Pharmacokinetic modelling of cefotaxime and desacetylcefotaxime—a population study in 25 elderly patients

Urien, Saı̈k; Nicolas, Laurent; Barré, Jérôme; Druguet, M.; D’yvoire, M. Bouvier; Maire, Pascal

doi:10.1007/s00228-003-0725-9

Cited by 13 publications

(11 citation statements)

References 7 publications

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“…Our data show that cefotaxime follows a two-compartment PK model with linear elimination related to the individual eCLcr. These results are in line with previous descriptions of a biphasic disposition in adults [21,22] and the findings of Urien et al [8], where a two-compartment model with CL influenced by weight, plasma creatinine and age (all parts of the eCLcr component) best described the data in elderly patients. That study also found serum protein concentrations to be a significant covariate.…”

Section: Discussionsupporting

confidence: 93%

“…The resulting cefotaxime typical CL value (11.1 L/h for a subject with ICU weight of 92 kg and with eCLcr of 94 mL/min) is in line with previously reported 10-13 L/h in patients with liver disease [23] and higher than 5.4 L/h in elderly patients [8]. Clearance of 15-17 L/h in healthy adult populations [21,22] is higher than in this ICU population as expected due to acute kidney injury in severe illness despite occasional cases of ARC.…”

Section: Discussionsupporting

confidence: 91%

“…They can also be used to obtain individual PK parameters based on measured drug concentrations, and subsequently for individual predictions and dose selection. In the case of cefotaxime, there are published population PK models for elderly patients [8] and paediatric patients [9][10][11][12], but to our knowledge, no such model for adult intensive care unit (ICU) patients has been published.…”

Section: Introductionmentioning

confidence: 99%

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Population pharmacokinetics of cefotaxime in intensive care patients

Swartling

Smekal

Furebring

et al. 2021

Eur J Clin Pharmacol

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Purpose To characterise the pharmacokinetics and associated variability of cefotaxime in adult intensive care unit (ICU) patients and to assess the impact of patient covariates. Methods This work was based on data from cefotaxime-treated patients included in the ACCIS (Antibiotic Concentrations in Critical Ill ICU Patients in Sweden) study. Clinical data from 51 patients at seven different ICUs in Sweden, given cefotaxime (1000–3000 mg given 2–6 times daily), were collected from the first day of treatment for up to three consecutive days. In total, 263 cefotaxime samples were included in the population pharmacokinetic analysis. Results A two-compartment model with linear elimination, proportional residual error and inter-individual variability (IIV) on clearance and central volume of distribution best described the data. The typical individual was 64 years, with body weight at ICU admission of 92 kg and estimated creatinine clearance of 94 mL/min. The resulting typical value of clearance was 11.1 L/h, central volume of distribution 5.1 L, peripheral volume of distribution 18.2 L and inter-compartmental clearance 14.5 L/h. The estimated creatinine clearance proved to be a significant covariate on clearance (p < 0.001), reducing IIV from 68 to 49%. Conclusion A population pharmacokinetic model was developed to describe cefotaxime pharmacokinetics and associated variability in adult ICU patients. The estimated creatinine clearance partly explained the IIV in cefotaxime clearance. However, the remaining unexplained IIV is high and suggests a need for dose individualisation using therapeutic drug monitoring where the developed model, after evaluation of predictive performance, may provide support.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

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Population pharmacokinetics of cefotaxime in intensive care patients

Swartling

Smekal

Furebring

et al. 2021

Eur J Clin Pharmacol

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“…The First Order Conditional Estimation with interaction (FOCEI) method was employed throughout the analysis. As has been previously reported, we observed that the pharmacokinetic data were best fit by a two‐compartment model 20,38,39. Cefotaxime clearance was parameterized using the Eqs.…”

Section: Resultsmentioning

confidence: 80%

Reduced Renal Clearance of Cefotaxime in Asians with a Low-Frequency Polymorphism of OAT3 (SLC22A8)

Yee

Nguyen

Brown

et al. 2013

Journal of Pharmaceutical Sciences

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Organic anion transporter 3 (OAT3, SLC22A8), a transporter expressed on the basolateral membrane of the proximal tubule, plays a critical role in the renal excretion of organic anions including many therapeutic drugs. The goal of this study was to evaluate the in vivo effects of the OAT3-Ile305Phe variant (rs11568482), present at 3.5% allele frequency in Asians, on drug disposition with a focus on cefotaxime, a cephalosporin antibiotic. In HEK293- Flp-In cells, the OAT3-Ile305Phe variant had a lower maximum cefotaxime transport activity, Vmax, [159 ± 3 nmol*(mg protein)−1/min (mean ± SD)] compared with the reference OAT3 [305 ± 28 nmol*(mg protein)−1/min, (mean ± SD), p < 0.01], whereas the Michaelis-Menten constant values (Km) did not differ. In healthy volunteers, we found volunteers that were heterozygous for the Ile305Phe variant and had a significantly lower cefotaxime renal clearance (CLR; mean ± SD: 84.8 ± 32.1 mL/min, n = 5) compared with volunteers that were homozygous for the reference allele (158 ± 44.1 mL/min, n = 10; p = 0.006). Furthermore, the net secretory component of cefotaxime renal clearance (CLsec) was reduced in volunteers heterozygous for the variant allele [33.3 ± 31.8 mL/min (mean ± SD)] compared with volunteers homozygous for the OAT3 reference allele [97.0 ± 42.2 mL/min (mean ± SD), p = 0.01]. In summary, our study suggests that a low-frequency reduced-function polymorphism of OAT3 associates with reduced cefotaxime CLR and CLsec.

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“…Some population PK studies concerning PIPC/TAZ in adult subjects have been reported [10][11][12][13][14][15][16][17][18][19]. In many antibiotics, including carbapenems and cephems, elderly patients have been reported to have different PK parameters than younger patients [21][22][23]. These age-related differences in PK parameters would increase the likelihood of drug toxicity and adverse reactions [24].…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetic Modeling and Pharmacodynamic Target Attainment Simulation of Piperacillin/Tazobactam for Dosing Optimization in Late Elderly Patients with Pneumonia

et al. 2020

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The aim of this study was to develop a population pharmacokinetic model for piperacillin (PIPC)/tazobactam (TAZ) in late elderly patients with pneumonia and to optimize the administration planning by applying pharmacokinetic/pharmacodynamic (PK/PD) criteria. PIPC/TAZ (total dose of 2.25 or 4.5 g) was infused intravenously three times daily to Japanese patients over 75 years old. The plasma concentrations of PIPC and TAZ were determined using high-performance liquid chromatography and modeled using the NONMEM program. PK/PD analysis with a random simulation was conducted using the final population PK model to estimate the probability of target attainment (PTA) profiles for various PIPC/TAZ-regimen-minimum-inhibitory-concentration (MIC) combinations. The PTAs for PIPC and TAZ were determined as the fraction that achieved at least 50% free time > MIC and area under the free-plasma-concentration-time curve over 24 h ≥ 96 µg h/mL, respectively. A total of 18 cases, the mean age of which was 86.5 ± 6.0 (75-101) years, were investigated. The plasma-concentration-time profiles of PIPC and TAZ were characterized by a two-compartment model. The parameter estimates for the final model, namely the total clearance, central distribution volume, peripheral distribution volume, and intercompartmental clearance, were 4.58 + 0.061 × (CL cr − 37.4) L/h, 5.39 L, 6.96 L, and 20.7 L/h for PIPC, and 5.00 + 0.059 × (CL cr − 37.4) L/h, 6.29 L, 7.73 L, and 24.0 L/h for TAZ, respectively, where CL cr is the creatinine clearance. PK/PD analysis using the final model showed that in drug-resistant strains with a MIC > 8 µg/mL, 4.5 g of PIPC/TAZ every 6 h was required, even for the patients with a CL cr of 50-60 mL/min. The population PK model developed in this study, together with MIC value, can be useful for optimizing the PIPC/TAZ dosage in the over-75-year-old patients, when they are administered PIPC/TAZ. Therefore, the findings of present study may contribute to improving the efficacy and safety of the administration of PIPC/TAZ therapy in late elderly patients with pneumonia.

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Pharmacokinetic modelling of cefotaxime and desacetylcefotaxime—a population study in 25 elderly patients

Abstract: Cefotaxime and desacetylcefotaxime elimination decreased with increasing age above 60 years. This decreased elimination was related to individual characteristics that are typically related to renal function.

Cited by 13 publications

References 7 publications

Population pharmacokinetics of cefotaxime in intensive care patients

Population pharmacokinetics of cefotaxime in intensive care patients

Reduced Renal Clearance of Cefotaxime in Asians with a Low-Frequency Polymorphism of OAT3 (SLC22A8)

Population Pharmacokinetic Modeling and Pharmacodynamic Target Attainment Simulation of Piperacillin/Tazobactam for Dosing Optimization in Late Elderly Patients with Pneumonia

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