A Sensitive Assay for Unbound Docetaxel Using Ultrafiltration plus HPLC-MS and Its Application to a Clinical Study.

INTRODUCTION: Docetaxel, a taxane used in the treatment of solid tumours, exerts pharmacological activity when in its unbound form. We report a sensitive assay to quantify unbound docetaxel after oral administration of docetaxel plus encequidar (oDox+E). Unbound drug quantification is important due to its direct correlation with drug-related toxicity and therapeutic efficacy. We improve on the sensitivity of current assay methods and demonstrate the utility of the assay on a novel formulation of oral docetaxel. METHODS: Ultrafiltration followed by high-performance liquid chromatography and tandem mass spectrometry (HPLC-MS/MS) was utilized. Long-term stability, precision, accuracy, and recovery experiments were conducted to validate the assay. Additionally, patient samples from a Phase I dose-escalation pharmacokinetic study were analyzed using the developed assay. RESULTS: The assay method exhibited long-term stability with an observed change between 0.8 and 6.9% after 131 days of storage at -60 °C. Precision and accuracy quality controls met the FDA acceptance criteria. An average recovery of 88% was obtained. Patient sample analysis demonstrated successful implementation of the assay. CONCLUSION: A validated sensitive assay was developed with an LLOQ of 0.084 ng/mL using 485 µL of human plasma. The sensitivity of the assay allowed quantification of unbound docetaxel concentrations in an early-phase oDox+E clinical study to compare it against IV docetaxel using pharmacokinetic modelling. Successful development of oDox+E represents an opportunity to replace the current IV docetaxel regimen with an oral regimen with lower cost, decreased side effects, and improve patient quality of life and experience.

Oral docetaxel plus encequidar - a phase 1 clinical trial.

PURPOSE: To determine the bioavailability, safety, and tolerability of a single dose of oral docetaxel plus encequidar (oDox + E) and compare its pharmacokinetic exposure with current standard of care IV docetaxel. INTRODUCTION: Docetaxel is a taxane widely used as an anti-neoplastic agent. Due to low oral bioavailability secondary to gut P-glycoprotein (P-gp) efflux, its current use is limited to intravenous administration. Oral docetaxel may provide a less resource intensive, more convenient, and tolerable alternative. Encequidar is a first in class, minimally absorbed, oral gut-specific P-gp inhibitor. We tested whether oDox + E can achieve comparable pharmacokinetic exposure to IV docetaxel. METHODS: A multicentre, phase I open-label, pharmacokinetic trial was undertaken to determine the bioavailability, safety, and tolerability of a single dose of oDox + E (at 75 mg/m2 + 15 mg, 150 mg/m2 + 15 mg, and 300 mg/m2 + 15 mg) in metastatic prostate cancer (mPC) patients compared to standard of care IV docetaxel as prescribed by their oncologists. The 15 mg of Encequidar at each dose level was given one hour prior to oral docetaxel. RESULTS: 11 patients were enrolled; 9 patients completed the study. Oral docetaxel exposure increased with dose, achieving the highest at 300 mg/m2 oDox + E (with AUC0 - infinity of 1343.3 ± 443.0 ng.h/mL compared to the IV docetaxel AUC0 - infinity of 2000 ± 325 ng.h/mL) and became non-linear at 300 mg/m2. The mean absolute bioavailability of oDox + E across all 3 dose levels was 16.14% (range: 8.19-25.09%). No patient deaths, dose limiting toxicity, treatment-related serious adverse event or grade 4 toxicity were observed. Maximal tolerated dose was not reached. CONCLUSION: oDox + E has a safe and tolerable adverse event profile in patients with metastatic prostate cancer. The increase in oral bioavailability of oDox + E suggests a multi-dose oDox + E regimen could theoretically achieve exposures comparable with standard of care IV docetaxel. Further development to examine the optimal multiple dose regimen of oDox + E is warranted. TRIAL REGISTRATION NUMBER: U1111-1173-5473.

Posaconazole in paediatric malignancy and haematopoietic stem cell transplant: dosing to achieve therapeutic concentration.

OBJECTIVES: Posaconazole is increasingly used for the treatment and prophylaxis of invasive fungal infections in immunocompromised children. We aimed to review evidence for paediatric posaconazole dosing regimens focusing on attainment of target concentrations and frequency of adverse effects. METHODS: In May 2023, the Cochrane, Embase, MEDLINE and PubMed databases were searched for articles reporting posaconazole dosing in children with malignancy or post-haematopoietic stem cell transplantation. Studies reporting the attainment of target serum concentrations were included. RESULTS: Overall, 24 studies were included. Eighteen studies of the oral suspension consistently reported poor attainment of target concentrations for prophylaxis (≥0.7 µg/mL, 12%-78%) despite high daily doses of 14-23 mg/kg/day (max. 1200 mg/day). Target attainment was significantly affected by gastric pH and food intake. Six studies of the delayed-release tablet (DRT) reported 58%-94% achieved concentrations ≥0.7 µg/mL, with the majority using lower doses of 4-12 mg/kg/day (max. 300 mg/day). Similarly, one study of powder for oral suspension found 67%-100% achieved target concentrations with a dose of 6 mg/kg/day (max. 300 mg/day). As expected, the IV formulation had high attainment of prophylaxis targets (81%-90%) with 6-10 mg/kg/day (max. 400 mg/day). All formulations were well tolerated, and no relationship between adverse effects and posaconazole concentrations was identified. CONCLUSIONS: The required posaconazole dose in immunocompromised children varies depending on the formulation. The IV infusion had the highest attainment of therapeutic concentration followed by the DRT and powder for suspension. By contrast, the oral suspension had low attainment of target concentrations despite higher daily doses.

Oral docetaxel plus encequidar - A pharmacokinetic model and evaluation against IV docetaxel.

The development of optimized dosing regimens plays a crucial role in oncology drug development. This study focused on the population pharmacokinetic modelling and simulation of docetaxel, comparing the pharmacokinetic exposure of oral docetaxel plus encequidar (oDox + E) with the standard of care intravenous (IV) docetaxel regimen. The aim was to evaluate the feasibility of oDox + E as a potential alternative to IV docetaxel. The article demonstrates an approach which aligns with the FDA's Project Optimus which aims to improve oncology drug development through model informed drug development (MIDD). The key question answered by this study was whether a feasible regimen of oDox + E existed. The purpose of this question was to provide an early GO / NO-GO decision point to guide drug development and improve development efficiency. METHODS:  A stepwise approach was employed to develop a population pharmacokinetic model for total and unbound docetaxel plasma concentrations after IV docetaxel and oDox + E administration. Simulations were performed from the final model to assess the probability of target attainment (PTA) for different oDox + E dose regimens (including multiple dose regimens) in relation to IV docetaxel using AUC over effective concentration (AUCOEC) metric across a range of effective concentrations (EC). A Go / No-Go framework was defined-the first part of the framework assessed whether a feasible oDox + E regimen existed (i.e., a PTA ≥ 80%), and the second part defined the conditions to proceed with a Go decision. RESULTS:  The overall population pharmacokinetic model consisted of a 3-compartment model with linear elimination, constant bioavailability, constant binding mechanics, and a combined error model. Simulations revealed that single dose oDox + E regimens did not achieve a PTA greater than 80%. However, two- and three-dose regimens at 600 mg achieved PTAs exceeding 80% for certain EC levels. CONCLUSION:  The study demonstrates the benefits of MIDD using oDox + E as a motivating example. A population pharmacokinetic model was developed for the total and unbound concentration in plasma of docetaxel after administration of IV docetaxel and oDox + E. The model was used to simulate oDox + E dose regimens which were compared to the current standard of care IV docetaxel regimen. A GO / NO-GO framework was applied to determine whether oDox + E should progress to the next phase of drug development and whether any conditions should apply. A two or three-dose regimen of oDox + E at 600 mg was able to achieve non-inferior pharmacokinetic exposure to current standard of care IV docetaxel in simulations. A Conditional GO decision was made based on this result and further quantification of the "effective concentration" would improve the ability to optimise the dose regimen.

Insight into the mechanism of action of ORG27569 at the cannabinoid type one receptor utilising a unified mathematical model.

Allosteric modulation of CB1 is therapeutically advantageous compared to orthosteric activation as it potentially offers reduced on-target adverse effects. ORG27569 is an allosteric modulator that increases orthosteric agonist binding to CB1 but decreases functional signalling. ORG27569 is characterised by a delay in disinhibition of agonist-induced cAMP inhibition (lag); however, the mechanism behind this kinetic lag is yet to be identified. We aimed to utilise a mathematical model to predict data and design in vitro experiments to elucidate mechanisms behind the unique signalling profile of ORG27569. The established kinetic ternary complex model includes the existence of a transitional state of CB1 bound to ORG27569 and CP55940 and was used to simulate kinetic cAMP data using NONMEM 7.4 and Matlab R2020b. These data were compared with empirical cAMP BRET data in HEK293 cells stably expressing hCB1. The pharmacometric model suggested that the kinetic lag in cAMP disinhibition by ORG27569 is caused by signal amplification in the cAMP assay and can be reduced by decreasing receptor number. This was confirmed experimentally, as reducing receptor number through agonist-induced internalisation resulted in a decreased kinetic lag by ORG27569. ORG27569 was found to have a similar interaction with CP55940 and the high efficacy agonist WIN55,212-2, and was suggested to have lower affinity for CB1 bound by the partial agonist THC compared to CP55940. Allosteric modulators have unique signalling profiles that are often difficult to interrogate exclusively in vitro. We have used a combined mathematical and in vitro approach to prove that ORG27569 causes a delay in disinhibition of agonist-induced cAMP inhibition due to large receptor reserve in this pathway. We also used the pharmacometric model to investigate the common phenomenon of probe dependence, to propose that ORG27569 binds with higher affinity to CB1 bound by high efficacy orthosteric agonists.

Training the next generation of pharmacometric modelers: a multisector perspective.

The current demand for pharmacometricians outmatches the supply provided by academic institutions and considerable investments are made to develop the competencies of these scientists on-the-job. Even with the observed increase in academic programs related to pharmacometrics, this need is unlikely to change in the foreseeable future, as the demand and scope of pharmacometrics applications keep expanding. Further, the field of pharmacometrics is changing. The field largely started when Lewis Sheiner and Stuart Beal published their seminal papers on population pharmacokinetics in the late 1970's and early 1980's and has continued to grow in impact and use since its inception. Physiological-based pharmacokinetics and systems pharmacology have grown rapidly in scope and impact in the last decade and machine learning is just on the horizon. While all these methodologies are categorized as pharmacometrics, no one person can be an expert in everything. So how do you train future pharmacometricians? Leading experts in academia, industry, contract research organizations, clinical medicine, and regulatory gave their opinions on how to best train future pharmacometricians. Their opinions were collected and synthesized to create some general recommendations.

A quantitative pharmacology model for cannabinoid CB1 receptor mediated by Gi/Gs protein competition.

BACKGROUND AND PURPOSE: Orthosteric agonism of the CB1 receptor normally associates with Gi signalling resulting in a net inhibition of cAMP production. Empirical evidence shows CB1 causes a net cAMP stimulation through Gs coupling under two conditions: co-stimulation with the D2 receptor and high-level CB1 expression. Two hypotheses have been proposed to account for these paradoxical effects, (1) Gi is consumed by coupling to D2 or extra CB1 and excess CB1 binds to Gs and (2), the formation of dimers CB1 -CB1 or CB1 -D2 switches Gi/Gs preference. This study explored the mechanisms of Gi/Gs preference based on a mathematical model of the CB1 receptor. EXPERIMENTAL APPROACH: The model was based on Hypothesis 1 and known mechanisms. The model was calibrated to align with multiple types of data (cAMP, Gi dissociation and internalisation). The key step of Hypothesis 1 was examined by simulation from the model. An experiment was proposed to distinguish Hypothesis 1 and 2. KEY RESULTS: The model successfully descripted multiple types of data under Hypothesis 1. Simulations from the model indicated that precoupling of G protein with receptors is necessary for this hypothesis. The model designed experiments to distinguish Hypothesis 1 and 2 by increasing Gi & Gs in parallel with CB1 overexpression. The two hypotheses result in distinct cAMP responses. CONCLUSION AND IMPLICATIONS: A mathematical model of CB1 -regulated Gi/Gs pathways was developed. It indicated Hypothesis 1 is feasible and G protein precoupling is a key step causing cAMP signalling switch. The model-designed experiments provided guides for future experimentation.

Optimal sample selection applied to information rich, dense data.

Dense data can be classified into superdense information-poor data (type 1 dense data) and dense information-rich data (type 2 dense data). Arbitrary, random, or optimal thinning may be applied to type 1 dense data to minimise computational burden and statistical issues (such as autocorrelation). In contrast, a prospective or retrospective optimal design can be applied to type 2 dense data to maximise information gain from limited resources (capital and/or time). Here we describe a retrospective optimal selection strategy for quantification of unbound drug concentration from a discrete set of plasma samples where the total drug concentration has been measured.

Effects of variations in atmospheric temperature and humidity on the estimation of exclusive breastfeeding status using the deuterium oxide dose-to-mother technique.

Background: The deuterium dose-to-mother (DTM) method measures the human milk intake of breastfed children. Recently, the use of this method has been expanded to classify babies objectively as exclusively breast fed (EBF) or not (non-EBF) based on quantification of non-milk oral water intake (NMOI). However, the calculation of NMOI estimates involves atmospheric temperature and humidity. Objective: To evaluate the effects of atmospheric temperature and humidity on NMOI calculation and the classification of exclusive breastfeeding. Methods: The effect of indoor temperature and relative humidity on NMOI and the estimated prevalence of non-EBF were examined in two existing data sets of DTM in children by varying temperature in the range of 15 to 35°C and relative humidity in the range of 20 to 80% representing the maximum span of indoor conditions expected. Population-level estimates of NMOI distributions were derived using the rstan package for R v2.21.2. Results: The NMOI decreased at a rate of -1.15 g/day per °C increase and at a rate of -1.01 g/day per percent increase in relative humidity; this was due to variations in non-oral water intake from the atmosphere, a component of the calculation of NMOI, which is dependent on temperature and humidity. For the various locations considered, the mean calculated NMOI varied between 24.6 and 53.3 g/day using the same input data. In the mixed-fed sample of babies, the prevalence of non-EBF based on the earlier defined NMOI cut-off of 86.6 g/day was reduced by 19% when relative humidity was increased by 60%. Conclusions: Atmospheric conditions are essential factors in the computation of NMOI, used in the objective classification of babies as exclusively breast fed or not, and should be considered when the DTM method is used to classify exclusive breastfeeding.

What do pharmacy users think of free pharmacy services? Investigating pharmacy users' perceptions, attitudes and willingness to pay for free healthcare from pharmacies.

Background: Evidence exists of pharmacists providing free or partially subsidised clinical services in order to meet patient healthcare needs. Little is known about how patients perceive the quality and importance of such unfunded services to their healthcare. Objectives: To explore pharmacy user perspectives about unfunded services such as their valuation, why they chose to access these services from the pharmacy as well as their willingness to pay should pharmacies need to start charging for the provision of such services owing to budgetary constraints. Methods: This study was nested in a larger nationwide study where 51 pharmacies were recruited across fourteen locations across New Zealand . Semi-structured interviews were conducted with patients who had accessed unfunded services in community pharmacies. Patients were followed up to identify their percieved health outcomes resulting from accessing the unfunded service. Results: A total of 253 patient interviews were conducted on-site across 51 pharmacies in New Zealand. Two main themes were identified pertaining to (1) patient-provider relationship and (2) Willingness to pay. A total of fifteen different considerations were found to influence pharmacy users' decisions to access health services from the pharmacy. It was found that 62.8% of patients were willing to pay for unfunded services and the majority paying NZD$10. Conclusion: Patients positively rate these services and largely deem them important for their healthcare. Willingness to pay for services were also variable between patients and were dependant on the type of service accessed.

A kinetic model for positive allosteric modulator (PAM)-antagonists for the type 1 cannabinoid (CB1 ) receptor.

BACKGROUND AND PURPOSE: The cannabinoid (CB1 ) receptor is among the most abundant G protein-coupled receptors in brain. Allosteric ligands bind to a different site on receptors than the orthosteric ligand can have effects that are unique to the allosteric ligand and modulate orthosteric ligand activity. We propose a unified mathematical model describing the interaction effects of the allosteric ligand Org27569 and the orthosteric agonist CP55940 on CB1 receptor. EXPERIMENTAL APPROACH: A ternary complex model was constructed, which incorporated kinetic properties to describe the time course of effects of Org27569 and CP55940 reported in the literature: (i) enhanced receptor binding of CP55940, (ii) reduced internalisation and (iii), time-dependent modulation of cAMP. Underlying mechanisms of time-dependent modulation by Org27569 were evaluated by simulation. KEY RESULTS: A hypothetical transitional state of CP55940-CB1 -Org27569, which can internalise but cannot inhibit cAMP, was shown to be necessary and was sufficient to describe the allosteric modulation by Org27569, prior to receptors adopting an inactive conformation. The model indicated that the formation of this transitional CP55940-CB1 -Org27569 state and final inactive CP55940-CB1 -Org27569 state contributes to the enhanced CP55940 binding. The inactive CP55940-CB1 -Org27569 cannot internalise or inhibit cAMP, leading to reduced internalisation and cessation of cAMP inhibition. CONCLUSIONS AND IMPLICATIONS: In conclusion, a kinetic mathematical model for CB1 receptor allosteric modulation was developed. However, a standard ternary complex model was not sufficient to capture the data and a hypothetical transitional state was required to describe the allosteric modulation properties of Org27569.

Individualized vancomycin dosing in infants: prospective evaluation of an online dose calculator.

BACKGROUND: Empiric vancomycin dosing regimens fail to achieve recommended target trough concentrations of 10-20 mg/L in the majority of infants. This study assessed the performance of a model-based dosing calculator (Vanc App) in achieving target vancomycin concentrations at first steady-state level. METHODS: This was a multicenter prospective study in four tertiary pediatric hospitals over an 18-month period. Infants aged 0-90 days with suspected Gram-positive sepsis requiring empiric vancomycin treatment were included if they did not meet any of the exclusion criteria: post-menstrual age (PMA) <25 weeks, weight <500 g, glycopeptide allergy, receiving extracorporeal membrane oxygenation, vancomycin use within the previous 72 h, and renal impairment. The Vanc App used a published population pharmacokinetic model to generate a dose based on the infant's PMA, weight, creatinine, and target vancomycin concentration. RESULTS: A total of 40 infants were included; 40% were female, median (range) weight was 2505 (700-4460) g and median (range) PMA was 37.4 (25.7-49.0) weeks. The median (range) vancomycin dose was 45 (24-79) mg/kg/day. All infants had trough vancomycin concentrations measured at steady-state (24-<48 hours) and 30 (75%) infants achieved target concentrations. Five infants had supratherapeutic (median 25, range 21-38 mg/L) and five had subtherapeutic (median 6, range <5-9 mg/L) concentrations. An area under the concentration-time curve (AUC0-24) of 400-650 mg/L.h was achieved in 33 (83%) infants. There were no infusion-related reactions or nephrotoxicity. CONCLUSION: Individualized intermittent vancomycin dosing using a model-based online calculator resulted in 75% and 83% of infants achieving target trough and AUC0-24, respectively, at first steady-state level. There were no vancomycin-related nephrotoxicity or infusion-related reactions.

Predicting serotonin toxicity in serotonin reuptake inhibitor overdose.

AIMS: We aimed to investigate the frequency of serotonin toxicity following overdose of antidepressants that inhibit serotonin reuptake and the factors that influence the probability of serotonin toxicity occurring. METHODS: This was a retrospective cohort study of overdoses that included selective serotonin reuptake inhibitors (SSRIs) (70%) and serotonin norepinephrine reuptake inhibitors (SNRIs) (30%) admitted to a tertiary toxicology unit over 23 years. A multivariate mixed effects logistic regression model using NONMEM (7.2.0) was used to determine factors that influenced the probability of serotonin toxicity occurring. RESULTS: There were 1978 overdoses in 1520 patients; median age 33 y (range: 13-86 years) and 64% female. Median defined daily dose equivalent (DDD) was 15 (1-420). Co-ingestants were taken in 1678/1978 (85%) overdoses: 11 co-ingested the monoamine oxidase-A inhibitor (MAOI) moclobemide, 99 (5%) co-ingested olanzapine, 58 (3%) co-ingested risperidone and 417 co-ingested a benzodiazepine (21%). Serotonin toxicity occurred in 269 overdoses (13.6%). The probability of serotonin toxicity increased slightly per 10 DDD units dose [OR, 1.01; 95% confidence intervals (CIs): 0.93-1.10], increased for an SNRI vs. an SSRI [OR, 1.07; 95% CI: 0.99-1.15], and markedly increased with co-ingestion of moclobemide [OR, 33.12; 95% CI: 7.5-147]. The probability decreased per 10 y age [OR, 0.84; 95% CI: 0.74-0.95], and with co-ingestion of the serotonin 2 A receptor (5-HT2A) antagonists olanzapine [OR, 0.40; 95% CI: 0.17-0.94] or risperidone [OR, 0.13; 95% CI: 0.02-0.99]. The probability of serotonin toxicity was 12.5% at 1 DDD (therapeutic), 12.7% at 15 DDDs and 19% at 420 DDDs. In overdoses of the median dose of 15 DDDs, co-ingestion of moclobemide increased the probability to 83%, and co-ingestion of olanzapine or risperidone decreased it to 5.5% and 1.8%, respectively. CONCLUSIONS: Serotonin toxicity is common following SSRI/SNRI overdose. Although dose increases probability, this was only a small effect. Co-ingestion with olanzapine or risperidone reduced the risk 2-6-fold, and moclobemide increased the risk 5-fold.

Investigating the provision, nature and associated costs of unfunded pharmacy services: A nationwide study.

BACKGROUND: There is increasing evidence of pharmacists providing free or partially subsidised patient-focused services in order to meet healthcare needs. Limited information exists about the types of unfunded services and their value. OBJECTIVES: (1) Identify the types of unfunded services provided nationally in New Zealand (NZ) and (2) Determine the costs associated with service provision. METHODS: A continuous observation time-motion study was conducted across New Zealand to characterise the provision of unfunded pharmacy services and the labour costs associated with their provision. The time-motion study spanned one business day (between seven to eight hours) in each participating pharmacy. The primary investigator (YA) spent one business day in each participating pharmacy (n = 51) and recorded details about the patient-focused services that were provided. Details included the type of service provided, approximate duration of the service and out-of-pocket costs borne by the patient. RESULTS: A total of 660 observations of unfunded services were recorded across the 51 pharmacies where 360 observation hours were carried out. Twenty-three types of unfunded services were identified, where minor ailments accounted for over half of the total observations. Labour costs associated with service provision were variable. CONCLUSION: Pharmacies across New Zealand are providing patient-focused services for which no funding is being provided.

In Vitro Characterization of 6-Methyl-3-(2-nitro-1-(thiophen-2-yl)ethyl)-2-phenyl-1H-indole (ZCZ011) at the Type 1 Cannabinoid Receptor: Allosteric Agonist or Allosteric Modulator?

Orthosteric activation of CB1 is known to cause a plethora of adverse side effects in vivo. Allosteric modulation is an exciting therapeutic approach and is hoped to offer improved therapeutic potential and a reduced on-target side effect profile compared to orthosteric agonists. This study aimed to systematically characterize the in vitro activity of the positive allosteric modulator ZCZ011, explicitly considering its effects on receptor regulation. HEK293 cells expressing hCB1 receptors were used to characterize ZCZ011 alone and in combination with orthosteric agonists. Real-time BRET approaches were employed for G protein dissociation, cAMP signaling, and ß-arrestin translocation. Characterization also included ERK1/2 phosphorylation (PerkinElmer AlphaLISA) and receptor internalization. ZCZ011 is an allosteric agonist of CB1 in all pathways tested, with a similar signaling profile to that of the partial orthosteric agonist Δ9-tetrahydrocannabinol. ZCZ011 also showed limited positive allosteric modulation in increasing the potency and efficacy of THC-induced ERK1/2 phosphorylation, ß-arrestin translocation, and receptor internalization. However, no positive allosteric modulation was observed for ZCZ011 in combination with either CP55940 or AMB-FUBINACA, in G protein dissociation, nor cAMP inhibition. Our study suggests that ZCZ011 is an allosteric agonist, with effects that are often difficult to differentiate from those of orthosteric agonists. Together with its pronounced agonist activity, the limited extent of ZCZ011 positive allosteric modulation suggests that further investigation into the differences between allosteric and orthosteric agonism is required, especially in receptor regulation end points.

Exploring Inductive Linearization for simulation and estimation with an application to the Michaelis-Menten model.

Nonlinear ordinary differential equations (ODEs) are common in pharmacokinetic-pharmacodynamic systems. Although their exact solutions cannot generally be determined via algebraic methods, their rapid and accurate solutions are desirable. Thus, numerical methods have a critical role. Inductive Linearization was proposed as a method to solve systems of nonlinear ODEs. It is an iterative approach that converts a nonlinear ODE into a linear time-varying (LTV) ODE, for which a range of standard integration techniques can then be used to solve (e.g., eigenvalue decomposition [EVD]). This study explores the properties of Inductive Linearization when coupled with EVD for integration of the LTV ODE and illustrates how the efficiency of the method can be improved. Improvements were based on three approaches, (1) incorporation of a convergence criterion for the iterative linearization process (for simulation and estimation), (2) creating more efficient step sizes for EVD (for simulation and estimation), and (3) updating the initial conditions of the Inductive Linearization (for estimation). The performance of these improvements were evaluated using single subject stochastic simulation-estimation with an application to a simple pharmacokinetic model with Michaelis-Menten elimination. The reference comparison was a standard non-stiff Runge-Kutta method with variable step size (ode45, MATLAB). Each of the approaches improved the speed of the Inductive Linearization technique without diminishing accuracy which, in this simple case, was faster than ode45 with comparable accuracy in the parameter estimates. The methods described here can easily be implemented in standard software programme such as R or MATLAB. Further work is needed to explore this technique for estimation in a population approach setting.

Optimal dosing of enoxaparin in overweight and obese children.

AIM: Current enoxaparin dosing guidelines in children are based on total body weight. This is potentially inappropriate in obese children as it may overestimate the drug clearance. Current evidence suggests that obese children may require lower initial doses of enoxaparin, therefore the aim of this work was to characterise the pharmacokinetics of enoxaparin in obese children and to propose a more appropriate dosing regimen. METHODS: Data from 196 unique encounters of 160 children who received enoxaparin treatment doses were analysed. Enoxaparin concentration was quantified using the chromogenic anti factor Xa (anti-Xa) assay. Patients provided a total of 552 anti-Xa samples. Existing published pharmacokinetic (PK) models were fitted and evaluated against our dataset using prediction-corrected visual predictive check plots (pcVPCs). A PK model was fitted using a nonlinear mixed-effects modelling approach. The fitted model was used to evaluate the current standard dosing and identify an optimal dosing regimen for obese children. RESULTS: Published models of enoxaparin pharmacokinetics in children did not capture the pharmacokinetics of enoxaparin in obese children as shown by pcVPCs. A one-compartment model with linear elimination best described the pharmacokinetics of enoxaparin. Allometrically scaled fat-free mass with an estimated exponent of 0.712 (CI 0.66-0.76) was the most influential covariate on clearance while linear fat-free mass was selected as the covariate on volume. Simulations from the model showed that fat-free mass-based dosing could achieve the target anti-Xa activity at steady state in 77.5% and 78.2% of obese and normal-weight children, respectively, compared to 65.2% and 75.5% for standard total body weight-based dosing. CONCLUSIONS: A population PK model that describes the time course of anti-Xa activity of enoxaparin was developed in a paediatric population. Based on this model, a unified dosing regimen was proposed that will potentially improve the success rate of target attainment in overweight/obese patients without the need for patient body size categorisation. Therefore, prospective validation of the proposed approach is warranted.