1.
Bouchene, Salim, 1984-, et al.
(författare)
A Whole-Body Physiologically Based Pharmacokinetic Model for Colistin and Colistin Methanesulfonate in Rat
2018
Ingår i: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7835 .- 1742-7843. ; 123:4, s. 407-422
Tidskriftsartikel (refereegranskat) abstract
Colistin is a polymyxin antibiotic used to treat patients infected with multidrug-resistant Gram-negative bacteria (MDR-GNB). The objective of this work was to develop a whole-body physiologically based pharmacokinetic (WB-PBPK) model to predict tissue distribution of colistin in rat. The distribution of a drug in a tissue is commonly characterized by its tissue-to-plasma partition coefficient, K-p. Colistin and its prodrug, colistin methanesulfonate (CMS) K-p priors, were measured experimentally from rat tissue homogenates or predicted in silico. The PK parameters of both compounds were estimated fitting invivo their plasma concentration-time profiles from six rats receiving an i.v. bolus of CMS. The variability in the data was quantified by applying a nonlinear mixed effect (NLME) modelling approach. A WB-PBPK model was developed assuming a well-stirred and perfusion-limited distribution in tissue compartments. Prior information on tissue distribution of colistin and CMS was investigated following three scenarios: K-p was estimated using in silico K-p priors (I) or K-p was estimated using experimental K-p priors (II) or K-p was fixed to the experimental values (III). The WB-PBPK model best described colistin and CMS plasma concentration-time profiles in scenario II. Colistin-predicted concentrations in kidneys in scenario II were higher than in other tissues, which was consistent with its large experimental K-p prior. This might be explained by a high affinity of colistin for renal parenchyma and active reabsorption into the proximal tubular cells. In contrast, renal accumulation of colistin was not predicted in scenario I. Colistin and CMS clearance estimates were in agreement with published values. The developed model suggests using experimental priors over in silico K-p priors for kidneys to provide a better prediction of colistin renal distribution. Such models might serve in drug development for interspecies scaling and investigate the impact of disease state on colistin disposition.
2.
Friberg, Lena E.
(författare)
Pivotal Role of Translation in Anti-Infective Development
2021
Ingår i: Clinical Pharmacology and Therapeutics. - : John Wiley & Sons. - 0009-9236 .- 1532-6535. ; 109:4, s. 856-866
Tidskriftsartikel (refereegranskat) abstract
The value of model-based translation in drug discovery and development is now effectively being recognized in many disease areas and among various stakeholders. Such quantitative approaches are expected to facilitate the selection on which compound to prioritize for successful development, predict the human efficacious dose based on preclinical data with adequate precision, guide design, and de-risk later development stages. The importance of time-dependencies, which are typically species-dependent due to different turnover rates of biological processes, is, however, often neglected. For bacterial infections, the choice of dosing regimen is typically relying on preclinical pharmacokinetic (PK) and pharmacodynamic (PD) data, because the bacterial load and disease severity, and consequently the PK/PD relationship, cannot be quantified well on clinical data, given the low-information end points used. It is time to recognize the limitations of using time-collapsed approaches for translation (i.e., methods where targets are based on summary measures of exposure and response). Models describing the full time-course captures important quantitative information of drug distribution, bacterial growth, antibiotic killing, and resistance development, and can account for species-differences in the PK profiles driving the killing. Furthermore, with a model-based approach for translation, we can take a holistic approach in development of a joint model for in vitro, in vivo, and clinical data, as well as incorporating information on the contribution of the immune system. Such advancements are anticipated to facilitate rational decision making during various stages of drug development and in the optimization of treatment regimens for different groups of patients.
3.
Gkoufa, Aikaterini, et al.
(författare)
Pulmonary and systemic pharmacokinetics of colistin methanesulfonate (CMS) and formed colistin following nebulisation of CMS among patients with ventilator-associated pneumonia
2022
Ingår i: International Journal of Antimicrobial Agents. - : Elsevier. - 0924-8579 .- 1872-7913. ; 59:6
Tidskriftsartikel (refereegranskat) abstract
There has been accumulating interest in nebulised colistin methanesulfonate (CMS) for the treatment of ventilator-associated pneumonia (VAP). In this study, pulmonary and systemic pharmacokinetics following nebulisation of CMS at a dose of 3 MIU and 5 MIU, using a vibrating mesh nebuliser, for VAP caused by extensively drug-resistant Gram-negative pathogens was assessed. Blood samples and minibronchoalveolar lavage (mini-BAL) was performed post-dose at 1, 4 and 8 h. Concentrations of CMS and formed colistin in mini-BAL and plasma were determined by liquid chromatography-tandem mass spectrometry, and pharmacokinetic analysis was conducted using a population approach. The study population included three groups ( n = 10 per group): (A) intravenous CMS and concomitantly nebulised CMS at a dose of 3 MIU (30 min duration); (B) nebulised CMS at a dose of 3 MIU (30 min duration) as monotherapy; and (C) nebulised CMS 5 MIU (45 min duration) as monotherapy. Mean plasma formed colistin concentrations were < 1 mg/L following CMS nebulisation as monotherapy (groups B and C). Predicted trough concentrations of formed colistin in the epithelial lining fluid (ELF) following 24-h dosing of 3 MIU and 5 MIU nebulised CMS were 120.4 mg/L and 200.7 mg/L, respectively. The model predicted that concomitant intravenous CMS (group A) had minimal impact on the formed colistin concentration in ELF. This study demonstrated high ELF formed colistin concentrations following nebulised CMS (constantly above colistin MICs), while plasma concentrations were lower than those associated with nephrotoxicity. Our results provide important information for optimisation of nebulised colistin therapy. (c) 2022 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.
4.
Lacroix, Brigitte, 1978-, et al.
(författare)
A Pharmacodynamic Markov Mixed-Effects Model for Determining the Effect of Exposure to Certolizumab Pegol on the ACR20 Score in Patients With Rheumatoid Arthritis
2009
Ingår i: Clinical Pharmacology and Therapeutics. - : Nature Publishing Group. - 0009-9236 .- 1532-6535. ; 86:4, s. 387-395
Tidskriftsartikel (refereegranskat) abstract
The American College of Rheumatology 20% preliminary definition of improvement of rheumatoid arthritis (ACR20) is widely used in clinical trials to assess response to treatment. The objective of this analysis was to develop an exposure-response model of ACR20 in subjects treated with certolizumab pegol, and to predict clinical outcome following various treatment schedules. At each visit, subjects were classified as being ACR20 responders, ACR20 non-responders, or having dropped out. A Markov mixed-effect model was developed to investigate the drug effect on the transitions between the 3 defined states. Increasing certolizumab pegol exposure predicted an increasing probability of becoming a responder and remaining a responder, as well as a reduced probability of dropping out of treatment. Simulations of the ACR20 response rate support dosing regimens of 400 mg at weeks 0, 2 and 4 followed by 200 mg every 2 weeks, or alternative maintenance regimen of 400 mg every 4 weeks.
5.
Sou, Tomás, et al.
(författare)
Model-Based Drug Development in Pulmonary Delivery : Pharmacokinetic Analysis of Novel Drug Candidates for Treatment of Pseudomonas aeruginosa Lung Infection
2019
Ingår i: Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0022-3549 .- 1520-6017. ; 108:1, s. 630-640
Tidskriftsartikel (refereegranskat) abstract
Antibiotic resistance is a major public health threat worldwide. In particular, about 80% of cystic fibrosis patients have chronic Pseudomonas aeruginosa (PA) lung infection resistant to many current antibiotics. We are therefore developing a novel class of antivirulence agents, quorum sensing inhibitors (QSIs), which inhibit biofilm formation and sensitize PA to antibiotic treatments. For respiratory conditions, targeted delivery to the lung could achieve higher local concentrations with reduced risk of adverse systemic events. In this study, we report the pharmacokinetics of 3 prototype QSIs after pulmonary delivery, and the simultaneous analysis of the drug concentration-time profiles from bronchoalveolar lavage, lung homogenate and plasma samples, using a pharmacometric modeling approach. In addition to facilitating the direct comparison and selection of drug candidates, the developed model was used for dosing simulation studies to predict in vivo exposure following different dosing scenarios. The results show that systemic clearance has limited impact on local drug exposure in the lung after pulmonary delivery. Therefore, we suggest that novel QSIs designed for pulmonary delivery as targeted treatments for respiratory conditions should ideally have a long residence time in the lung for local efficacy with rapid clearance after systemic absorption for reduced risk of systemic adverse events.
6.
Thorsted, Anders, et al.
(författare)
Pharmacodynamics of immune response biomarkers of interest for evaluation of treatment effects in bacterial infections
2020
Ingår i: International Journal of Antimicrobial Agents. - : ELSEVIER. - 0924-8579 .- 1872-7913. ; 56:3
Tidskriftsartikel (refereegranskat) abstract
This mini-review discusses the pharmacodynamics of immune-related biomarkers in the area of bacterial infectious diseases that could be of interest from a pharmacokinetic (PK) and pharmacokinetic/pharmacodynamic (PK/PD) perspective in the evaluation of treatment effects. The host response to an infection is often poorly defined both in preclinical assessments and in clinical practice when it comes to characterisation of PK and PK/PD relationships. Through population modelling, the time courses and variability of immune response variables can be quantified. Incorporation of such biomarker information into PK and PK/PD models may guide the evaluation of individual response to treatment (right antibiotic, more antibiotic, less antibiotic) and when to stop treatment. Furthermore, translation of results from pre clinical systems to clinical scenarios may be improved with the incorporation of biomarker information. Potential biomarkers for these purposes are discussed and a few modelling examples are provided. (c) 2020 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.
7.
Wallin, Johan E., et al.
(författare)
A tool for neutrophil guided dose adaptation in chemotherapy
2009
Ingår i: Computer Methods and Programs in Biomedicine. - : Elsevier BV. - 0169-2607 .- 1872-7565. ; 93:3, s. 283-291
Tidskriftsartikel (refereegranskat) abstract
Chemotherapy dosing in anticancer treatment is a balancing act between achieving concentrations that are effective towards the malignancy and that result in acceptable side-effects. Neutropenia is one major side-effect of many antitumor agents, and is related to an increased risk of infection. A model capable of describing the time-course of myelosuppression from administered drug could be used in individual dose selection. In this paper we describe the transfer of a previously developed semi-mechanistic model for myelosuppression from NONMEM to a dosing tool in MS Excel, with etoposide as an example. The tool proved capable to solve a differential equation system describing the pharmacokinetics and pharmacodynamics, with estimation performance comparable to NONMEM. In the dosing tool the user provides neutrophil measures from a previous treatment course and request for the dose that results in a desired nadir in the upcoming course through a Bayesian estimation procedure.
8.
Zhao, Chenyan, et al.
(författare)
Combination of polymyxin B and minocycline against multidrug-resistant Klebsiella pneumoniae : interaction quantified by pharmacokinetic/pharmacodynamic modelling from in vitro data
2020
Ingår i: International Journal of Antimicrobial Agents. - : ELSEVIER. - 0924-8579 .- 1872-7913. ; 55:6
Tidskriftsartikel (refereegranskat) abstract
Lack of effective treatment for multidrug-resistant Klebsiella pneumoniae (MDR-Kp) necessitates finding and optimising combination therapies of old antibiotics. The aims of this study were to quantify the combined effect of polymyxin B and minocycline by building an in silico semi-mechanistic pharmacokinetic/pharmacodynamic (PKPD) model and to predict bacterial kinetics when exposed to the drugs alone and in combination at clinically achievable unbound drug concentration-time profiles. A clinical K. pneumoniae strain resistant to polymyxin B [minimum inhibitory concentration (MIC) = 16 mg/L] and minocycline (MIC = 16 mg/L) was selected for extensive in vitro static time-kill experiments. The strain was exposed to concentrations of 0.0625-48 ? MIC, with seven samples taken per experiment for viable counts during 0-28 h. These observations allowed the development of the PKPD model. The final PKPD model included drug-induced adaptive resistance for both drugs. Both the minocycline-induced bacterial killing and resistance onset rate constants were increased when polymyxin B was co-administered, whereas polymyxin B parameters were unaffected. Predictions at clinically used dosages from the developed PKPD model showed no or limited antibacterial effect with monotherapy, whilst combination therapy kept bacteria below the starting inoculum for 20 h at high dosages [polymyxin B 2.5 mg/kg + 1.5 mg/kg every 12 h (q12h); minocycline 400 mg + 200 mg q12h, loading + maintenance doses]. This study suggests that polymyxin B and minocycline in combination may be of clinical benefit in the treatment of infections by MDR-Kp and for isolates that are non-susceptible to either drug alone. (C) 2020 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by-nc-nd/4.0/)
9.
Zhao, Chenyan, et al.
(författare)
Population pharmacokinetics of apramycin from first-in-human plasma and urine data to support prediction of efficacious dose
2022
Ingår i: Journal of Antimicrobial Chemotherapy. - : Oxford University Press (OUP). - 0305-7453 .- 1460-2091. ; 77:10, s. 2718-2728
Tidskriftsartikel (refereegranskat) abstract
Background Apramycin is under development for human use as EBL-1003, a crystalline free base of apramycin, in face of increasing incidence of multidrug-resistant bacteria. Both toxicity and cross-resistance, commonly seen for other aminoglycosides, appear relatively low owing to its distinct chemical structure. Objectives To perform a population pharmacokinetic (PPK) analysis and predict an efficacious dose based on data from a first-in-human Phase I trial. Methods The drug was administered intravenously over 30 min in five ascending-dose groups ranging from 0.3 to 30 mg/kg. Plasma and urine samples were collected from 30 healthy volunteers. PPK model development was performed stepwise and the final model was used for PTA analysis. Results A mammillary four-compartment PPK model, with linear elimination and a renal fractional excretion of 90%, described the data. Apramycin clearance was proportional to the absolute estimated glomerular filtration rate (eGFR). All fixed effect parameters were allometrically scaled to total body weight (TBW). Clearance and steady-state volume of distribution were estimated to 5.5 L/h and 16 L, respectively, for a typical individual with absolute eGFR of 124 mL/min and TBW of 70 kg. PTA analyses demonstrated that the anticipated efficacious dose (30 mg/kg daily, 30 min intravenous infusion) reaches a probability of 96.4% for a free AUC/MIC target of 40, given an MIC of 8 mg/L, in a virtual Phase II patient population with an absolute eGFR extrapolated to 80 mL/min. Conclusions The results support further Phase II clinical trials with apramycin at an anticipated efficacious dose of 30 mg/kg once daily.
10.
Karaiskos, Ilias, et al.
(författare)
Colistin Population Pharmacokinetics after Application of a Loading Dose of 9 MU Colistin Methanesulfonate in Critically Ill Patients
2015
Ingår i: Antimicrobial Agents and Chemotherapy. - 0066-4804 .- 1098-6596. ; 59:12, s. 7240-7248
Tidskriftsartikel (refereegranskat) abstract
Colistin has been revived, in the era of extensively drug-resistant (XDR) Gram-negative infections, as the last-resort treatment in critically ill patients. Recent studies focusing on the optimal dosing strategy of colistin have demonstrated the necessity of a loading dose at treatment initiation (D. Plachouras, M. Karvanen, L. E. Friberg, E. Papadomichelakis, A. Antoniadou, I. Tsangaris, I. Karaiskos, G. Poulakou, F. Kontopidou, A. Armaganidis, O. Cars, and H. Giamarellou, Antimicrob Agents Chemother 53:3430-3436, 2009, http://dx.doi.org/10.1128/AAC.01361-08; A. F. Mohamed, I. Karaiskos, D. Plachouras, M. Karvanen, K. Pontikis, B. Jansson, E. Papadomichelakis, A. Antoniadou, H. Giamarellou, A. Armaganidis, O. Cars, and L. E. Friberg, Antimicrob Agents Chemother 56:4241-4249, 2012, http://dx.doi.org/10.1128/AAC.06426-11; S.M. Garonzik, J. Li, V. Thamlikitkul, D.L. Paterson, S. Shoham, J. Jacob, F. P. Silveira, A. Forrest, and R. L. Nation, Antimicrob Agents Chemother 55:3284-3294, 2011, http://dx.doi.org/10.1128/AAC.01733-10). In 19 critically ill patients with suspected or microbiologically documented infections caused by XDR Gram-negative strains, a loading dose of 9 MU colistin methanesulfonate (CMS) (similar to 270 mg colistin base activity) was administered with a maintenance dose of 4.5 MU every 12 h, commenced after 24 h. Patients on renal replacement were excluded. CMS infusion was given over 30 min or 1 h. Repeated blood sampling was performed after the loading dose and after the 5th or 6th dose. Colistin concentrations and measured CMS, determined after hydrolization to colistin and including the partially sulfomethylated derivatives, were determined with a liquid chromatography-tandem mass spectrometry assay. Population pharmacokinetic analysis was conducted in NONMEM with the new data combined with data from previous studies. Measured colistimethate concentrations were described by 4 compartments for distribution and removal of sulfomethyl groups, while colistin disposition followed a 1-compartment model. The average observed maximum colistin A plus B concentration was 2.65 mg/liter after the loading dose (maximum time was 8 h). A significantly higher availability of the measured A and B forms of colistimethate and colistin explained the higher-than-expected concentrations in the present study compared to those in previous studies. Creatinine clearance was a time-varying covariate of colistimethate clearance. The incidence of acute renal injury was 20%.
