Amoxicillin pharmacokinetics in pregnant women with preterm premature rupture of the membranes

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Objective
This study was undertaken to study the pharmacokinetics of intravenously administered amoxicillin in pregnant women with preterm premature rupture of the membranes (PPROM).

Study Design
Healthy women with PPROM were recruited and treated with amoxicillin (2 g initially and 1 g subsequently). Blood samples were obtained from the opposite arm and concentrations determined with the use of high-pressure liquid chromatography. Nonlinear mixed-effects modeling was performed in nonlinear mixed effect (population) modeling.

Results
The pharmacokinetics of 17 patients was described by a 3-compartment model. Clearance and volume of distribution at steady state were 22.8 L/h and 21.4 L/h, respectively, similar to values in nonpregnant individuals. There was little variability between patients. No relationship was observed between values of individual pharmacokinetic parameters and various covariates.

Conclusion
The pharmacokinetics of amoxicillin in pregnant patients with PPROM similar to nonpregnant individuals. Given the small interindividual variability in pharmacokinetics, no dose adjustments are required to account for differences between subjects under normal circumstances.

Key words: clearance; interindividual variability; pregnancy; preterm premature rupture of the membranes; volume of distribution

Preterm premature rupture of the membranes (PPROM) complicates approximately 3% of pregnancies and is responsible for one-third of all preterm births. Subclinical intraamniotic infection has been implicated as a major etiologic factor in the pathogenesis of PPROM. The consequential maternal and neonatal morbidity are attributed to ascending infections from the vagina after rupture of the membranes. Antibiotic therapy has been recommended in the management of patients with PPROM to prevent or treat ascending intra-amniotic infection.

Amoxicillin, a penicillin derivative, is an antibiotic frequently used in the management of PPROM. It is active against common pathogens that can cause infection in neonates, in particular Streptococcus agalactiae. The currently recommended amoxicillin dosages in pregnancy are derived from studies that used ampicillin. These dosage regimens essentially do not differ from regimens used in nonpregnant individuals and are based on the assumption that pharmacokinetics in pregnancy and in young men are similar. In nonpregnant individuals, a slow elimination phase has been suggested for penicillin G and amoxicillin. Especially for bacteria with a low minimum inhibitory concentration (MIC), like S agalactiae, a slow elimination phase would be of clinical importance. In women with PPROM, the presence of such elimination phase would be beneficial for efficacy of the prophylaxis by increasing the time the amoxicillin concentration remains above the MIC. However, during pregnancy physiologic changes occur that may modify the pharmacokinetics of drugs, such as increase in plasma volume, increase in fat content, presence of the fetus, and changes in elimination rate or metabolism. These changes can be expected to affect the pharmacokinetics of drugs in various ways. If changes in pharmacokinetics indeed occur, pregnant women and their fetuses are inherently at risk for underdosing or overdosing when they are treated with dosage regimens developed for nonpregnant individuals. A clear example is the drastic decrease in concentration of the antiepileptic drug lamotrigine during pregnancy.

Despite the widespread use of amoxicillin in pregnant women, the pharmacokinetics in patients with PPROM has not been adequately studied. The objective of this study is to describe the pharmacokinetics in this vulnerable patient group and to develop a population pharmacokinetic model. Because the pharmacokinetics in individual patients may be affected by various factors, it is important that the method of data analysis allows identification of such factors. Therefore, pharmacokinetic data analysis that uses nonlinear mixed effects (“population”) modeling was applied. This method has distinct statistical advantages, especially for such patient groups. The data of the whole population are simultaneously analyzed, while taking into account interindividual and intraindividual variability in, respectively, the model parameters and the observations by assuming a stochastic distribution. The influence of specific characteristics on the individual pharmacokinetic parameters can be assessed by including these characteristics as covariates in the pharmacokinetic model. A more detailed background of population modeling can be found elsewhere.

Full Article

Presented in part at the 16th European Congress of Clinical Microbiology and Infectious Diseases, Nice, France, April 1-4, 2006.

Anouk E. Muller MD, Joost DeJongh PhD, Paul M. Oostvogel MD, PhD, Rob A. Voskuyl PhD, P. Joep Dorr MD, PhD, Meindert Danhof PharmD, PhD and Johan W. Mouton MD, PhD
Department of Obstetrics and Gynecology, Medical Centre Haaglanden, Lijnbaan, the Hague
Department of Clinical Microbiology, Medical Centre Haaglanden, Lijnbaan, the Hague
LAP&P Consultants BV, Leiden, the Netherlands
Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, the Netherlands
Department of Clinical Microbiology and Infectious Diseases, Canisius Wilhelmina Hospital, Nijmegen, the Netherlands.
Received 2 January 2007; revised 21 February 2007; accepted 11 May 2007.  Available online 3 December 2007.

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