Development of a population pharmacokinetic model and optimal sampling strategies for intravenous ciprofloxacin

A. Forrest, C. H. Ballow, David E. Nix, M. C. Birmingham, J. J. Schentag

Research output: Contribution to journalArticle

110 Citations (Scopus)

Abstract

Data obtained from 74 acutely ill patients treated in two clinical efficacy trials were used to develop a population model of the pharmacokinetics of intravenous (i.v.) ciprofloxacin. Dosage regimens ranged between 200 mg every 12 h and 400 mg every 8 h. Plasma samples (2 to 19 per patient; mean ± standard deviation = 7 ± 5) were obtained and assayed (by high-performance liquid chromatography) for ciprofloxacin. These data and patient covariates were modelled by iterative two-stage analysis, an approach which generates pharmacokinetic parameter values for both the population and each individual patient. The final model was used to implement a maximum a posteriori-Bayesian pharmacokinetic parameter value estimator. Optimal sampling theory was used to determine the best (maximally informative) two-, three-, four-, five-, and six-sample study designs (e.g., optimal sampling strategy 2 [OSS2] was the two-sample strategy) for identifying a patient's pharmacokinetic parameter values. These OSSs and the population model were evaluated by selecting the relatively rich data sets, those with 7 to 10 samples obtained in a single dose interval (n = 29), and comparing the parameter estimates (obtained by the maximum a posteriori-Bayesian estimator) based on each of the OSSs with those obtained by fitting all of the available data from each patient. Distributional clearance and apparent volumes were significantly related to body size (e.g., weight in kilograms or body surface area in meters squared); plasma clearance (CL(T) in liters per hour) was related to body size and renal function (creatinine clearance [CL(CR)] in milliliters per minute per 1.73 m2) by the equation CL(T) = (0.00145 · CL(CR) + 0.167) · weight. However, only 30% of the variance in CL(T) was explained by this relationship, and no other patient covariates were significant. Compared with previously published data, this target population had smaller distribution volumes (by 30%; P < 0.01) and CL(T) (by 44%; P < 0.001) than weight- and CL(CR)-matched stable volunteers. The OSSs provided parameter estimates that showed good to excellent concordance with those obtained from all available data. Even with only two well-timed plasma samples, estimates of CL(T) (or area under the concentration-time curve [AUC]) were unbiased and precise (e.g., r2 for AUC for all data versus AUC for OSS2 was >0.99) and concentration-time profiles were accurately reconstructed. These results will be used to model the pharmacodynamic relationships between ciprofloxacin exposure and response and to aid in developing algorithms for individual optimization of ciprofloxacin dosage regimens.

Original languageEnglish (US)
Pages (from-to)1065-1072
Number of pages8
JournalAntimicrobial Agents and Chemotherapy
Volume37
Issue number5
StatePublished - 1993
Externally publishedYes

Fingerprint

Ciprofloxacin
Pharmacokinetics
Population
Body Size
Weights and Measures
Health Services Needs and Demand
Body Surface Area
Creatinine
High Pressure Liquid Chromatography
Clinical Trials
Kidney

ASJC Scopus subject areas

  • Pharmacology (medical)

Cite this

Development of a population pharmacokinetic model and optimal sampling strategies for intravenous ciprofloxacin. / Forrest, A.; Ballow, C. H.; Nix, David E.; Birmingham, M. C.; Schentag, J. J.

In: Antimicrobial Agents and Chemotherapy, Vol. 37, No. 5, 1993, p. 1065-1072.

Research output: Contribution to journalArticle

Forrest, A. ; Ballow, C. H. ; Nix, David E. ; Birmingham, M. C. ; Schentag, J. J. / Development of a population pharmacokinetic model and optimal sampling strategies for intravenous ciprofloxacin. In: Antimicrobial Agents and Chemotherapy. 1993 ; Vol. 37, No. 5. pp. 1065-1072.
@article{17e6ab0ab6e44799a790852cadfdffa9,
title = "Development of a population pharmacokinetic model and optimal sampling strategies for intravenous ciprofloxacin",
abstract = "Data obtained from 74 acutely ill patients treated in two clinical efficacy trials were used to develop a population model of the pharmacokinetics of intravenous (i.v.) ciprofloxacin. Dosage regimens ranged between 200 mg every 12 h and 400 mg every 8 h. Plasma samples (2 to 19 per patient; mean ± standard deviation = 7 ± 5) were obtained and assayed (by high-performance liquid chromatography) for ciprofloxacin. These data and patient covariates were modelled by iterative two-stage analysis, an approach which generates pharmacokinetic parameter values for both the population and each individual patient. The final model was used to implement a maximum a posteriori-Bayesian pharmacokinetic parameter value estimator. Optimal sampling theory was used to determine the best (maximally informative) two-, three-, four-, five-, and six-sample study designs (e.g., optimal sampling strategy 2 [OSS2] was the two-sample strategy) for identifying a patient's pharmacokinetic parameter values. These OSSs and the population model were evaluated by selecting the relatively rich data sets, those with 7 to 10 samples obtained in a single dose interval (n = 29), and comparing the parameter estimates (obtained by the maximum a posteriori-Bayesian estimator) based on each of the OSSs with those obtained by fitting all of the available data from each patient. Distributional clearance and apparent volumes were significantly related to body size (e.g., weight in kilograms or body surface area in meters squared); plasma clearance (CL(T) in liters per hour) was related to body size and renal function (creatinine clearance [CL(CR)] in milliliters per minute per 1.73 m2) by the equation CL(T) = (0.00145 · CL(CR) + 0.167) · weight. However, only 30{\%} of the variance in CL(T) was explained by this relationship, and no other patient covariates were significant. Compared with previously published data, this target population had smaller distribution volumes (by 30{\%}; P < 0.01) and CL(T) (by 44{\%}; P < 0.001) than weight- and CL(CR)-matched stable volunteers. The OSSs provided parameter estimates that showed good to excellent concordance with those obtained from all available data. Even with only two well-timed plasma samples, estimates of CL(T) (or area under the concentration-time curve [AUC]) were unbiased and precise (e.g., r2 for AUC for all data versus AUC for OSS2 was >0.99) and concentration-time profiles were accurately reconstructed. These results will be used to model the pharmacodynamic relationships between ciprofloxacin exposure and response and to aid in developing algorithms for individual optimization of ciprofloxacin dosage regimens.",
author = "A. Forrest and Ballow, {C. H.} and Nix, {David E.} and Birmingham, {M. C.} and Schentag, {J. J.}",
year = "1993",
language = "English (US)",
volume = "37",
pages = "1065--1072",
journal = "Antimicrobial Agents and Chemotherapy",
issn = "0066-4804",
publisher = "American Society for Microbiology",
number = "5",

}

TY - JOUR

T1 - Development of a population pharmacokinetic model and optimal sampling strategies for intravenous ciprofloxacin

AU - Forrest, A.

AU - Ballow, C. H.

AU - Nix, David E.

AU - Birmingham, M. C.

AU - Schentag, J. J.

PY - 1993

Y1 - 1993

N2 - Data obtained from 74 acutely ill patients treated in two clinical efficacy trials were used to develop a population model of the pharmacokinetics of intravenous (i.v.) ciprofloxacin. Dosage regimens ranged between 200 mg every 12 h and 400 mg every 8 h. Plasma samples (2 to 19 per patient; mean ± standard deviation = 7 ± 5) were obtained and assayed (by high-performance liquid chromatography) for ciprofloxacin. These data and patient covariates were modelled by iterative two-stage analysis, an approach which generates pharmacokinetic parameter values for both the population and each individual patient. The final model was used to implement a maximum a posteriori-Bayesian pharmacokinetic parameter value estimator. Optimal sampling theory was used to determine the best (maximally informative) two-, three-, four-, five-, and six-sample study designs (e.g., optimal sampling strategy 2 [OSS2] was the two-sample strategy) for identifying a patient's pharmacokinetic parameter values. These OSSs and the population model were evaluated by selecting the relatively rich data sets, those with 7 to 10 samples obtained in a single dose interval (n = 29), and comparing the parameter estimates (obtained by the maximum a posteriori-Bayesian estimator) based on each of the OSSs with those obtained by fitting all of the available data from each patient. Distributional clearance and apparent volumes were significantly related to body size (e.g., weight in kilograms or body surface area in meters squared); plasma clearance (CL(T) in liters per hour) was related to body size and renal function (creatinine clearance [CL(CR)] in milliliters per minute per 1.73 m2) by the equation CL(T) = (0.00145 · CL(CR) + 0.167) · weight. However, only 30% of the variance in CL(T) was explained by this relationship, and no other patient covariates were significant. Compared with previously published data, this target population had smaller distribution volumes (by 30%; P < 0.01) and CL(T) (by 44%; P < 0.001) than weight- and CL(CR)-matched stable volunteers. The OSSs provided parameter estimates that showed good to excellent concordance with those obtained from all available data. Even with only two well-timed plasma samples, estimates of CL(T) (or area under the concentration-time curve [AUC]) were unbiased and precise (e.g., r2 for AUC for all data versus AUC for OSS2 was >0.99) and concentration-time profiles were accurately reconstructed. These results will be used to model the pharmacodynamic relationships between ciprofloxacin exposure and response and to aid in developing algorithms for individual optimization of ciprofloxacin dosage regimens.

AB - Data obtained from 74 acutely ill patients treated in two clinical efficacy trials were used to develop a population model of the pharmacokinetics of intravenous (i.v.) ciprofloxacin. Dosage regimens ranged between 200 mg every 12 h and 400 mg every 8 h. Plasma samples (2 to 19 per patient; mean ± standard deviation = 7 ± 5) were obtained and assayed (by high-performance liquid chromatography) for ciprofloxacin. These data and patient covariates were modelled by iterative two-stage analysis, an approach which generates pharmacokinetic parameter values for both the population and each individual patient. The final model was used to implement a maximum a posteriori-Bayesian pharmacokinetic parameter value estimator. Optimal sampling theory was used to determine the best (maximally informative) two-, three-, four-, five-, and six-sample study designs (e.g., optimal sampling strategy 2 [OSS2] was the two-sample strategy) for identifying a patient's pharmacokinetic parameter values. These OSSs and the population model were evaluated by selecting the relatively rich data sets, those with 7 to 10 samples obtained in a single dose interval (n = 29), and comparing the parameter estimates (obtained by the maximum a posteriori-Bayesian estimator) based on each of the OSSs with those obtained by fitting all of the available data from each patient. Distributional clearance and apparent volumes were significantly related to body size (e.g., weight in kilograms or body surface area in meters squared); plasma clearance (CL(T) in liters per hour) was related to body size and renal function (creatinine clearance [CL(CR)] in milliliters per minute per 1.73 m2) by the equation CL(T) = (0.00145 · CL(CR) + 0.167) · weight. However, only 30% of the variance in CL(T) was explained by this relationship, and no other patient covariates were significant. Compared with previously published data, this target population had smaller distribution volumes (by 30%; P < 0.01) and CL(T) (by 44%; P < 0.001) than weight- and CL(CR)-matched stable volunteers. The OSSs provided parameter estimates that showed good to excellent concordance with those obtained from all available data. Even with only two well-timed plasma samples, estimates of CL(T) (or area under the concentration-time curve [AUC]) were unbiased and precise (e.g., r2 for AUC for all data versus AUC for OSS2 was >0.99) and concentration-time profiles were accurately reconstructed. These results will be used to model the pharmacodynamic relationships between ciprofloxacin exposure and response and to aid in developing algorithms for individual optimization of ciprofloxacin dosage regimens.

UR - http://www.scopus.com/inward/record.url?scp=0027197110&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0027197110&partnerID=8YFLogxK

M3 - Article

C2 - 8517693

AN - SCOPUS:0027197110

VL - 37

SP - 1065

EP - 1072

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

SN - 0066-4804

IS - 5

ER -