Simulating realistic patient profiles from pharmacokinetic models by a machine learning postprocessing correction of residual variability.

We address the problem of model misspecification in population pharmacokinetics (PopPK), by modeling residual unexplained variability (RUV) by machine learning (ML) methods in a postprocessing step after conventional model building. The practical purpose of the method is the generation of realistic virtual patient profiles and the quantification of the extent of model misspecification, by introducing an appropriate metric, to be used as an additional diagnostic of model quality. The proposed methodology consists of the following steps: After developing a PopPK model, the individual residual errors IRES = DV-IPRED, are computed, where DV are the observations and IPRED the individual predictions and are modeled by ML to obtain IRESML. Correction of the IPREDs can then be carried out as DVML = IPRED + IRESML. The methodology was tested in a PK study of ropinirole, for which a PopPK model was developed while a second deliberately misspecified model was also considered. Various supervised ML algorithms were tested, among which Random Forest gave the best results. The ML model was able to correct individual predictions as inspected in diagnostic plots and most importantly it simulated realistic profiles that resembled the real data and canceled out the artifacts introduced by the elevated RUV, even in the case of the heavily misspecified model. Furthermore, a metric to quantify the extent of model misspecification was introduced based on the R2 between IRES and IRESML, following the rationale that the greater the extent of variability explained by the ML model, the higher the degree of model misspecification present in the original model.

Extrapolation of lung pharmacokinetics of antitubercular drugs from preclinical species to humans using PBPK modelling.

OBJECTIVES: To develop physiologically based pharmacokinetic (PBPK) models for widely used anti-TB drugs, namely rifampicin, pyrazinamide, isoniazid, ethambutol and moxifloxacin lung pharmacokinetics (PK)-regarding both healthy and TB-infected tissue (cellular lesion and caseum)-in preclinical species and to extrapolate to humans. METHODS: Empirical models were used for the plasma PK of each species, which were connected to multicompartment permeability-limited lung models within a middle-out PBPK approach with an appropriate physiological parameterization that was scalable across species. Lung's extracellular water (EW) was assumed to be the linking component between healthy and infected tissue, while passive diffusion was assumed for the drug transferring between cellular lesion and caseum. RESULTS: In rabbits, optimized unbound fractions in intracellular water of rifampicin, moxifloxacin and ethambutol were 0.015, 0.056 and 0.08, respectively, while the optimized unbound fractions in EW of pyrazinamide and isoniazid in mice were 0.25 and 0.17, respectively. In humans, all mean extrapolated daily AUC and Cmax values of various lung regions were within 2-fold of the observed ones. Unbound concentrations in the caseum were lower than unbound plasma concentrations for both rifampicin and moxifloxacin. For rifampicin, unbound concentrations in cellular rim are slightly lower, while for moxifloxacin they are significantly higher than unbound plasma concentrations. CONCLUSIONS: The developed PBPK approach was able to extrapolate lung PK from preclinical species to humans and to predict unbound concentrations in the various TB-infected regions, unlike empirical lung models. We found that plasma free drug PK is not always a good surrogate for TB-infected tissue unbound PK.

Donepezil Brain and Blood Pharmacokinetic Modeling after Nasal Film and Oral Solution Administration in Mice.

Intranasal delivery is a non-invasive mode of administration, gaining popularity due to its potential for targeted delivery to the brain. The anatomic connection of the nasal cavity with the central nervous system (CNS) is based on two nerves: olfactory and trigeminal. Moreover, the high vasculature of the respiratory area enables systemic absorption avoiding possible hepatic metabolism. Due to these physiological peculiarities of the nasal cavity, compartmental modeling for nasal formulation is considered a demanding process. For this purpose, intravenous models have been proposed, based on the fast absorption from the olfactory nerve. However, most of the sophisticated approaches are required to describe the different absorption events occurring in the nasal cavity. Donepezil was recently formulated in the form of nasal film ensuring drug delivery in both bloodstream and the brain. In this work, a three-compartment model was first developed to describe donepezil oral brain and blood pharmacokinetics. Subsequently, using parameters estimated by this model, an intranasal model was developed dividing the administered dose into three fractions, corresponding to absorption directly to the bloodstream and brain, as well as indirectly to the brain expressed through transit compartments. Hence, the models of this study aim to describe the drug flow on both occasions and quantify the direct nose-to-brain and systemic distribution.

Implementation of non-linear mixed effects models defined by fractional differential equations.

Fractional differential equations (FDEs), i.e. differential equations with derivatives of non-integer order, can describe certain experimental datasets more accurately than classic models and have found application in pharmacokinetics (PKs), but wider applicability has been hindered by the lack of appropriate software. In the present work an extension of NONMEM software is introduced, as a FORTRAN subroutine, that allows the definition of nonlinear mixed effects (NLME) models with FDEs. The new subroutine can handle arbitrary user defined linear and nonlinear models with multiple equations, and multiple doses and can be integrated in NONMEM workflows seamlessly, working well with third party packages. The performance of the subroutine in parameter estimation exercises, with simple linear and nonlinear (Michaelis-Menten) fractional PK models has been evaluated by simulations and an application to a real clinical dataset of diazepam is presented. In the simulation study, model parameters were estimated for each of 100 simulated datasets for the two models. The relative mean bias (RMB) and relative root mean square error (RRMSE) were calculated in order to assess the bias and precision of the methodology. In all cases both RMB and RRMSE were below 20% showing high accuracy and precision for the estimates. For the diazepam application the fractional model that best described the drug kinetics was a one-compartment linear model which had similar performance, according to diagnostic plots and Visual Predictive Check, to a three-compartment classic model, but including four less parameters than the latter. To the best of our knowledge, it is the first attempt to use FDE systems in an NLME framework, so the approach could be of interest to other disciplines apart from PKs.

Pharmacokinetic/Pharmacodynamic Determination of Systemic MIC Breakpoints for Intermittent, Extended, and Continuous Infusion Dosage Regimens of Mecillinam.

Intravenous mecillinam has been used for the treatment of urosepsis at several dosing regimens, including a dose of 1,000 mg three times a day (TID). In the current pharmacokinetic/pharmacodynamic (PK/PD) study, we analyzed intermittent, extended, and continuous infusion regimens of mecillinam to provide dosage recommendations to treat infections caused by Enterobacterales exhibiting relatively higher mecillinam MICs than the wild-type strains. Monte Carlo simulation studies indicated that regimens of 1,000 mg TID and 1,000 to 1,200 mg four times a day (QID) are efficacious against wild-type and extended-spectrum ß-lactamase-producing Enterobacterales, respectively. Prolonged infusion regimens (extended and continuous) could cover carbapenemase producers with a higher range of MICs (2 to 8 mg/L). IMPORTANCE Previous studies have shown that intravenous mecillinam might be suitable for treatment of urosepsis. Since multidrug-resistant Enterobacterales are common pathogens in such infections, an effort was made to delineate intermittent, extended, and continuous infusion regimens that could cover pathogens exhibiting relatively higher mecillinam MICs than the wild-type strains. Our PK/PD analysis has shown that mecillinam might be considered a valuable therapeutic option for the treatment of systemic infections caused by extended-spectrum ß-lactamase- and carbapenemase-producing Enterobacterales exhibiting mecillinam MICs up to 8 mg/L.

In Silico Dosimetry Study of Tc99m-Tetrofosmin in Children Using a Novel PBPK Model in Humans Built from SPECT Imaging Data.

PURPOSE: The aim of this work is to develop a Physiologically Based Pharmacokinetic model (PBPK) for the radiopharmaceutical Tc99m-Tetrofosmin in humans, from literature SPECT imaging data, to carry out in-silico dosimetry studies in children and extrapolate dosing. METHODS: A whole body PBPK model was developed from literature data from humans of Tc99m-Tetrofosmin tissue distribution. A data driven approach to estimate partition coeffects, permeability parameters and clearances was carried out, while some parameters were determined using a standard in silico PBPK method. Paediatric PK data for all tissues were simulated by changing the physiological parameters from the adult to paediatric values. Absorbed and effective doses for children of all ages were calculated using S-values from literature of Tc99m that have been computed from anthropomorphic phantoms. RESULTS: Using the results from each tissue, satisfactory goodness-of-fit was achieved, assessed by visual inspection and a coefficient of determination of R2 = 0.965 while all estimated parameters had good standard errors. Paediatric simulations of Tetrofosmin distribution showed that paediatric profiles are not very different to the those of adults. The effective doses per unit of administered activity for 15 yo, 10 yo, 5 yo and 1 yo children were calculated to be 1.2, 1.7, 2.6 and 4.8 times higher, respectively than the adult value. Based on these calculations maximum administered activity scale more than proportionately to body weight. CONCLUSIONS: A PBPK model of tetrofosmin in adults has been developed from SPECT imaging data and was extrapolated to conduct in-silico dosimetry studies in children of all ages.

Pharmacokinetic Characteristics of Nebulized Colistimethate Sodium Using Two Different Types of Nebulizers in Critically Ill Patients with Ventilator-Associated Respiratory Infections.

Background: Rising antimicrobial resistance has led to a revived interest in inhaled colistin treatment in the critically ill patient with ventilator-associated respiratory infection (VARI). Nebulization via vibrating mesh nebulizers (VMNs) is considered the current standard-of-care, yet the use of generic jet nebulizers (JNs) is more widespread. Few data exist on the intrapulmonary pharmacokinetics of colistin when administered through VMNs, while there is a complete paucity regarding the use of JNs. Methods: In this study, 18 VARI patients who received 2 million international units of inhaled colistimethate sodium (CMS) through a VMN were pharmacokinetically compared with six VARI patients who received the same drug dose through a JN, in the absence of systemic CMS administration. Results: Surprisingly, VMN and JN led to comparable formed colistin exposures in the epithelial lining fluid (ELF) (median (IQR) AUC0-24: 86.2 (46.0-185.9) mg/L∙h with VMN and 91.5 (78.1-110.3) mg/L∙h with JN). The maximum ELF concentration was 10.4 (4.7-22.6) mg/L and 7.4 (6.2-10.3) mg/L, respectively. Conclusions: Based on our results, JN might be considered a viable alternative to the theoretically superior VMN. Therapeutic drug monitoring in the ELF can be advised due to the observed low exposure, high variability, and appreciable systemic absorption.

General clinical and methodological considerations on the extrapolation of pharmacokinetics and optimization of study protocols for small molecules and monoclonal antibodies in children.

Pharmacometric modelling plays a key role in both the design and analysis of regulatory trials in paediatric drug development. Studies in adults provide a rich source of data to inform the paediatric investigation plans, including knowledge on drug pharmacokinetics (PK), safety and efficacy. In children, drug disposition differs widely from birth to adolescence but extrapolating adult to paediatric PK, safety and efficacy either with pharmacometric or physiologically based approaches can help design or in some cases reduce the need for clinical studies. Aspects to consider when extrapolating PK include the maturation of drug metabolizing enzyme expression, glomerular filtration, drug excretory systems, and the expression and activity of specific transporters in conjunction with other drug properties such as fraction unbound. Knowledge of these can be used to develop extrapolation tools such as allometric scaling plus maturation functions or physiologically based PK. PK/pharmacodynamic approaches and well-designed clinical trials in children are of key importance in paediatric drug development. In this white paper, state-of-the-art of current methods used for paediatric extrapolation will be discussed. This paper is part of a conect4children implementation of innovative methodologies including pharmacometric and physiologically based PK modelling in clinical trial design/paediatric drug development through dissemination of expertise and expert advice. The suggestions arising from this white paper should define a minimum set of standards in paediatric modelling and contribute to the regulatory science.

Developing Clinically Relevant Dissolution Specifications (CRDSs) for Oral Drug Products: Virtual Webinar Series.

A webinar series that was organised by the Academy of Pharmaceutical Sciences Biopharmaceutics focus group in 2021 focused on the challenges of developing clinically relevant dissolution specifications (CRDSs) for oral drug products. Industrial scientists, together with regulatory and academic scientists, came together through a series of six webinars, to discuss progress in the field, emerging trends, and areas for continued collaboration and harmonisation. Each webinar also hosted a Q&A session where participants could discuss the shared topic and information. Although it was clear from the presentations and Q&A sessions that we continue to make progress in the field of CRDSs and the utility/success of PBBM, there is also a need to continue the momentum and dialogue between the industry and regulators. Five key areas were identified which require further discussion and harmonisation.

Efficacy and safety of Mydriatic Microdrops for Retinopathy Of Prematurity Screening (MyMiROPS): study protocol for a non-inferiority crossover randomized controlled trial.

BACKGROUND: Retinopathy of prematurity (ROP) eye examination screening presupposes adequate mydriasis for an informative fundoscopy of preterm infants at risk, on a weekly basis. Systemic absorption of the instilled mydriatic regimens has been associated with various adverse events in this fragile population. This report aims to present the fully developed protocol of a full-scale trial for testing the hypothesis that the reduced mydriatic drop volume achieves adequate mydriasis while minimizing systemic adverse events. METHODS: A non-inferiority crossover randomized controlled trial will be performed to study the efficacy and safety of combined phenylephrine 1.67% and tropicamide 0.33% microdrops compared with standard drops in a total of 93 preterm infants requiring ROP screening. Primary outcome will be the pupil diameter at 45 (T45) min after instillation. Pupil diameter at T90 and T120 will constitute secondary efficacy endpoints. Mixed-effects linear regression models will be developed, and the 95% confidence interval approach will be used for assessing non-inferiority. Whole blood samples will be analyzed using hydrophilic liquid chromatography-tandem mass spectrometry method (HILIC-MS/MS), for gathering pharmacokinetic (PK) data on the instilled phenylephrine, at nine specific time points within 3 h from mydriasis. Pooled PK data will be used due to ethical restrictions on having a full PK profile per infant. Heart rate, oxygen saturation, blood pressure measurements, and 48-h adverse events will also be recorded. DISCUSSION: This protocol is designed for a study powered to assess non-inferiority of microdrops compared with standard dilating drops. If our hypothesis is confirmed, microdrops may become a useful tool in ROP screening. TRIAL REGISTRATION: ClinicalTrials.gov NCT05043077 . Registered on 2 September 2021.

Development of a Population Pharmacokinetic Model of Busulfan in Children and Evaluation of Different Sampling Schedules for Precision Dosing.

We develop a population pharmacokinetic model to describe Busulfan pharmacokinetics in paediatric patients and investigate by simulations the impact of various sampling schedules on the calculation of AUC. Seventy-six children had 2 h infusions every 6 h. A two-compartment linear model was found to adequately describe the data. A lag-time was introduced to account for the delay of the administration of the drug through the infusion pump. The mean values of clearance, central volume of distribution, intercompartmental clearance, and peripheral volume of distribution were 10.7 L/h, 39.5 L, 4.68 L/h and 17.5 L, respectively, normalized for a Body Weight (BW) of 70 kg. BW was found to explain a portion of variability with an allometric relationship and fixed exponents of 0.75 on clearance parameters and 1 on volumes. Interindividual variability for clearance and volume of distribution was found to be 28% and 41%, respectively, and interoccasion variability for clearance was found to be 11%. Three sampling schedules were assessed by simulations for bias and imprecision to calculate AUC by a non-compartmental and a model-based method. The latter was found to be superior in all cases, while the non-compartmental was unbiased only in sampling up to 12 h corresponding to a once-daily dosing regimen.

Population Pharmacokinetic Modelling of the Complex Release Kinetics of Octreotide LAR: Defining Sub-Populations by Cluster Analysis.

The aim of the study is to develop a population pharmacokinetic (PPK) model, of Octreotide long acting repeatable (LAR) formulation in healthy volunteers, which describes the highly variable, multiple peak absorption pattern of the pharmacokinetics of the drug, in individual and population levels. An empirical absorption model, coupled with a one-compartment distribution model with linear elimination was found to describe the data well. Absorption was modelled as a weighted sum of a first order and three transit compartment absorption processes, with delays and appropriately constrained model parameters. Identifiability analysis verified that all twelve parameters of the structural model are identifiable. A machine learning method, i.e., cluster analysis, was performed as pre-processing of the PK profiles, to define subpopulations, before PPK modelling. It revealed that 13% of the patients deviated considerably from the typical absorption pattern and allowed better characterization of the observed heterogeneity and variability of the study, while the approach may have wider applicability in building PPK models. The final model was evaluated by goodness of fit plots, Visual Predictive Check plots and bootstrap. The present model is the first to describe the multiple-peak absorption pattern observed after octreotide LAR administration and may be useful to provide insights and validate hypotheses regarding release from PLGA-based formulations.

Population pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide metabolite in patients with autoimmune glomerulonephritis.

OBJECTIVES: To develop a simultaneous population pharmacokinetic model of cyclophosphamide (CY) and 4-hydroxycyclophosphamide (4-OH) in patients with glomerulonephritis. METHODS: In total, 23 patients participated in a pharmacokinetic evaluation using dense plasma sampling. A population pharmacokinetic model was developed in Monolix Suite 2020R1 that simultaneously describes the kinetics of CY and 4-OH. Several structural and residual error models were evaluated and patient variables were tested as potential covariates. The final model was selected based on visual predictive check and bootstrap. Simulations of plasma concentrations for various doses were conducted. KEY FINDINGS: A model including two compartments for CY and one for 4-OH was found to best describe the data. A proportional error model for both compounds was chosen. The following estimates were found for the main CY pharmacokinetic parameters: total clearance, 13.3 l/h with inter-individual variability (IIV) 32%, and central volume of distribution, 59.8 l with IIV 12%. The metabolite elimination rate constant was 4.3 h-1 with IIV 36% and the proportion of metabolism 64%. Sex was a significant covariate on the central volume of CY, with females exhibiting 25% lower value than males. CONCLUSIONS: A population pharmacokinetic model was developed for CY and 4-OH in patients with autoimmune glomerulonephritis. Simulations using various dose regimens allow for informed dosing before the initiation of therapy.

Population pharmacokinetics of anidulafungin in ICU patients assessing inter- and intrasubject variability.

AIMS: The population pharmacokinetics (PK) of anidulafungin in critically ill patients hospitalized in intensive care units (ICUs) was explored with the intention of evaluating and optimizing dosing regimens. METHODS: A PK study was conducted in a cohort of 13 patients treated with anidulafungin using intensive sampling during multiple periods per patient and the high-performance liquid chromatography method for drug quantification. A population PK model was developed to describe the concentration-time course of anidulafungin and the inter-individual (IIV) and interoccasion variability (IOV) of the PK parameters. Model-based PK simulations have been performed to estimate the probability of target attainment (PTA), given the pharmacokinetic/pharmacodynamic target of free 24-hour area under the free drug concentration-time curve over minimum inhibitory concentration for several dosing regimens. RESULTS: A two-compartment PK model, with first-order elimination, best described the data with population clearance (CL) and central/peripheral volume of distribution (V1/V2) of 0.778 L/h and 10.2/21.1 L, respectively, and a mean ± s.d. AUC0-24 of 119.97 ± 46.23 mg·h/L. Pronounced IIV and IOV variability was found for CL (38% and 31%) and V1 (47% and 30%), respectively. Sequential Organ Failure Assessment (SOFA) and Body Mass Index (BMI) were found to be covariates on CL and V1, respectively. Low PTA values were calculated for borderline Clinical & Laboratory Standards Institute (CLSI)-susceptible Candida strains. CONCLUSIONS: Although anidulafungin exposure was found comparable to that in healthy volunteers, elevated interindividual and significant interoccasion variability was found in critically ill ICU patients, which resulted in reduced PTA values in these patients.

Population pharmacokinetics of micafungin over repeated doses in critically ill patients: a need for a loading dose?

OBJECTIVES: To study the population pharmacokinetics of micafungin in critically ill patients, evaluate and optimize dosage regimens. METHODS: An HPLC-fluorescence bioassay for micafungin was developed, fully validated and applied to a pharmacokinetic study conducted in 14 ICU patients. Dense blood sampling was performed from days 1 to 7. A population pharmacokinetic model accounting for interindividual (IIV) and interoccasion variability (IOV) of the PK parameters was developed. Simulations were performed to estimate the probability of target attainment (PTA) for several dosing regimens. KEY FINDINGS: A two-compartment pharmacokinetic model best described the data, with population clearance CL = 1.31 L/h and central volume V1 = 14.2 L. The relatively high IOV observed (45% for CL, 27% for V1) sets limits for the dose individualization in this population. The low PTA on the first day of treatment suggests the need of a loading dose. PTA and CFR estimates show that the current micafungin dosage may be insufficient for the treatment of borderline susceptible Candida strains. CONCLUSIONS: A loading dose of up to 300 mg of micafungin is needed for the treatment of invasive candidiasis in ICU patients while a maintenance dose of up to 200 mg can be considered in empirical antifungal treatment.

Optimization of a paediatric fixed dose combination mini-tablet and dosing regimen for the first line treatment of tuberculosis.

We aim to optimize the paediatric dosing regimen of isoniazid, rifampicin and pyrazinamide for the first-line treatment of tuberculosis, based on a fixed dose combination (FDC) mini-tablet using simulations. An optimization problem was set up to determine the 3 strengths of the drugs of the mini-tablet and 4 cutoff points that define the weight bands of a dosing chart, simultaneously. Using Monte Carlo simulations, first, exposure targets were determined for the 3 drugs, from published population pharmacokinetic models for adults, assuming that the approved doses for adults are de facto efficacious. Then optimal strengths and cutoff points were determined by matching children exposures generated from population pharmacokinetic models to the adults targets. The optimal dosing strengths of the FDC tablet were found to be 95 mg of rifampicin, 200 mg of pyrazinamide and 75 mg of isoniazid, and the 4 body weight bands for 1 to 4 mini-tablets, respectively were: 4 to 8 kg, 8 to 12 kg, 12 to 18 kg and 18 to 28 kg. Children with body weight ≥ 28 kg will be treated with adult dosages. The higher doses proposed were evaluated to be much closer to the adult targets compared to the existing recommended by WHO paediatric doses.

Population pharmacokinetic reanalysis of a Diazepam PBPK model: a comparison of Stan and GNU MCSim.

The aim of this study is to benchmark two Bayesian software tools, namely Stan and GNU MCSim, that use different Markov chain Monte Carlo (MCMC) methods for the estimation of physiologically based pharmacokinetic (PBPK) model parameters. The software tools were applied and compared on the problem of updating the parameters of a Diazepam PBPK model, using time-concentration human data. Both tools produced very good fits at the individual and population levels, despite the fact that GNU MCSim is not able to consider multivariate distributions. Stan outperformed GNU MCSim in sampling efficiency, due to its almost uncorrelated sampling. However, GNU MCSim exhibited much faster convergence and performed better in terms of effective samples produced per unit of time.

Minocycline susceptibility breakpoints for Acinetobacter baumannii: do we need to re-evaluate them?

Minocycline is an old broad-spectrum tetracycline indicated for the treatment of various infections, including those due to minocycline-susceptible Acinetobacter spp. Susceptibility data worldwide are showing increasing rates of resistance of Acinetobacter baumannii to almost all antimicrobial classes, whereas minocycline seems to remain relatively potent against this significant pathogen. Since no new effective drugs have been released against MDR A. baumannii, minocycline is an attractive choice. Tracing back minocycline CLSI susceptibility breakpoints, it is evident that they have been based on old pharmacokinetic approaches. In an attempt to integrate the scarce new pharmacodynamic data, a Monte Carlo simulation was performed. It seems that the currently used breakpoints are, 8-fold elevated according to the approved dosage regimen, giving erroneously higher rates of minocycline susceptibility of A. baumannii. Therefore, current minocycline breakpoints merit re-evaluation in order to deliver reliable susceptibility profiles for selecting the appropriate therapy.

Pharmacokinetics of Daptomycin in Critically Ill Pediatric Patients.

The pharmacokinetics of daptomycin (10 mg/kg once daily) was studied in 4 critically ill pediatric patients aged 8 to 14 yrs. The area under the concentration-time curve from time zero to infinity (AUC0-∞) of plasma concentrations on day 1 ranged between 123.8 to 663.9 µg · h/ml, with lower values observed in septic and burn patients; clearance ranged from 15.1 to 80.7 ml/h/kg. Higher-than-recommended doses of daptomycin may be needed in septic children to ensure optimal drug exposure. Interpatient variability may suggest a role for therapeutic drug monitoring.