An in silico approach to determine challenges in the bioavailability of ciprofloxacin, a poorly soluble weak base with borderline solubility and permeability characteristics

Hansmann, Simone; Miyaji, Yoshihiro; Dressman, Jennifer B.

doi:10.1016/j.ejpb.2017.10.019

Cited by 29 publications

(23 citation statements)

References 33 publications

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“…A mechanistic description of the oral absorption of ciprofloxacin has been covered by two publications. First, Martinez et al investigated the peculiarities of the oral absorption of ciprofloxacin with dedicated clinical trials and sophisticated stepwise information of model processes [ 109 ], while Hansmann et al recently focused on the dosage form dissolution mechanisms and tried to inform in vivo behavior with in vitro dissolution, transfer and two-stage experiments [ 116 ]. Both approaches were conducted using a commercial platform, but described systemic exposure with a (non)compartmental approach.…”

Section: Discussionmentioning

confidence: 99%

A Physiologically-Based Pharmacokinetic Model to Describe Ciprofloxacin Pharmacokinetics Over the Entire Span of Life

et al. 2018

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BackgroundPhysiologically-based pharmacokinetic (PBPK) modeling has received growing interest as a useful tool for the assessment of drug pharmacokinetics by continuous knowledge integration.ObjectiveThe objective of this study was to build a ciprofloxacin PBPK model for intravenous and oral dosing based on a comprehensive literature review, and evaluate the predictive performance towards pediatric and geriatric patients.MethodsThe aim of this report was to establish confidence in simulations of the ciprofloxacin PBPK model along the development process to facilitate reliable predictions outside of the tested adult age range towards the extremes of ages. Therefore, mean data of 69 published clinical trials were identified and integrated into the model building, simulation and verification process. The predictive performance on both ends of the age scale was assessed using individual data of 258 subjects observed in own clinical trials.ResultsCiprofloxacin model verification demonstrated no concentration-related bias and accurate simulations for the adult age range, with only 4.8% of the mean observed data points for intravenous administration and 12.1% for oral administration being outside the simulated twofold range. Predictions towards the extremes of ages for the area under the plasma concentration–time curve (AUC) and the maximum plasma concentration (Cmax) over the entire span of life revealed a reliable estimation, with only two pediatric AUC observations outside the 90% prediction interval.ConclusionOverall, this ciprofloxacin PBPK modeling approach demonstrated the predictive power of a thoroughly informed middle-out approach towards age groups of interest to potentially support the decision-making process.Electronic supplementary materialThe online version of this article (10.1007/s40262-018-0661-6) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

A Physiologically-Based Pharmacokinetic Model to Describe Ciprofloxacin Pharmacokinetics Over the Entire Span of Life

et al. 2018

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“…They observed that fasting resulted in significant variability of in vivo absorption, and supersaturation and precipitation plays a significant role in precisely predicting the systemic bioavailability. Hansmann et al carried out in silico PBPK distribution modelling to generate more insight on the in vivo plasma profile of ciprofloxacin on different patient populations and varying gastric environments by simulating a hypochlorhydric and achlorhydric environment (50). The volume of distribution Kambayashi et al also studied the precipitation kinetics of two weakly basic drugs (i.e., dipyridamole and ketoconazole) in the intestinal lumen by using a simplified transfer model approach to obtain in vitro dissolution data, which is further integrated into Stella simulation software to predict the in vivo drug behavior (51).…”

Section: Applications Of In Silico Techniquesmentioning

confidence: 99%

Physiologically Based Pharmacokinetic (PBPK) Modelling for In Vitro-In Vivo Extrapolation: Emphasis on the Use of Dissolution Data

Ghate¹,

Chaudhari²,

Lewis

2019

Dissolution Technol.

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Recently the pharmaceutical sector has witnessed a drastic rise in the advancement and incorporation of computerbased technology into several unit operations. Drug dissolution profiling is an important consideration for the successful development of immediate and extended orally delivered formulations. Physiologically based pharmacokinetic (PBPK) modelling has gained a lot of attention when compared to the one-and two-compartmental modelling in establishing a relationship between the in vitro and in vivo parameters. Moreover, the influence of various factors like food, disease, population variations, transporters, and gastric emptying play a significant part in the in vivo outcome of the dosage form. In silico techniques are capable of addressing these limitations by incorporation of near-to-life replica of the in vivo conditions and are able to provide newer interpretations of conventional dissolution data that cannot be concluded by the generation of pharmacokinetic descriptors alone. This review focuses on the various in silico tools including the theory and studies conducted with dissolution data in recent years.

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“…At about the same time, Hansmann et al . conducted a similar ‘dumping’ test by predissolving ciprofloxacin tablets for 10 min in 250 ml FaSSGF and then gently pouring the resulting solution into 350 ml FaSSIF over a period of 30 s . The results of both the ‘dumping’ test and the corresponding transfer experiment were coupled with in silico PBPK modelling using SimCyp ® (Simcyp Ltd., Sheffield, UK).…”

Section: Biorelevant In Vitro Two‐stage Testing In Formulationmentioning

confidence: 99%

“…Variation in the vessel size across the test set‐ups may be more problematic regarding the comparability of test results, as the smaller minivessels, together with their downsized paddles, can lead to different hydrodynamics inside the test vessel compared to the standard vessels in pharmacopeial set‐ups. While some manufacturers aim at scaling down all dimensions to maintain comparable hydrodynamics, others have adopted designs that move away from this scaling feature …”

Section: Biorelevant In Vitro Two‐stage Testing In Formulationmentioning

confidence: 99%

Development, current applications and future roles of biorelevant two-stage in vitro testing in drug development

Fiolka

Dressman

2018

Journal of Pharmacy and Pharmacology

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Objectives Various types of two stage in vitro testing have been used in a number of experimental settings. In addition to its application in quality control and for regulatory purposes, two-stage in vitro testing has also been shown to be a valuable technique to evaluate the supersaturation and precipitation behavior of poorly soluble drugs during drug development. Key findings The so-called 'transfer model', which is an example of two-stage testing, has provided valuable information about the in vivo performance of poorly soluble, weakly basic drugs by simulating the gastrointestinal drug transit from the stomach into the small intestine with a peristaltic pump. The evolution of the transfer model has resulted in various modifications of the experimental model set-up. Concomitantly, various research groups have developed simplified approaches to two-stage testing to investigate the supersaturation and precipitation behavior of weakly basic drugs without the necessity of using a transfer pump. Summary Given the diversity among the various two-stage test methods available today, a more harmonized approach needs to be taken to optimize the use of two stage testing at different stages of drug development.

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An in silico approach to determine challenges in the bioavailability of ciprofloxacin, a poorly soluble weak base with borderline solubility and permeability characteristics

Cited by 29 publications

References 33 publications

A Physiologically-Based Pharmacokinetic Model to Describe Ciprofloxacin Pharmacokinetics Over the Entire Span of Life

A Physiologically-Based Pharmacokinetic Model to Describe Ciprofloxacin Pharmacokinetics Over the Entire Span of Life

Physiologically Based Pharmacokinetic (PBPK) Modelling for In Vitro-In Vivo Extrapolation: Emphasis on the Use of Dissolution Data

Development, current applications and future roles of biorelevant two-stage in vitro testing in drug development

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