No abstract

Fentanyl is an anesthetic/analgesic commonly used in surgical and recovery settings. CYP3A4 and CYP3A5 encode enzymes, which metabolize fentanyl; genetic variants in these genes impact fentanyl pharmacokinetics in adults. Pharmacokinetic (PK) studies are difficult to replicate in children due to the burden of additional blood taken solely for research purposes. The aim of this study is to test the effect of CYP3A5 and CYP3A4 genetic variants on fentanyl PKs in children using opportunistically collected samples. Fentanyl concentrations were measured from remnant blood specimens and dosing data were extracted from electronic health records. Variant data defining CYP3A4*1G and CYP3A5*3 and *6 alleles were available from prior genotyping; alleles with no variant were defined as *1. The study cohort included 434 individuals (median age 9 months, 52% male subjects) and 1,937 fentanyl concentrations were available. A two-compartment model was selected as the base model, and the final covariate model included age, weight, and surgical severity score. Clearance was significantly associated with either CYP3A5*3 or CYP3A5*6 alleles, but not the CYP3A4*1G allele. A genotype of CYP3A5*1/*3 or CYP3A5*1/*6 (i.e., intermediate metabolizer status) was associated with a 0.84-fold (95% confidence interval (CI): 0.71-1.00) reduction in clearance vs. CYP3A5*1/*1 (i.e., normal metabolizer status). CYP3A5*3/*3, CYP3A5*3/*6, or CYP3A5*6/*6 (i.e., poor metabolizer status) was associated with a 0.76-fold (95% CI: 0.58-0.99) reduction in clearance. In the final model, expected clearance was 8.9 and 6.8 L/hour for a normal and poor metabolizer, respectively, with median population covariates (9 months old, 7.7 kg, low surgical severity).

Aims: Our objectives were to perform a population pharmacokinetic analysis of dexmedetomidine in children using remnant specimens and electronic health records (EHRs) and explore the impact of patient's characteristics and pharmacogenetics on dexmedetomidine clearance. Methods: Dexmedetomidine dosing and patient data were gathered from EHRs and combined with opportunistically sampled remnant specimens. Population pharmacokinetic models were developed using nonlinear mixed-effects modelling. Stage 1 developed a model without genotype variables; Stage 2 added pharmacogenetic effects. Results: Our final study population included 354 post-cardiac surgery patients aged 0-22 years (median 16 mo). The data were best described with a 2-compartment model with allometric scaling for weight and Hill maturation function for age. Population parameter estimates and 95% confidence intervals were 27.3 L/h (24.0-31.1 L/ h) for total clearance, 161 L (139-187 L) for central compartment volume of distribution, 26.0 L/h (22.5-30.0 L/h) for intercompartmental clearance and 7903 L (5617-11 119 L) for peripheral compartment volume of distribution. The estimate for postmenstrual age when 50% of adult clearance is achieved was 42.0 weeks (41.5-42.5 weeks) and the Hill coefficient estimate was 7.04 (6.99-7.08). Genotype was not statistically or clinically significant. Conclusion:Our study demonstrates the use of real-world EHR data and remnant specimens to perform a population pharmacokinetic analysis and investigate covariate effects in a large paediatric population. Weight and age were important predictors of clearance. We did not find evidence for pharmacogenetic effects of UGT1A4 or UGT2B10 genotype or CYP2A6 risk score.

The causes for disparities in implementation of precision medicine are complex, due in part to differences in clinical care and a lack of engagement and recruitment of under-represented populations in studies. New tools and large genetic cohorts can change these circumstances and build access to personalized medicine for disadvantaged populations.

The Src substrate Tks5 helps scaffold matrix-remodeling invadopodia in invasive cancer cells. Focus was directed here on how the five SH3 domains of Tks5 impact that activity. Mutations designed to inhibit protein-protein interactions were created in the individual SH3 domains of Tks5, and the constructs were introduced into the LNCaP prostate carcinoma cell line, a model system with intrinsically low Tks5 expression and which our lab had previously showed the dependence of Src-dependent Tks5 phosphorylation on invadopodia development. In LNCaP cells, acute increases in wild-type Tks5 led to increased gelatin matrix degradation. A similar result was observed when Tks5 was mutated in its 4 th or 5 th SH3 domains. This was in contrast to the 1 st , 2 nd , and 3 rd SH3 domain mutations of Tks5 where each had a remarkable accentuating effect on gelatin degradation. Conversely, in the invadopodia-competent Src-3T3 model system, mutations in any one of the first three SH3 domains had a dominant negative effect that largely eliminated the presence of invadopodia, inhibited gelatin degradation activity, and redistributed both Src, cortactin, and Tks5 to what are likely endosomal compartments. A hypothesis involving Tks5 conformational states and the regulation of endosomal trafficking is presented as an explanation for these seemingly disparate results.