Optimization of flucloxacillin dosing regimens in critically ill patients using population pharmacokinetic modelling of total and unbound concentrations

Background: Initial appropriate anti-infective therapy is associated with improved outcomes in patients with severe infections. In critically ill patients, altered pharmacokinetic (PK) behaviour is common and known to influence the achievement of PK/pharmacodynamic targets. Objectives: To describe population PK and optimized dosing regimens for flucloxacillin in critically ill patients. Methods: First, we developed a population PK model, estimated between-patient variability (BPV) and identified covariates that could explain BPV through non-linear mixed-effects analysis, using total and unbound concentrations obtained from 35 adult critically ill patients treated with intermittent flucloxacillin. Second, we validated the model using external datasets from two different countries. Finally, frequently prescribed dosing regimens were evaluated using Monte Carlo simulations. Results: A two-compartment model with non-linear protein binding was developed and validated. BPV of the maximum binding capacity decreased from 42.2% to 30.4% and BPV of unbound clearance decreased from 88.1% to 71.6% upon inclusion of serumalbumin concentrations and estimated glomerular filtration rate (eGFR; by CKD-EPI equation), respectively. PTA (target of 100%fT(>MIC)) was 91% for patients with eGFR of 33mL/min and 1 g q6h, 87% for patients with eGFR of 96 mL/min and 2 g q4h and 71% for patients with eGFR of 153 mL/min and 2 g q4h. Conclusions: For patients with high creatinine clearance who are infected with moderately susceptible pathogens, therapeutic drug monitoring is advised since there is a risk of underexposure to flucloxacillin. Due to the non-linear protein binding of flucloxacillin and the high prevalence of hypoalbuminaemia in critically ill patients, dose adjustments should be based on unbound concentrations

Model-informed dose optimization of mycophenolic acid in pediatric kidney transplant patients

PurposeWe aimed to develop and evaluate a population PK model of mycophenolic acid (MPA) in pediatric kidney transplant patients to aid MPA dose optimization.MethodsData were collected from pediatric kidney transplant recipients from a Dutch academic hospital (Radboudumc, the Netherlands). Pharmacokinetic model-building and model-validation analyses were performed using NONMEM. Subsequently, we externally evaluated the final model using data from another academic hospital. The final model was used to develop an optimized dosing regimen.ResultsThirty pediatric patients were included of whom 266 measured MPA plasma concentrations, including 20 full pharmacokinetic (PK) curves and 24 limited sampling curves, were available. A two-compartment model with a transition compartment for Erlang-type absorption best described the data. The final population PK parameter estimates were Ktr (1.48 h-1; 95% CI, 1.15-1.84), CL/F (16.0 L h-1; 95% CI, 10.3-20.4), Vc/F (24.9 L; 95% CI, 93.0-6.71E25), Vp/F (1590 L; 95% CI, 651-2994), and Q/F (36.2 L h-1; 95% CI, 9.63-74.7). The performance of the PK model in the external population was adequate. An optimized initial dose scheme based on bodyweight was developed. With the licensed initial dose, 35% of patients were predicted to achieve the target AUC, compared to 42% using the optimized scheme.ConclusionWe have successfully developed a pharmacokinetic model for MPA in pediatric renal transplant patients. The optimized dosing regimen is expected to result in better target attainment early in treatment. It can be used in combination with model-informed follow-up dosing to further individualize the dose when PK samples become available

Genetic architecture of subcortical brain structures in 38,851 individuals

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease

Genetic architecture of subcortical brain structures in 38,851 individuals

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease

Optimization of anti-infective dosing regimens during online haemodiafiltration

Online haemodiafiltration (HDF) is increasingly used in clinical practice as a routine intermittent dialysis modality. It is well known that renal impairment and renal replacement therapy can substantially affect the pharmacokinetic behaviour of several drugs. However, surprisingly few data are available on the need for specific dose adjustments during HDF. Due to convection, drug clearance may be increased during HDF as compared with standard haemodialysis. This may be of particular interest in patients undergoing anti-infective therapy, since under-dosing may compromise patient outcomes and promote the emergence of bacterial resistance. Drug clearance during HDF is determined by (i) dialysis characteristics, (ii) drug characteristics and (iii) patient characteristics. In this review, we will discuss these different determinants of drug clearance during HDF and advise on how to adjust the dose of antibacterial, antimycotic and antiviral agents in patients undergoing HDF. In addition, the possible added value of therapeutic drug monitoring is discussed. The review provides guidance for optimization of anti-infective dosing regimens in HDF patients

Antibiotic exposure at the site of infection: principles and assessment of tissue penetration

Introduction: Since the majority of bacterial infections occur at sites outside the bloodstream, antibiotic tissue concentrations are of significant relevance to optimize treatment. The aim of this review is to aid the clinician in choosing optimal regimens for the treatment of extravascular infections. Areas covered: We discuss the principles of antibiotic tissue penetration and assess different approaches to obtain data on this subject. Finally, we present tissue penetration data for several relevant groups of antibiotic agents in a number of extravascular sites. Data were obtained from an extensive literature search in PubMed until February 2019. Expert opinion: There is still a long way to go before reliable information about tissue penetration of antibiotics is sufficiently available to serve as a basis for the design of optimal strategies for drug and dose selection. At this moment, there is a lack of robust data on tissue penetration, where both the sampling and measurement techniques as well as the relationship between tissue concentrations and clinical outcome of antibiotic treatment have to be better defined

Dried blood spots voor het bepalen van de serumconcentratie van tamoxifen en zijn actieve metaboliet endoxifen

OBJECTIVE To establish the relationship between dried blood spot (DBS) and serum concentrations of tamoxifen and endoxifen in order to allow the use of DBS sampling, a simple and patient-friendly alternative to venous sampling, in clinical practice. The antiestrogenic effect of tamoxifen is suggested to be mainly attributable to its metabolite endoxifen, and a minimum therapeutic threshold for endoxifen in serum has been proposed. DESIGN AND METHODS Paired DBS and serum samples were obtained from 50 patients using tamoxifen and analysed using HPLC-MS/MS. Serum concentrations were calculated from DBS concentrations using the formula: calculated serum concentration = DB S concentration/Id-haematocrit] + [blood cell/serum ratio) x haematocrit). The blood cell/serum ratio was determined ex vivo by incubating a batch of whole blood spiked with both analytes and imputed as a fixed value. The average haematocrit for female adults was imputed as a fixed value. Calculated and analysed serum concentrations were compared using weighted Deming regression. RESULTS Weighted Deming regression analysis comparing 44 matching pairs of DBS and serum samples showed a proportional bias for both analytes. Serum concentrations were calculated using [Tam]s.cals = [Tam)DBS/0.779 and [End)s.cal(; = [End]DBS/0.663. Calculated serum concentrations were within 20% of analysed serum concentrations in 84 and 100% of patient samples for tamoxifen and endoxifen, respectively. CONCLUSION DBS concentrations of tamoxifen and endoxifen were equal to serum concentrations after correction for haematocrit and blood cell/serum ratio. DBS sampling can be used in clinical practice

Dried blood spots voor het bepalen van de serumconcentratie van tamoxifen en zijn actieve metaboliet endoxifen

OBJECTIVE To establish the relationship between dried blood spot (DBS) and serum concentrations of tamoxifen and endoxifen in order to allow the use of DBS sampling, a simple and patient-friendly alternative to venous sampling, in clinical practice. The antiestrogenic effect of tamoxifen is suggested to be mainly attributable to its metabolite endoxifen, and a minimum therapeutic threshold for endoxifen in serum has been proposed. DESIGN AND METHODS Paired DBS and serum samples were obtained from 50 patients using tamoxifen and analysed using HPLC-MS/MS. Serum concentrations were calculated from DBS concentrations using the formula: calculated serum concentration = DB S concentration/Id-haematocrit] + [blood cell/serum ratio) x haematocrit). The blood cell/serum ratio was determined ex vivo by incubating a batch of whole blood spiked with both analytes and imputed as a fixed value. The average haematocrit for female adults was imputed as a fixed value. Calculated and analysed serum concentrations were compared using weighted Deming regression. RESULTS Weighted Deming regression analysis comparing 44 matching pairs of DBS and serum samples showed a proportional bias for both analytes. Serum concentrations were calculated using [Tam]s.cals = [Tam)DBS/0.779 and [End)s.cal(; = [End]DBS/0.663. Calculated serum concentrations were within 20% of analysed serum concentrations in 84 and 100% of patient samples for tamoxifen and endoxifen, respectively. CONCLUSION DBS concentrations of tamoxifen and endoxifen were equal to serum concentrations after correction for haematocrit and blood cell/serum ratio. DBS sampling can be used in clinical practice

A multi-gram-scale stereoselective synthesis of Z-endoxifen

Z-Endoxifen is widely regarded as the most active metabolite of tamoxifen, and has recently demonstrated a 26.3% clinical benefit in a phase I clinical trial to treat metastatic breast cancer after the failure of standard endocrine therapy. Future pharmacological and pre-clinical studies of Z-endoxifen would benefit from reliable and efficient synthetic access to the drug. Here, we describe a short and efficient, stereoselective synthesis of Z-endoxifen capable of delivering multi-gram (37 g) quantities of the drug in >97% purity with a Z/E ratio >99% after trituration