Estimating the variability in fraction absorbed as a paradigm for informing formulation development in early clinical drug development

Rabbie, Sarit C.; Martín, Paul; Flanagan, Talia; Basit, Abdul W.; Standing, Joseph F.

doi:10.1016/j.ejps.2016.04.005

Cited by 3 publications

(3 citation statements)

References 10 publications

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“…Each study group was tested as a covariate and retained in the model if it decreased an objective function value by at least 3.84 (statistical significance level 0.05). Oral bioavail-ability was included in the model by logit transformation (1/(1 + EXP(−(F + IIV F ))), where F is a parameter for bioavailability and IIV F its interindividual variability) to ensure its value between 0 and 1 [44]. Standard error for F was calculated by the delta method.…”

Section: Discussionmentioning

confidence: 99%

The Pharmacokinetic Profile and Bioavailability of Enteral N-Acetylcysteine in Intensive Care Unit

et al. 2021

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Background and Objectives: N-acetylcysteine (NAC) is a mucolytic agent used to prevent ventilator-associated pneumonia in intensive care units. This study aimed to evaluate the oral bioavailability of NAC in critically ill patients with pneumonia, isolated acute brain injury and abdominal sepsis. Materials and Methods: This quantitative and descriptive study compared NAC’s pharmacokinetics after intravenous and enteral administration. 600 mg of NAC was administered in both ways, and the blood levels for NAC were measured. Results: 18 patients with pneumonia, 19 patients with brain injury and 17 patients with abdominal sepsis were included in the population pharmacokinetic modelling. A three-compartmental model without lag-time provided the best fit to the data. Oral bioavailability was estimated as 11.6% (95% confidence interval 6.3–16.9%), similar to bioavailability in healthy volunteers and patients with chronic pulmonary diseases. Conclusions: The bioavailability of enteral NAC of ICU patients with different diseases is similar to the published data on healthy volunteers.

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Section: Discussionmentioning

confidence: 99%

The Pharmacokinetic Profile and Bioavailability of Enteral N-Acetylcysteine in Intensive Care Unit

et al. 2021

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“…The hepatic volume (V H ) in litres was associated to the subject body weight (WT, kg) as indicated by Noda et al in Equation :

V_{H} = 0.05012 \times {WT}^{0.78}

Hepatic blood flow in males was reported as 50.4 L/h/L of hepatic volume

Q_{H} = 50.4 \times V_{H}

To describe the disposition of agomelatine and its metabolites, both 1‐ and 2‐compartmental models were tested.…”

Section: Methodsmentioning

confidence: 99%

A semiphysiological population pharmacokinetic model of agomelatine and its metabolites in Chinese healthy volunteers

Xie

Vermeulen

Colin

et al. 2019

Brit J Clinical Pharma

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Aims: Agomelatine is an antidepressant for major depressive disorders. It undergoes extensive first-pass hepatic metabolism and displays irregular absorption profiles and large interindividual variability (IIV) and interoccasion variability of pharmacokinetics. The objective of this study was to characterize the complex pharmacokinetics of agomelatine and its metabolites in healthy subjects.Methods: Plasma concentration-time data of agomelatine and its metabolites were collected from a 4-period, cross-over bioequivalence study, in which 44 healthy subjects received 25 mg agomelatine tablets orally. Nonlinear mixed effects modelling was used to characterize the pharmacokinetics and variability of agomelatine and its metabolites. Deterministic simulations were carried out to investigate the influence of pathological changes due to liver disease on agomelatine pharmacokinetics.Results: A semiphysiological pharmacokinetic model with parallel first-order absorption and a well-stirred liver compartment adequately described the data.The estimated IIV and interoccasion variability of the intrinsic clearance of agomelatine were 130.8% and 28.5%, respectively. The IIV of the intrinsic clearance turned out to be the main cause of the variability of area under the curve-based agomelatine exposure. Simulations demonstrated that a reduction in intrinsic clearance or liver blood flow, and an increase in free drug fraction had a rather modest influence on agomelatine exposures (range: −50 to 200%).Portosystemic shunting, however, substantially elevated agomelatine exposure by 12.6-109.1-fold.Conclusions: A semiphysiological pharmacokinetic model incorporating first-pass hepatic extraction was developed for agomelatine and its main metabolites.The portosystemic shunting associated with liver disease might lead to significant alterations of agomelatine pharmacokinetics, and lead to substantially increased exposure.

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“…Oral drug delivery is one of the most commonly used routes for drug administration due to its ease of use, patient acceptance and non-invasiveness. To formulate a drug for oral administration, bioavailability should be considered since it reflects the proportion of the dose that can reach systemic circulation and provide the expected therapeutic effect (Rabbie et al, 2016). Many drugs that are currently on the market or newly developed have poor bioavailability, meaning they do not reach the minimum effective concentration in the bloodstream due to factors such as limited solubility, poor absorption, and rapid metabolism.…”

Section: Introductionmentioning

confidence: 99%

Lipospheres and Pro-Nanolipospheres: Advancements in Drug Delivery Systems

Motawee

Khafagy²,

Gardouh³

et al. 2023

Records of Pharmaceutical and Biomedical Sciences

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The usefulness of nanotechnology nowadays in improving the performance of different active pharmaceutical ingredients (API) has generated a great deal of excitement worldwide. These nano-systems offer the advantage of higher bioavailability, lower toxicity, and the ability to deliver drugs with low half-life or low permeability. Lipid nano-based carriers have been extensively used for their ability to protect the API from degradation and their safety as these used lipids are generally regarded as safe. Lipospheres and Pro-nanolipospheres are among the promising systems for the delivery of water-insoluble drugs. They are composed of aqueous dispersible particles with a rigid hydrophobic lipid centre, coated by an outer protective phospholipid exterior. These lipospheres and Pro-nanolipospheres have the advantage of being easy to scale up, high dispersibility in aqueous media, and improved physical stability, making them the perfect candidate for the delivery of different APIs using different routes including oral, parenteral, intranasal and topical routes.

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Estimating the variability in fraction absorbed as a paradigm for informing formulation development in early clinical drug development

Cited by 3 publications

References 10 publications

The Pharmacokinetic Profile and Bioavailability of Enteral N-Acetylcysteine in Intensive Care Unit

The Pharmacokinetic Profile and Bioavailability of Enteral N-Acetylcysteine in Intensive Care Unit

A semiphysiological population pharmacokinetic model of agomelatine and its metabolites in Chinese healthy volunteers

Lipospheres and Pro-Nanolipospheres: Advancements in Drug Delivery Systems

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