J Lyle Bootman, Raymond J Townsend, and. William F McGhan. 2 Pharmacoeconomics: An International Perspective. Michael Dickson and J Lyle Bootman.
I N T E R N ATIONAL REPORT
Relationship Between Clinical and Biologic Variables and Chloramphenicol Pharmacokinetic Parameters in Pediatric Patients with Sepsis Gustavo Lugo Goytia, Ismael Lares-Asseff, María Gabriela Pérez Guillé, Adrián Guillé Pérez, and Cynthia Larios Mejía
OBJECTIVE:
To evaluate the influence of several clinical and biologic factors on the disposition kinetics of oral chloramphenicol in pediatric patients and to determine the usefulness of this information to predict chloramphenicol serum concentrations.
STUDY DESIGN:
The clinical, biologic, and pharmacokinetic data of 30 consecutive pediatric patients diagnosed with sepsis and admitted to a tertiary care center were analyzed retrospectively. The patients were randomly assigned to a study group and a validation group. The model was developed by a three-step approach involving Bayesian estimation of pharmacokinetic parameters, selection of covariates by principal component analysis, and final selection by stepwise multiple linear regression. The model was tested in the study group and compared with a general population model using a prediction error analysis. RESULTS :
Regression analysis revealed that weight, albumin, and white blood cell (WBC) count were the most important determinants for chloramphenicol distribution volume, whereas age, WBC count, and serum creatinine were the most important determinants for chloramphenicol clearance. The performance of the constructed population model improved significantly in terms of both bias and precision compared with the general model when tested in the validation group.
CONCLUSIONS:
Clinical and biologic factors may significantly influence chloramphenicol’s disposition in pediatric patients with sepsis and therefore should be considered in programming dosage regimens.
KEY WORDS: chloramphenicol, covariates, pharmacokinetics, multiple regression, sepsis.
Ann Pharmacother 2000;34:393-7.
he use of drugs for treatment of several diseases repreT sents a basic therapeutic tool for the physician. However, drug therapy can only be effective if the correct drug is given at the right dose. Therefore, dosage regimens need to be optimized for each patient using the information available about the related demographic, clinical, biologic, or physiologic variables, especially for drugs with narrow therapeutic indexes. The average values of the population pharmacokinetic parameters cannot be used directly to design an optimal individualized dose regimen, since they do not consider the specific clinical and biologic variables of the individual patient. Therefore, it is more appropriate to apply population parameters that take this information into account.1 Ample interindividual pharmacokinetic variability has been described for several drugs. An important part of this variability has been explained by patient factors that in
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some way influence the disposition of each drug’s kinetics.2 In this manner, knowledge of these factors may be relevant for designing an initial dosage regimen more appropriate for the individual patient. Chloramphenicol is an antimicrobial agent that continues to be widely used in developing countries to treat severe infections in pediatric patients. However, its use can be associated with the development of serious complications due to its narrow therapeutic margin and its wide interindividual pharmacokinetic variability.3,4 Hence, knowledge of the clinical and biologic factors that explain this variability may offer important information on the design for more effective and safe individualized dosage regimens. The purpose of this study was to characterize oral chloramphenicol’s pharmacokinetics in a population of pediatric patients with sepsis. Accordingly, our main objectives were to evaluate the influence of several clinical and biologic factors on the disposition kinetics of this drug, and to determine the usefulness of this information for predicting chloramphenicol’s serum concentrations.
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95% CI does not include zero, it is concluded that the difference reaches statistical significance.
Methods Thirty consecutive pediatric patients diagnosed with sepsis who had received chloramphenicol and had serum chloramphenicol concentrations measured at the Pediatric National Institute in Mexico City were analyzed retrospectively. The diagnosis of sepsis was established based on previously reported criteria.5 All patients were receiving oral chloramphenicol 100 mg/kg/d divided every eight to 12 hours. Blood samples at steady-state were taken two, six, and eight or 12 hours after a dose. Chloramphenicol concentrations were determined by a fluorometric method following the technique reported by Clarenburg and Ramakrisma.6 The intraday and interday coefficient of variation was
