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

Abstract

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.

Development of a physiologically based pharmacokinetic (PBPK) population model for Chinese elderly subjects

“…To date, a few studies have been conducted on PBPK models to predict drug concentration in the geriatric population. In these models, alterations of certain physiological parameters with aging were considered, such as alveolar ventilation, cardiac output, different organs (e.g., liver, brain, heart, kidney, spleen, left and right lung) weights, and blood flows [9][10][11][12][13]. However, most models were developed in the Caucasian geriatric population whose physiological variables and PK characteristics were not necessarily same as Chinese geriatric population.…”

A Physiologically-Based Pharmacokinetic Framework for Prediction of Drug Exposure in Malnourished Children

“…= intrinsic clearance (µL/min/mg protein). 1 as per PK-Sim ® library value if not indicated otherwise, 2 as reported in Schlender et al, 2018 [ 29 ] if not indicated otherwise, 3 optimized, 4 Carver et al, 1989 [ 27 ], 5 Charman et al, 2020 [ 47 ], 6 ChemAxon ( ), 7 Kotila et al, 2013 [ 42 ], 8 solubility in mg/mL at indicated pH (@ pH), 9 ALOGPS 2.1 ( ), 10 B:P optimized via V f.proteins = 0.19 and V f.lipid = 0 in blood cell, 11 B:P optimized via V f.proteins = 0.06 and V f.lipid = 0 in blood cell, 12 calculated in PK-Sim ® , 13 Absorption modification Enhancement factors for Cecum = 26.24 and other regions of large intestines = 0.…”

“…The ciprofloxacin PBPK model used in this study was adapted from a previously published model [ 29 ]. Some model refinements were performed to match the clinical plasma concentrations in healthy American adult volunteers ( n = 14) after a 750-mg oral dose [ 30 ].…”

Development and Evaluation of a Physiologically Based Pharmacokinetic Drug-Disease Model of Propranolol for Suggesting Model Informed Dosing in Liver Cirrhosis Patients

“…A value of 5.24×10 −6 cm/min was used in this model after the parameter identification feature of the modeling program. 37 The specific intestinal permeability of propranolol reported in the literature ranged from 2.8×10 −4 -6.67×10 −4 and 6.67 ± 3.42 ×10 −4 cm/s. 38,39…”