Scaling beta‐lactam antimicrobial pharmacokinetics from early life to old age

Lonsdale, Derrick; Baker, Emma H.; Kipper, Karin; Barker, Charlotte I. S.; Philips, Barbara J.; Rhodes, Andrew; Standing, Joseph F.

doi:10.1111/bcp.13756

Cited by 16 publications

(17 citation statements)

References 159 publications

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“…Their estimated AGE 50 of 86.8 years, however, is significantly higher than what we found for vancomycin (61.6 years). In addition to differences in elimination processes, the different handling of renal function in the study by Lonsdale et al [35] compared with our analysis might explain the different AGE 50 estimates. Indeed, as seen from Table 2, during model building, AGE 50 ranged from 67.4 to 79.8 years depending on the method used to standardise SCR.…”

Section: Discussioncontrasting

confidence: 50%

“…By extending this standardised model with an additional sigmoidal decline function, we were able to describe the deterioration in vancomycin clearance with age. Recently, Lonsdale et al [35] have used the same methodology to describe beta-lactam antimicrobial pharmacokinetics from early life to old age. Notwithstanding that tubular secretion and/or re-absorption are likely involved in beta-lactam elimination, these authors found a PMA 50 estimate of 49.7 weeks, which is in line with our findings.…”

Section: Discussionmentioning

confidence: 99%

“…Figure 1 shows the typical-for-PMA standardised clearance (L h −1 70 kg −1 ) for all patients in our dataset. Figure 1 also shows the maturation-decline function as estimated by Lonsdale et al [35] in a recent pooled analysis of three commonly used beta-lactam antibiotics.…”

Section: Population-pharmacokinetic Modellingmentioning

confidence: 99%

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Vancomycin Pharmacokinetics Throughout Life: Results from a Pooled Population Analysis and Evaluation of Current Dosing Recommendations

et al. 2019

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Background and Objectives Uncertainty exists regarding the optimal dosing regimen for vancomycin in different patient populations, leading to a plethora of subgroup-specific pharmacokinetic models and derived dosing regimens. We aimed to investigate whether a single model for vancomycin could be developed based on a broad dataset covering the extremes of patient characteristics. Furthermore, as a benchmark for current dosing recommendations, we evaluated and optimised the expected vancomycin exposure throughout life and for specific patient subgroups. Methods A pooled population-pharmacokinetic model was built in NONMEM based on data from 14 different studies in different patient populations. Steady-state exposure was simulated and compared across patient subgroups for two US Food and Drug Administration/European Medicines Agency-approved drug labels and optimised doses were derived. Results The final model uses postmenstrual age, weight and serum creatinine as covariates. A 35-year-old, 70-kg patient with a serum creatinine level of 0.83 mg dL −1 (73.4 µmol L −1) has a V 1 , V 2 , CL and Q 2 of 42.9 L, 41.7 L, 4.10 L h −1 and 3.22 L h −1. Clearance matures with age, reaching 50% of the maximal value (5.31 L h −1 70 kg −1) at 46.4 weeks postmenstrual age then declines with age to 50% at 61.6 years. Current dosing guidelines failed to achieve satisfactory steady-state exposure across patient subgroups. After optimisation, increased doses for the Food and Drug Administration label achieve consistent target attainment with minimal (± 20%) risk of under-and over-dosing across patient subgroups. Conclusions A population model was developed that is useful for further development of age and kidney function-stratified dosing regimens of vancomycin and for individualisation of treatment through therapeutic drug monitoring and Bayesian forecasting.

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Section: Discussioncontrasting

confidence: 50%

Section: Discussionmentioning

confidence: 99%

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Vancomycin Pharmacokinetics Throughout Life: Results from a Pooled Population Analysis and Evaluation of Current Dosing Recommendations

et al. 2019

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“…The overall quality of evidence (QoE) was rated strong (n = 2) or intermediate (n = 3). The beta-lactams benzylpenicillin, intravenous co-amoxiclav, piperacillin-tazobactam, cefotaxime, and meropenem were well described by Lonsdale et al 15 (DES = 7, strong QoE) across the entire age range. Oral co-amoxiclav was simulated according to the model by deVelde et al 48 (DES = 10, intermediate QoE); ampicillin-sulbactam was modeled according to Soto et al 49 (DES = 9, intermediate QoE); ceftriaxone according to Standing et al 36 (DES = 10, intermediate QoE); and ceftazidime by using the model from Li et al 50 (DES = 7, strong QoE).…”

Section: Selected Pk Models For Simulationmentioning

confidence: 72%

“…66 Models that are scalable across the entire pediatric age range are still lacking for many antibiotics. For beta-lactams a recent study by Lonsdale et al 15 developed a maturation function that is able to describe the maturation of the mostly renal clearance mechanisms in beta-lactams from neonates to elderly patients. For other drug classes similar investigations are still missing.…”

Section: Reviewmentioning

confidence: 99%

Variation in Target Attainment of Beta‐Lactam Antibiotic Dosing Between International Pediatric Formularies

Gastine

Hsia

Clements

et al. 2021

Clin Pharma and Therapeutics

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As antimicrobial susceptibility of common bacterial pathogens decreases, ensuring optimal dosing may preserve the use of older antibiotics in order to limit the spread of resistance to newer agents. Beta‐lactams represent the most widely prescribed antibiotic class, yet most were licensed prior to legislation changes mandating their study in children. As a result, significant heterogeneity persists in the pediatric doses used globally, along with quality of evidence used to inform dosing. This review summarizes dosing recommendations from the major pediatric reference sources and tries to answer the questions: Does beta‐lactam dose heterogeneity matter? Does it impact pharmacodynamic target attainment? For three important severe clinical infections—pneumonia, sepsis, and meningitis—pharmacokinetic models were identified for common for beta‐lactam antibiotics. Real‐world demographics were derived from three multicenter point prevalence surveys. Simulation results were compared with minimum inhibitory concentration distributions to inform appropriateness of recommended doses in targeted and empiric treatment. While cephalosporin dosing regimens are largely adequate for target attainment, they also pose the most risk of neurotoxicity. Our review highlights aminopenicillin, piperacillin, and meropenem doses as potentially requiring review/optimization in order to preserve the use of these agents in future.

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Population pharmacokinetics of meropenem in critically ill children with different renal functions

Rapp

Urien

Foissac

et al. 2019

Eur J Clin Pharmacol

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Scaling beta‐lactam antimicrobial pharmacokinetics from early life to old age

Abstract: Critical illness is associated with greater PK variability than in healthy volunteers. The maturation models presented will be useful for optimizing beta-lactam dosing, although a prospective, age-inclusive study is warranted for external validation.

Cited by 16 publications

References 159 publications

Vancomycin Pharmacokinetics Throughout Life: Results from a Pooled Population Analysis and Evaluation of Current Dosing Recommendations

Vancomycin Pharmacokinetics Throughout Life: Results from a Pooled Population Analysis and Evaluation of Current Dosing Recommendations

Variation in Target Attainment of Beta‐Lactam Antibiotic Dosing Between International Pediatric Formularies

Population pharmacokinetics of meropenem in critically ill children with different renal functions

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