Pharmacokinetics of obese adults: Not only an increase in weight

Gouju, Julien; Legeay, Samuel

doi:10.1016/j.biopha.2023.115281

Cited by 16 publications

(5 citation statements)

References 178 publications

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“…However, this is consistent with the increase in total drug CL that is often described in obese patients (while a similar body weight-normalized CL is usually described) (Gouju and Legeay, 2023). The higher drug CL in obese patients can also be explained by some physiological changes during obesity, such as increased blood flow, activation of the renin-angiotensin system, and glomerular hyperfiltration (Gouju and Legeay, 2023). Dosing recommendations for vancomycin usually end with an eGFR category of ≥1.5 mL/s/1.73 m 2 .…”

Section: Discussionsupporting

confidence: 89%

“…Total daily doses in each eGFR category may appear to be higher than generally reported for normal-weight patients. However, this is consistent with the increase in total drug CL that is often described in obese patients (while a similar body weight-normalized CL is usually described) ( Gouju and Legeay, 2023 ). The higher drug CL in obese patients can also be explained by some physiological changes during obesity, such as increased blood flow, activation of the renin–angiotensin system, and glomerular hyperfiltration ( Gouju and Legeay, 2023 ).…”

Section: Discussionsupporting

confidence: 87%

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Vancomycin population pharmacokinetics and dosing proposal for the initial treatment in obese adult patients

Polášková,

Murínová,

Gregorová

et al. 2024

Front. Pharmacol.

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AimThe aim of this study was to develop a vancomycin population pharmacokinetic model in adult obese patients and propose covariate-based dosing individualization in order to maximize the achievement of the newly recommended PK/PD target, according to a revised consensus guideline from 2020.MethodsTherapeutic drug monitoring data from initial vancomycin therapy (first 3 days of treatment) in adult obese (BMI ≥ 30 kg/m2) patients from 2013 to 2022 were analyzed using a non-linear mixed-effects modeling method, and Monte Carlo simulations were then used to find the optimal dosage maximizing the PK/PD target attainment.ResultsA total of 147 vancomycin serum levels obtained from 138 patients were included in the analysis. Based on the covariate model diagnosis among all tested variables, no reliable predictor of vancomycin volume of distribution (Vd) was identified, while clearance (CL) was positively correlated with eGFR and lean body mass. Creatinine-based eGFR predicted vancomycin CL better than cystatin C-based eGFR. The median (interquartile range) value from conditional modes of individual estimates of Vd, CL, and elimination half-life in our population was 74.0 (70.5–75.4) L, 6.65 (4.95–8.42) L/h, and 7.7 (6.0–10.0) h, respectively.ConclusionWe proposed dosing individualization based on the covariate found in order to maximize the achievement of the newly recommended PK/PD target of the AUC/MIC ratio of 400–600. Clinical pharmacy/pharmacology interventions may lead to an improvement in vancomycin dosing with a reflection in PK/PD target attainment.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 87%

Vancomycin population pharmacokinetics and dosing proposal for the initial treatment in obese adult patients

Polášková,

Murínová,

Gregorová

et al. 2024

Front. Pharmacol.

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“…Therefore, the following disposition is dependent on the tissue/blood partition coefficients. Desflurane has a negligible body metabolism (0.02%) ( Eger, 1995 ; Gouju and Legeay, 2023 ) and a lower fat/blood partition coefficient than sevoflurane (15 vs. 41) ( Jakobsson, 2012 ). In the current study, the arterial and pulmonary artery concentrations dropped to one-tenth after the 2-h disposition phase.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of desflurane uptake and disposition in piglets

Lu,

Ho,

et al. 2024

Front. Pharmacol.

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Introduction:Many respiratory but few arterial blood pharmacokinetics of desflurane uptake and disposition have been investigated. We explored the pharmacokinetic parameters in piglets by comparing inspiratory, end-tidal, arterial blood, and mixed venous blood concentrations of desflurane.Methods:Seven piglets were administered inspiratory 6% desflurane by inhalation over 2 h, followed by a 2-h disposition phase. Inspiratory and end-tidal concentrations were detected using an infrared analyzer. Femoral arterial blood and pulmonary artery mixed venous blood were sampled to determine desflurane concentrations by gas chromatography at 1, 3, 5, 10, 20, 30, 40, 50, 60, 80, 100, and 120 min during each uptake and disposition phase. Respiratory and hemodynamic parameters were measured simultaneously. Body uptake and disposition rates were calculated by multiplying the difference between the arterial and pulmonary artery blood concentrations by the cardiac output.Results:The rates of desflurane body uptake increased considerably in the initial 5 min (79.8 ml.min−1) and then declined slowly until 120 min (27.0 ml.min−1). Similar characteristics of washout were noted during the subsequent disposition phase. Concentration–time curves of end-tidal, arterial, and pulmonary artery blood concentrations fitted well to zero-order input and first-order disposition kinetics. Arterial and pulmonary artery blood concentrations were best fitted using a two-compartment model. After 2 h, only 21.9% of the desflurane administered had been eliminated from the body.Conclusion:Under a fixed inspiratory concentration, desflurane body uptake in piglets corresponded to constant zero-order infusion, and the 2-h disposition pattern followed first-order kinetics and best fitted to a two-compartment model.

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“…), composition of the extracellular matrix, pressure of interstitial fluid, pH and tumor heterogeneity, presence of hypoxic regions in the tumor, etc. (Gouju & Legeay, 2023;Matuszewskaet al, 2021;Ozcan, 2023;Sriraman et al, 2014). The intrinsic apoptosis pathway is initiated by stress or injury that happens within the cells such as hypoxia, DNA damage, nutrient deprivation, high intracellular Ca2+, etc.…”

Section: Tumor-host Interacting Factorsmentioning

confidence: 99%

Chemotherapy Resistance in Cancer: Mechanism and Roadmap to Evade Exploring Apoptosis

Halder

2024

IJALSR

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Chemotherapy resistance indicates the non-responsiveness of cancer cells to the cytotoxic and inhibitory effects of chemo drugs attributed to either intrinsic or extrinsic resistance mechanisms in cancer cells. Studies so far indicate that drug resistance can be triggered by a multitude of factors such as the over-expression of drug efflux pumps, DNA repair mechanisms, modifications in the drug target such as point mutations and gene amplification, over-expression of anti-apoptotic proteins and down-regulation of pro-apoptotic signals, presence of cancer stem cells and immune-suppressive cells, excessive cytokine production, tumor heterogeneity, epigenetic changes, activation of alternate pro-survival signaling pathways, etc. Both host and tumor-related factors can contribute to therapy resistance. Currently, chemo resistance poses the foremost setback in the successful treatment of cancer, and it exerts significant stress on the available medical resources. Besides the costs associated with the treatment, patients go through severe emotional and physical trauma. Chemotherapy resistance is also a major contributor to accelerated metastasis and invasion. Dose-escalation is not always practical since the associated side effects may increase apart from increasing the treatment costs. Several studies are ongoing to address this issue productively, such as therapeutic molecules designed to restore the apoptotic machinery. Site-specific delivery of pro-apoptotic agents such as small molecules, antibodies, peptides, etc. targeting the apoptosis pathway is also thoroughly studied. Moreover, the efficacy of combination strategies is also a topic of research.

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Pharmacokinetics of obese adults: Not only an increase in weight

Cited by 16 publications

References 178 publications

Vancomycin population pharmacokinetics and dosing proposal for the initial treatment in obese adult patients

Vancomycin population pharmacokinetics and dosing proposal for the initial treatment in obese adult patients

Pharmacokinetics of desflurane uptake and disposition in piglets

Chemotherapy Resistance in Cancer: Mechanism and Roadmap to Evade Exploring Apoptosis

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