henry Pertinez, Rachel Mlota, Elizabeth Molyneux, Nuria Lopez, Fraction K. Dzinjalamala, Joep J. Van Oosterhout, Steve Ward, Saye Khoo, Gerry Davies

Tropical Disease Biology

Research output: Contribution to journal › Article › peer-review

21 Citations (Scopus)

Abstract

AIMS

Low rifampicin plasma concentrations can lead to treatment failure and increased risk of developing drug resistant tuberculosis. The objectives of this study were to characterize the population pharmacokinetics (popPK) of rifampicin in Malawian children and adults with tuberculosis, simulate exposures under revised WHO dosing guidelines that aim to reduce the risk of low exposures of rifampicin and examine predicted exposures using weight- and age-based dosing bands under new dosing recommendations.

METHODS

Patients were recruited at least two weeks after initiation of the intensive phase of treatment and received RIF in FDC of anti-TB drugs. A total of 5-6 rich and 1-2 sparse samples were collected. nonmem (v7.2) was used to build a population-PK model.

RESULTS

A 165 TB patients, 115 adults and 50 children, aged 7 months to 65 years and weighing 4.8 to 87 kg, were included in the one compartment model with first order absorption best described the data. The mean population estimate for CL/F was 23.9 (l h(-1) 70 kg(-1) ) with inter-individual variability of 46.6%. Exposure was unaffected by HIV status. Relative bioavailability in children was estimated at 49% lower compared to adults (100% relative bioavailability). Simulations showed significantly lower rifampicin exposure in children vs. adults. In children average AUC was 13.5 mg l(-1) h, which was nearly half that was observed in adults (26.3 mg l(-1) h). Using age as a surrogate for weight in dosing bands gave similar results compared with the weight bands. Increasing dose to approximately 15 mg kg(-1) , increased AUC in children to an average of 22 mgl(-1) h. bringing expected exposures in children closer to those predicted for adults.

CONCLUSION

The popPK model developed can be used to optimize rifampicin exposures through dosing simulations. WHO dosing recommendations may not be achieved using currently licensed fixed dose combination formulations of TB therapy.

Original language	English
Pages (from-to)	679-687
Number of pages	9
Journal	British Journal of Clinical Pharmacology
Volume	81
Issue number	4
DOIs	https://doi.org/10.1111/bcp.12848
Publication status	Published - 15 Mar 2016

Keywords

children
dosing bands
NONMEM
population PK
tuberculosis

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1111/bcp.12848

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@article{f7077d4836bb47a1ab8a166ae0e24953,

title = "A simultaneous population pharmacokinetic analysis of rifampicin in Malawian adults and children.",

abstract = "AIMSLow rifampicin plasma concentrations can lead to treatment failure and increased risk of developing drug resistant tuberculosis. The objectives of this study were to characterize the population pharmacokinetics (popPK) of rifampicin in Malawian children and adults with tuberculosis, simulate exposures under revised WHO dosing guidelines that aim to reduce the risk of low exposures of rifampicin and examine predicted exposures using weight- and age-based dosing bands under new dosing recommendations.METHODSPatients were recruited at least two weeks after initiation of the intensive phase of treatment and received RIF in FDC of anti-TB drugs. A total of 5-6 rich and 1-2 sparse samples were collected. nonmem (v7.2) was used to build a population-PK model.RESULTSA 165 TB patients, 115 adults and 50 children, aged 7 months to 65 years and weighing 4.8 to 87 kg, were included in the one compartment model with first order absorption best described the data. The mean population estimate for CL/F was 23.9 (l h(-1) 70 kg(-1) ) with inter-individual variability of 46.6\%. Exposure was unaffected by HIV status. Relative bioavailability in children was estimated at 49\% lower compared to adults (100\% relative bioavailability). Simulations showed significantly lower rifampicin exposure in children vs. adults. In children average AUC was 13.5 mg l(-1) h, which was nearly half that was observed in adults (26.3 mg l(-1) h). Using age as a surrogate for weight in dosing bands gave similar results compared with the weight bands. Increasing dose to approximately 15 mg kg(-1) , increased AUC in children to an average of 22 mgl(-1) h. bringing expected exposures in children closer to those predicted for adults.CONCLUSIONThe popPK model developed can be used to optimize rifampicin exposures through dosing simulations. WHO dosing recommendations may not be achieved using currently licensed fixed dose combination formulations of TB therapy.",

keywords = "children, dosing bands, NONMEM, population PK, tuberculosis",

author = "Alessandro Schipani and Henry Pertinez and Rachel Mlota and Elizabeth Molyneux and Nuria Lopez and Dzinjalamala, \{Fraction K.\} and \{Van Oosterhout\}, \{Joep J.\} and Steve Ward and Saye Khoo and Gerry Davies",

year = "2016",

month = mar,

day = "15",

doi = "10.1111/bcp.12848",

language = "English",

volume = "81",

pages = "679--687",

journal = "British Journal of Clinical Pharmacology",

issn = "0306-5251",

publisher = "Wiley-Blackwell Publishing Ltd",

number = "4",

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TY - JOUR

T1 - A simultaneous population pharmacokinetic analysis of rifampicin in Malawian adults and children.

AU - Schipani, Alessandro

AU - Pertinez, Henry

AU - Mlota, Rachel

AU - Molyneux, Elizabeth

AU - Lopez, Nuria

AU - Dzinjalamala, Fraction K.

AU - Van Oosterhout, Joep J.

AU - Ward, Steve

AU - Khoo, Saye

AU - Davies, Gerry

PY - 2016/3/15

Y1 - 2016/3/15

N2 - AIMSLow rifampicin plasma concentrations can lead to treatment failure and increased risk of developing drug resistant tuberculosis. The objectives of this study were to characterize the population pharmacokinetics (popPK) of rifampicin in Malawian children and adults with tuberculosis, simulate exposures under revised WHO dosing guidelines that aim to reduce the risk of low exposures of rifampicin and examine predicted exposures using weight- and age-based dosing bands under new dosing recommendations.METHODSPatients were recruited at least two weeks after initiation of the intensive phase of treatment and received RIF in FDC of anti-TB drugs. A total of 5-6 rich and 1-2 sparse samples were collected. nonmem (v7.2) was used to build a population-PK model.RESULTSA 165 TB patients, 115 adults and 50 children, aged 7 months to 65 years and weighing 4.8 to 87 kg, were included in the one compartment model with first order absorption best described the data. The mean population estimate for CL/F was 23.9 (l h(-1) 70 kg(-1) ) with inter-individual variability of 46.6%. Exposure was unaffected by HIV status. Relative bioavailability in children was estimated at 49% lower compared to adults (100% relative bioavailability). Simulations showed significantly lower rifampicin exposure in children vs. adults. In children average AUC was 13.5 mg l(-1) h, which was nearly half that was observed in adults (26.3 mg l(-1) h). Using age as a surrogate for weight in dosing bands gave similar results compared with the weight bands. Increasing dose to approximately 15 mg kg(-1) , increased AUC in children to an average of 22 mgl(-1) h. bringing expected exposures in children closer to those predicted for adults.CONCLUSIONThe popPK model developed can be used to optimize rifampicin exposures through dosing simulations. WHO dosing recommendations may not be achieved using currently licensed fixed dose combination formulations of TB therapy.

AB - AIMSLow rifampicin plasma concentrations can lead to treatment failure and increased risk of developing drug resistant tuberculosis. The objectives of this study were to characterize the population pharmacokinetics (popPK) of rifampicin in Malawian children and adults with tuberculosis, simulate exposures under revised WHO dosing guidelines that aim to reduce the risk of low exposures of rifampicin and examine predicted exposures using weight- and age-based dosing bands under new dosing recommendations.METHODSPatients were recruited at least two weeks after initiation of the intensive phase of treatment and received RIF in FDC of anti-TB drugs. A total of 5-6 rich and 1-2 sparse samples were collected. nonmem (v7.2) was used to build a population-PK model.RESULTSA 165 TB patients, 115 adults and 50 children, aged 7 months to 65 years and weighing 4.8 to 87 kg, were included in the one compartment model with first order absorption best described the data. The mean population estimate for CL/F was 23.9 (l h(-1) 70 kg(-1) ) with inter-individual variability of 46.6%. Exposure was unaffected by HIV status. Relative bioavailability in children was estimated at 49% lower compared to adults (100% relative bioavailability). Simulations showed significantly lower rifampicin exposure in children vs. adults. In children average AUC was 13.5 mg l(-1) h, which was nearly half that was observed in adults (26.3 mg l(-1) h). Using age as a surrogate for weight in dosing bands gave similar results compared with the weight bands. Increasing dose to approximately 15 mg kg(-1) , increased AUC in children to an average of 22 mgl(-1) h. bringing expected exposures in children closer to those predicted for adults.CONCLUSIONThe popPK model developed can be used to optimize rifampicin exposures through dosing simulations. WHO dosing recommendations may not be achieved using currently licensed fixed dose combination formulations of TB therapy.

KW - children

KW - dosing bands

KW - NONMEM

KW - population PK

KW - tuberculosis

U2 - 10.1111/bcp.12848

DO - 10.1111/bcp.12848

M3 - Article

SN - 0306-5251

VL - 81

SP - 679

EP - 687

JO - British Journal of Clinical Pharmacology

JF - British Journal of Clinical Pharmacology

IS - 4

ER -

A simultaneous population pharmacokinetic analysis of rifampicin in Malawian adults and children.

Abstract

Keywords

UN SDGs

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