A Population Pharmacokinetic Model Does Not Predict the Optimal Starting Dose of Tacrolimus in Pediatric Renal Transplant Recipients in a Prospective Study: Lessons Learned and Model Improvement

Background and Objective: Bodyweight-based dosing of tacrolimus is considered standard care. Currently, at first steady state, a third of pediatric kidney transplant recipients has a tacrolimus pre-dose concentration within the target range. We investigated whether adaptation of the starting dose according to a validated dosing algorithm could increase this proportion. Methods: This was a multi-center, single-arm, prospective trial with a planned interim analysis after 16 patients, in which the tacrolimus starting dose was based on bodyweight, cytochrome P450 3A5 genotype, and donor status (living vs. deceased donor). Results: At the interim analysis, 31% of children had a tacrolimus pre-dose concentration within the target range. As the original dosing algorithm was poorly predictive of tacrolimus exposure, the clinical trial was terminated prematurely. Next, the original model was improved by including the data of the children included in this trial, thereby doubling the number of children in the model building cohort. Data were best described with a two-compartment model with inter-individual variability, allometric scaling, and inter-occasion variability on clearance. Cytochrome P450 3A5 genotype, hematocrit, and creatinine influenced the tacrolimus clearance. A new starting dose model was developed in which the cytochrome P450 3A5 genotype was incorporated. Both models were successfully internally and externally validated. Conclusions: The weight-normalized starting dose of tacrolimus should be higher in patients with a lower bodyweight and in those who are cytochrome P450 3A5 expressers

A Population Pharmacokinetic Model to Predict the Individual Starting Dose of Tacrolimus Following Pediatric Renal Transplantation

Background: Multiple clinical, demographic, and genetic factors affect the pharmacokinetics of tacrolimus in children, yet in daily practice, a uniform body-weight based starting dose is used. It can take weeks to reach the target tacrolimus pre-dose concentration. Objectives: The objectives of this study were to determine the pharmacokinetics of tacrolimus immediately after kidney transplantation and to find relevant parameters for dose individualization using a population pharmacokinetic analysis. Methods: A total of 722 blood samples were collected from 46 children treated with tacrolimus over the first 6 weeks after renal transplantation. Non-linear mixed-effects modeling (NONMEM®) was used to develop a population pharmacokinetic model and perform a covariate analysis. Simulations were performed to determine the optimal starting dose and to develop dosing guidelines. Results: The data were accurately described by a two-compartment model with allometric scaling for bodyweight. Mean tacrolimus apparent clearance was 50.5 L/h, with an inter-patient variability of 25%. Higher bodyweight, lower estimated glomerular filtration rate, and higher hematocrit levels resulted in lower total tacrolimus clearance. Cytochrome P450 3A5 expressers and recipients who received a kidney from a deceased donor had a significantly higher tacrolimus clearance. The model was successfully externally validated. In total, these covariates explained 41% of the variability in clearance. From the significant covariates, the cytochrome P450 3A5 genotype, bodyweight, and donor type were useful to adjust the starting dose to reach the target pre-dose concentration. Dosing guidelines range from 0.27 to 1.33 mg/kg/day. Conclusion: During the first 6 weeks after transplantation, the tacrolimus weight-normalized starting dose should be higher in pediatric kidney transplant recipients with a lower bodyweight, those who express the cytochrome P450 3A5 genotype, and those who receive a kidney from a deceased donor

Oxidative stabilization of mixed mayonnaises made with linseed oil and saturated medium-chain triglyceride oil

Mayonnaises, made with either saturated medium chain triglyceride (MCT) oil or unsaturated purified linseed oil (LSO), were mixed. Raman confocal microspectrometry demonstrated that lipid droplets in mixed mayonnaise remained intact containing either MCT oil or LSO. Peroxide formation during storage was lower in mixed mayonnaise compared to LSO mayonnaise, while in mixed oil mayonnaise the level of peroxides was constantly low. Mixed oil mayonnaise had a lower rate of oxygen consumption than mixed mayonnaise, LSO mayonnaise having the highest rate. The decay of water-soluble nitroxyl radicals showed radicals are formed in the aqueous phase with the same rate independent of the lipids. This was also reflected in decay of α-tocopherol during storage being similar in MCT and LSO mayonnaises, but being stable in mixed oil mayonnaise and mixed mayonnaise. Results suggest that other effects than simply diluting unsaturated triglycerides with saturated triglycerides is causing the oxidative stabilization observed for mixed mayonnaise and mixed oil mayonnais

Towards a conceptual and operational union of bacterial systematics, ecology, and evolution

To completely understand the ecology of a bacterial community, we need to identify its ecologically distinct populations (ecotypes). The greatest promise for enumerating a community's constituent ecotypes is held by molecular approaches that identify bacterial ecotypes as DNA sequence clusters. These approaches succeed when ecotypes correspond with sequence clusters, but some models of bacterial speciation predict a one-to-many and others a many-to-one relationship between ecotypes and sequence clusters. A further challenge is that sequence-based phylogenies often contain a hierarchy of clusters and subclusters within clusters, and there is no widely accepted theory to guide systematists and ecologists to the size of cluster most likely to correspond to ecotypes. While present systematics attempts to use universal thresholds of sequence divergence to help demarcate species, the recently developed ‘community phylogeny’ approach assumes no universal thresholds, but demarcates ecotypes based on the analysis of a lineage's evolutionary dynamics. Theory-based approaches like this one can give a conceptual framework as well as operational criteria for hypothesizing the identity and membership of ecotypes from sequence data; ecology-based approaches can then confirm that the putative ecotypes are actually ecologically distinct. Bacterial ecotypes that are demonstrated to have a history of coexistence as ecologically distinct lineages (based on sequence analysis) and as a prognosis of future coexistence (based on ecological differences), are the fundamental units of bacterial ecology and evolution, and should be recognized by bacterial systematics

Embracing Monogenic Parkinson's Disease: The MJFF Global Genetic PD Cohort

BACKGROUND: As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited. OBJECTIVE: The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD. METHODS: We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype-phenotype relationships were analyzed. RESULTS: We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published. CONCLUSIONS: Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene-targeted clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Using global team science to identify genetic Parkinson's disease worldwide

Talks on rare diseases in the field of neurology often start with a statement like this: “About 80% of all rare diseases have a neurologic manifestation and about 80% of those are genetic in origin.” Although these numbers probably represent more of an estimate than well‐documented evidence, rapidly advancing and cost‐effective sequencing technologies have led to the quickly growing identification of patients with hereditary neurological diseases..