Investigating the Critical Variables of Azithromycin Oral Absorption Using In Vitro Tests and PBPK Modeling

Guimarães, Mariana; Somville, Pascal; Vertzoni, Maria; Fotaki, Nikoletta

doi:10.1016/j.xphs.2021.09.013

Cited by 5 publications

(5 citation statements)

References 43 publications

(101 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore it has a low potential to penetrate blood cells. In contrast to daptomycin, several hundred liters are the distribution volumes of the macrolides class of antibiotics such as azithromycinfor which the RBP was estimated to be 1 ( Johnson et al, 2016 ; Guimarães et al, 2021 ). On the other hand, it is possible that we used 1.2 as optimized logP value, which might be quite a bit higher than experimental, resulting in the need to use a lower RBP to satisfy the daptomycin distribution.…”

Section: Discussionmentioning

confidence: 99%

Physiologically based pharmacokinetic modeling of daptomycin dose optimization in pediatric patients with renal impairment

You

Zhou

et al. 2022

Front. Pharmacol.

View full text Add to dashboard Cite

Background and Objective: Daptomycin is used to treat Gram-positive infections in adults and children and its dosing varies among different age groups. We focused on the pharmacokinetics of daptomycin in children with renal impairment, which has not been evaluated.Methods: A physiologically based pharmacokinetic (PBPK) model of daptomycin was established and validated to simulate its disposition in healthy populations and adults with renal impairment, along with a daptomycin exposure simulated in pediatric patients with renal impairment.Results: The simulated PBPK modeling results for various regimens of intravenously administered daptomycin were consistent with observed data according to the fold error below the threshold of 2. The Cmax and AUC of daptomycin did not differ significantly between children with mild-to-moderate renal impairment and healthy children. The AUC increased by an average of 1.55-fold and 1.85-fold in severe renal impairment and end-stage renal disease, respectively. The changes were more significant in younger children and could reach a more than 2-fold change. This scenario necessitates further daptomycin dose adjustments.Conclusion: Dose adjustments take into account the efficacy and safety of the drug; however, the steady-state Cmin of daptomycin may be above 24.3 mg/L in a few instances. We recommend monitoring creatine phosphokinase more than once a week when using daptomycin in children with renal impairment.

show abstract

Section: Discussionmentioning

confidence: 99%

Physiologically based pharmacokinetic modeling of daptomycin dose optimization in pediatric patients with renal impairment

You

Zhou

et al. 2022

Front. Pharmacol.

View full text Add to dashboard Cite

show abstract

“…Taking the community‐acquired pneumonia as an example, the most significant characteristics of azithromycin in children is that it has tissue accumulation, and the tissue concentration can reach 10 times more than the serum concentration (Willmann et al., 2005). The MIC value of azithromycin is 0.5 μg/ml (Guimarães et al., 2021), and the fAUC 24 /MIC needs to reach 25 to successfully treat the infection (Mahmood, 2006). The pediatric physiology‐based pharmacokinetic model for optimizing pediatric dosing regimens to match (within 20%) azithromycin exposure in the median adult (70‐kg body weight) azithromycin.…”

Section: Discussionmentioning

confidence: 99%

“…The herein-developed PBPK model from adult to pediatrics is different from the published PBPK models for azithromycin in pediatrics from Guimarães et al (2021). In our reserach, through parameter optimization of the absorption and dissolution process, -253 children in different age groups, we used the transformed individual parameters to establish pediatric models.…”

Section: Discussionmentioning

confidence: 99%

“…Taking the community-acquired pneumonia as an example, the most significant characteristics of azithromycin in children is that it has tissue accumulation, and the tissue concentration can reach 10 times more than the serum concentration (Willmann et al, 2005). The MIC value of azithromycin is 0.5 μg/ml (Guimarães et al, 2021), and the fAUC…”

Section: Discussionmentioning

confidence: 99%

“…Since biliary elimination appears to be reasonably well‐developed reaching adult levels at birth or in the first few months of postnatal age, no scaling was applied to biliary clearance (Guimarães et al., 2021).…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Develop adult extrapolation to pediatrics and pediatric dose optimization based on the physiological pharmacokinetic model of azithromycin

Liang

Zhang

et al. 2023

Biopharm & Drug Disp

View full text Add to dashboard Cite

Physiologically-based pharmacokinetic (PBPK) models are more frequently used for supporting pediatric dose selection in small-molecule drugs. Through literature research, drug parameters of azithromycin and clinical data from different studies were obtained. Through parameter optimization of the absorption and dissolution process, the adult intravenous model was extended to the adult oral model. The adult intravenous and oral PBPK models are precise to meet the AAFE<2 standard, and the pharmacokinetic parameters of the predicted values of the model are all within the mean standard deviation of the clinical observations. The values of plasma protein unbound fraction, renal clearance, and gastric juice pH between adults and pediatrics were changed by using the age-dependent pediatric organ maturity formula, and the adult model was extrapolated to the pediatric model. The final developed pediatric PBPK model was used to evaluate optimal dosing for children of different developmental ages. The relationship between the frist dose and age was as follows: 8.8 mg/kg/day from 0.5 to 2 years old, 9.2 mg/kg/day from 3 to 6 years old, 9.4 mg/kg/day from 7 to 12 years old, and 8.2 mg/kg/day from 13 to 18 years old, taken in half for 2-5 days. Simultaneously, the simulated exposures achieved with the dosing regimen proposed were comparable to adult plasma exposures for treatment of community-acquired pneumonia. A reasonable azithromycin pharmacokinetic-pharmacodynamic model for adults and pediatrics has been established, which can be demonstrated by the use of literature pediatric data to develop pediatric PBPK models, expanding the scope of this powerful modeling tool.

show abstract

Mechanistic Modeling of In Vitro Biopharmaceutic Data for a Weak Acid Drug: A Pathway Towards Deriving Fundamental Parameters for Physiologically Based Biopharmaceutic Modeling

Kowthavarapu,

Charbe,

Gupta

et al. 2024

AAPS J

View full text Add to dashboard Cite

Investigating the Critical Variables of Azithromycin Oral Absorption Using In Vitro Tests and PBPK Modeling

Cited by 5 publications

References 43 publications

Physiologically based pharmacokinetic modeling of daptomycin dose optimization in pediatric patients with renal impairment

Physiologically based pharmacokinetic modeling of daptomycin dose optimization in pediatric patients with renal impairment

Develop adult extrapolation to pediatrics and pediatric dose optimization based on the physiological pharmacokinetic model of azithromycin

Mechanistic Modeling of In Vitro Biopharmaceutic Data for a Weak Acid Drug: A Pathway Towards Deriving Fundamental Parameters for Physiologically Based Biopharmaceutic Modeling

Contact Info

Product

Resources

About