Developmental changes rather than repeated administration drive paracetamol glucuronidation in neonates and infants

Purpose: Based on recovered metabolite ratios in urine, it has been concluded that paracetamol glucuronidation may be up-regulated upon multiple dosing. This study investigates paracetamol clearance in neonates and infants after single and multiple dosing using a population modelling approach. Methods: A population pharmacokinetic model was developed in NONMEM VI, based on paracetamol plasma concentrations from 54 preterm and term neonates and infants, and on paracetamol, paracetamol-glucuronide and paracetamol-sulphate amounts in urine from 22 of these patients. Patients received either a single intravenous propacetamol dose or up to 12 repeated doses. Results: Paracetamol and metabolite disposition was best described with one-compartment models. The formation clearance of paracetamol-sulphate was 1.46 mL/min/kg1.4, which was about 5.5 times higher than the formation clearance of the glucuronide of 0.266 mL/min/kg. The renal excretion rate constants of both met

Waveguide-coupled micro-ball lens array suitable for mass fabrication

We demonstrate a fabrication procedure for the direct integration of micro-ball lenses on planar integrated optical channel waveguide chips with the aim to reduce the divergence of light that arises from the waveguide in both horizontal and vertical directions. Fabrication of the lenses is based on photoresist reflow which is a procedure that allows for the use of photolithography for careful alignment of the lenses with respect to the waveguides and enables mass production. We present in detail the design and fabrication procedures. Optical characterization of the fabricated micro-ball lenses demonstrates a good performance in terms of beam-size reduction and beam shape. The beam half divergence angle of 1544 nm light is reduced from 12.4° to 1.85°

Mutations in the gene PDE6C encoding the catalytic subunit of the cone photoreceptor phosphodiesterase in patients with achromatopsia

Biallelic PDE6C mutations are a known cause for rod monochromacy, better known as autosomal recessive achromatopsia (ACHM), and early‐onset cone photoreceptor dysfunction. PDE6C encodes the catalytic α′‐subunit of the cone photoreceptor phosphodiesterase, thereby constituting an essential part of the phototransduction cascade. Here, we present the results of a study comprising 176 genetically preselected patients who remained unsolved after Sanger sequencing of the most frequent genes accounting for ACHM, and were subsequently screened for exonic and splice site variants in PDE6C applying a targeted next generation sequencing approach. We were able to identify potentially pathogenic biallelic variants in 15 index cases. The mutation spectrum comprises 18 different alleles, 15 of which are novel. Our study significantly contributes to the mutation spectrum of PDE6C and allows for a realistic estimate of the prevalence of PDE6C mutations in ACHM since our entire ACHM cohort comprises 1,074 independent families.In a cohort of 176 genetically undiagnosed achromatopsia patients, we performed screening of the PDE6C gene and identified potentially pathogenic biallelic variants in 15 cases. Taking into account a previous screening approach, we calculate a prevalence of 2.4% for PDE6C mutations in our cohort, which is most probably representative for the Western population. As achromatopsia is in the focus of retinal gene therapy with four clinical trials ongoing, our study provides a valuable resource for putative gene therapy trials targeting PDE6C.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146275/1/humu23606-sup-0001-SuppMat.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146275/2/humu23606_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146275/3/humu23606.pd

Classical approximation to quantum cosmological correlations

We investigate up to which order quantum effects can be neglected in calculating cosmological correlation functions after horizon exit. As a toy model, we study $\phi^3$ theory on a de Sitter background for a massless minimally coupled scalar field $\phi$. We find that for tree level and one loop contributions in the quantum theory, a good classical approximation can be constructed, but for higher loop corrections this is in general not expected to be possible. The reason is that loop corrections get non-negligible contributions from loop momenta with magnitude up to the Hubble scale H, at which scale classical physics is not expected to be a good approximation to the quantum theory. An explicit calculation of the one loop correction to the two point function, supports the argument that contributions from loop momenta of scale $H$ are not negligible. Generalization of the arguments for the toy model to derivative interactions and the curvature perturbation leads to the conclusion that the leading orders of non-Gaussian effects generated after horizon exit, can be approximated quite well by classical methods. Furthermore we compare with a theorem by Weinberg. We find that growing loop corrections after horizon exit are not excluded, even in single field inflation.Comment: 44 pages, 1 figure; v2: corrected errors, added references, conclusions unchanged; v3: added section in which we compare with stochastic approach; this version matches published versio

A Pediatric Covariate Function for CYP3A-Mediated Midazolam Clearance Can Scale Clearance of Selected CYP3A Substrates in Children

Recently a framework was presented to assess whether pediatric covariate models for clearance can be extrapolated between drugs sharing elimination pathways, based on extraction ratio, protein binding, and other drug properties. Here we evaluate when a pediatric covariate function for midazolam clearance can be used to scale clearance of other CYP3A substrates. A population PK model including a covariate function for clearance was developed for midazolam in children aged 1– 17 years. Commonly used CYP3A substrates were selected and using the framework, it was assessed whether the midazolam covariate function accurately scales their clearance. For eight substrates, reported pediatric clearance values were compared numerically and graphically with clearance values scaled using the midazolam covariate function. For sildenafil, clearance values obtained with population PK modeling based on pediatric concentration-time data were compared with those scaled with the midazolam covariate function. According to the framework, a midazolam covariate function will lead to systemically accurate clearance scaling (absolute prediction error (PE) < 30%) for CYP3A substrates binding to albumin with an extraction ratio between 0.35 and 0.65 when binding < 10% in adults, between 0.05 and 0.55 when binding > 90%, and with an extraction ratio ranging between these values when binding between 10 and 90%. Scaled clearance values for eight commonly used CYP3A substrates were reasonably accurate (PE < 50%). Scaling of sildenafil clearance was accurate (PE < 30%). We defined for which CYP3A substrates a pediatric covariate function for midazolam clearance can accurately scale plasma clearance in children. This scaling approach may be useful for CYP3A substrates with scarce or no available pediatric PK information

Application of the Convection–Dispersion Equation to Modelling Oral Drug Absorption

Models of systemic drug absorption after oral administration are frequently based on a direct or a delayed first-order rate process. In practice, the use of the first-order approach to predict drug concentrations in blood plasma frequently yields a considerable mismatch between predicted and measured concentration profiles. This is particularly true for the upswing of the plasma concentration after oral administration. The current investigation explores an alternative model to describe the absorption rate based on the convection–dispersion equation describing the transport of chemicals through the GI tract. This equation is governed by two parameters, transport velocity and dispersion coefficient. One solution of this equation for a specific set of initial and boundary conditions was used to model absorption of paracetamol in a 22-year-old man after oral administration. The GI-tract passage rate in this subject was influenced by co-administration of drugs that stimulate or delay gastric emptying. The transport-limited absorption function is more accurate in describing the plasma concentration versus time curve after oral administration than the first-order model. Additionally, it provides a mechanistic explanation for the observed curve through the differences in GI-tract passage rate

Not-in-trial simulation I: Bridging cardiovascular risk from clinical trials to real-life conditions

Aims The assessment of heart rate-corrected QT (QTc) interval prolongation relies on the evidence of drug effects in healthy subjects. This study demonstrates the relevance of pharmacokinetic-pharmacodynamic (PKPD) relationships to characterize drug-induced QTc interval prolongation and explore the discrepancies between clinical trials and real-life conditions. Methods d,l-Sotalol data from healthy subjects and from the Rotterdam Study cohort were used to assess treatment response in a phase I setting and in a real-life conditions, respectively. Using modelling and simulation, drug effects at therapeutic doses were predicted in both populations. Results Inclusion criteria were shown to restrict the representativeness of the trial population in comparison to real-life conditions. A significant part of the typical patient population was excluded from trials due to weight and baseline QTc interval criteria. Relative risk was significantly different between sotalol users with and without heart failure, hypertension, diabetes and myocardial infarction (P < 0.01). Although drug effects do cause an increase in the relative risk of QTc interval prolongation, the presence of diabetes represented an increase from 4.0 [95% confidence interval (CI) 2.7-5.8] to 6.5 (95% CI 1.6-27.1), whilst for myocardial infarction it increased from 3.4 (95% CI 2.3-5.13) to 15.5 (95% CI 4.9-49.3). Conclusions Our findings show that drug effects on QTc interval do not explain the observed QTc values in the population. The prevalence of high QTc values in the real-life population can be assigned to co-morbidities and concomitant medications. These findings substantiate the need to account for these factors when evaluating the cardiovascular risk of medicinal products

Mechanism-based pharmacokinetic-pharmacodynamic modeling of the dopamine D-2 receptor occupancy of olanzapine in rats

A mechanism-based PK-PD model was developed to predict the time course of dopamine D-2 receptor occupancy (D2RO) in rat striatum following administration of olanzapine, an atypical antipsychotic drug. A population approach was utilized to quantify both the pharmacokinetics and pharmacodynamics of olanzapine in rats using the exposure (plasma and brain concentration) and D2RO profile obtained experimentally at various doses (0.01-40 mg/kg) administered by different routes. A two-compartment pharmacokinetic model was used to describe the plasma pharmacokinetic profile. A hybrid physiology- and mechanism-based model was developed to characterize the D-2 receptor binding in the striatum and was fitted sequentially to the data. The parameters were estimated using nonlinear mixed-effects modeling . Plasma, brain concentration profiles and time course of D2RO were well described by the model; validity of the proposed model is supported by good agreement between estimated association and dissociation rate constants and in vitro values from literature. This model includes both receptor binding kinetics and pharmacokinetics as the basis for the prediction of the D2RO in rats. Moreover, this modeling framework can be applied to scale the in vitro and preclinical information to clinical receptor occupancy