Parent-Metabolite Pharmacokinetic Models for Tramadol – Tests of Assumptions and Predictions

Allometric principles were used to discern cross-species differences in (±)-tramadol disposition and formation of its primary analgesic metabolite, (±)-O-desmethyl-tramadol (M1). Species differences in formation of M1 may help predict the analgesic effectiveness of tramadol. Tramadol was administered intravenously by a zero-order (constant infusion) process or rapid bolus dose and racemic concentrations of tramadol and M1 measured. Data were pooled to define differences between species (human, rat, cat, dog, goat, donkey and horse). A two-compartment linear disposition model with first-order elimination was used to describe tramadol and M1 disposition. Slow metabolizers were detected in 6% of the population and tramadol clearance to M1 was 16.2% that of extensive metabolizers. Tramadol clearance to M1 was slower and tramadol clearance by other pathways was faster in rats, dogs, and horses compared to humans. There are substantial differences between species in the pharmacokinetics of tramadol and its M1 metabolite, which are not explained by differences in body weight. The hypothesis that volumes of distribution are similar across species was shown not to be true. M1 exposure in the goat, donkey and cat was comparable to humans, which indicates it is likely to be an effective analgesic at typically used doses in these species but not in dogs or horses

A new methodology for automating acoustic emission detection of metallic fatigue fractures in highly demanding aerospace environments: An overview

The acoustic emission (AE) phenomenon has many attributes that make it desirable as a structural health monitoring or non-destructive testing technique, including the capability to continuously and globally monitor large structures using a sparse sensor array and with no dependency on defect size. However, AE monitoring is yet to fulfil its true potential, due mainly to limitations in location accuracy and signal characterisation that often arise in complex structures with high levels of background noise. Furthermore, the technique has been criticised for a lack of quantitative results and the large amount of operator interpretation required during data analysis. This paper begins by introducing the challenges faced in developing an AE based structural health monitoring system and then gives a review of previous progress made in addresing these challenges. Subsequently an overview of a novel methodology for automatic detection of fatigue fractures in complex geometries and noisy environments is presented, which combines a number of signal processing techniques to address the current limitations of AE monitoring. The technique was developed for monitoring metallic landing gear components during pre-flight certification testing and results are presented from a full-scale steel landing gear component undergoing fatigue loading. Fracture onset was successfully identify automatically at 49,000 fatigue cycles prior to final failure (validated by the use of dye penetrant inspection) and the fracture position was located to within 10. mm of the actual location

Spatial scanning for anomaly detection in acoustic emission testing of an aerospace structure

Acoustic emission (AE) monitoring of engineering structures potentially provides a convenient, cost-effective means of performing structural health monitoring. Networks of AE sensors can be easily and unobtrusively installed upon structures, giving the ability to detect and locate damage-related strain releases ('events') in the structure. Use of the technique is not widespread due to the lack of a simple and effective method for detecting abnormal activity levels: the sensitivity of AE sensor networks is such that events unrelated to damage are prevalent in most applications. In this publication, we propose to monitor AE activity in a structure using a spatial scanning statistic, developed and used effectively in the field of epidemiology. The technique is demonstrated on an aerospace structure an Airbus A320 main landing gear fitting undergoing fatigue loading, and the method is compared to existing techniques. Despite its simplicity, the scanning statistic proves to be an extremely effective tool in detecting the onset of damage in the structure: it requires little to no user intervention or expertise, is inexpensive to compute and has an easily interpretable output. Furthermore, the generic nature of the method allows the technique to be used in a variety of monitoring scenarios, to detect damage in a wide range of structures

Tramadol and O-desmethyl tramadol clearance maturation and disposition in humans: a pooled pharmacokinetic study

BACKGROUND AND OBJECTIVES: We aimed to study the impact of size, maturation and cytochrome P450 2D6 (CYP2D6) genotype activity score as predictors of intravenous tramadol disposition. METHODS: Tramadol and O-desmethyl tramadol (M1) observations in 295 human subjects (postmenstrual age 25 weeks to 84.8 years, weight 0.5-186 kg) were pooled. A population pharmacokinetic analysis was performed using a two-compartment model for tramadol and two additional M1 compartments. Covariate analysis included weight, age, sex, disease characteristics (healthy subject or patient) and CYP2D6 genotype activity. A sigmoid maturation model was used to describe age-related changes in tramadol clearance (CLPO), M1 formation clearance (CLPM) and M1 elimination clearance (CLMO). A phenotype-based mixture model was used to identify CLPM polymorphism. RESULTS: Differences in clearances were largely accounted for by maturation and size. The time to reach 50 % of adult clearance (TM50) values was used to describe maturation. CLPM (TM50 39.8 weeks) and CLPO (TM50 39.1 weeks) displayed fast maturation, while CLMO matured slower, similar to glomerular filtration rate (TM50 47 weeks). The phenotype-based mixture model identified a slow and a faster metabolizer group. Slow metabolizers comprised 9.8 % of subjects with 19.4 % of faster metabolizer CLPM. Low CYP2D6 genotype activity was associated with lower (25 %) than faster metabolizer CLPM, but only 32 % of those with low genotype activity were in the slow metabolizer group. CONCLUSIONS: Maturation and size are key predictors of variability. A two-group polymorphism was identified based on phenotypic M1 formation clearance. Maturation of tramadol elimination occurs early (50 % of adult value at term gestation).status: publishe

Tramadol and o-desmethyl tramadol clearance maturation and disposition in humans: a pooled pharmacokinetic study.

BACKGROUND AND OBJECTIVES We aimed to study the impact of size, maturation and cytochrome P450 2D6 (CYP2D6) genotype activity score as predictors of intravenous tramadol disposition. METHODS Tramadol and O-desmethyl tramadol (M1) observations in 295 human subjects (postmenstrual age 25 weeks to 84.8 years, weight 0.5-186 kg) were pooled. A population pharmacokinetic analysis was performed using a two-compartment model for tramadol and two additional M1 compartments. Covariate analysis included weight, age, sex, disease characteristics (healthy subject or patient) and CYP2D6 genotype activity. A sigmoid maturation model was used to describe age-related changes in tramadol clearance (CLPO), M1 formation clearance (CLPM) and M1 elimination clearance (CLMO). A phenotype-based mixture model was used to identify CLPM polymorphism. RESULTS Differences in clearances were largely accounted for by maturation and size. The time to reach 50 % of adult clearance (TM50) values was used to describe maturation. CLPM (TM50 39.8 weeks) and CLPO (TM50 39.1 weeks) displayed fast maturation, while CLMO matured slower, similar to glomerular filtration rate (TM50 47 weeks). The phenotype-based mixture model identified a slow and a faster metabolizer group. Slow metabolizers comprised 9.8 % of subjects with 19.4 % of faster metabolizer CLPM. Low CYP2D6 genotype activity was associated with lower (25 %) than faster metabolizer CLPM, but only 32 % of those with low genotype activity were in the slow metabolizer group. CONCLUSIONS Maturation and size are key predictors of variability. A two-group polymorphism was identified based on phenotypic M1 formation clearance. Maturation of tramadol elimination occurs early (50 % of adult value at term gestation)

Use of Macro Fibre Composite Transducers as Acoustic Emission Sensors

The need for ever lighter and more efficient aerospace structures and components has led to continuous optimization pushing the limits of structural performance. In order to ensure continued safe operation during long term service it is desirable to develop a structural health monitoring (SHM) system. Acoustic emission (AE) offers great potential for real time global monitoring of aerospace structures, however currently available commercial sensors have limitations in size, weight and adaptability to complex structures. This work investigates the potential use of macro-fibre composite (MFC) film transducers as AE sensors. Due to the inhomogeneous make-up of MFC transducers their directional dependency was examined and found to have limited effect on signal feature data. However, signal cross-correlations revealed a strong directional dependency. The sensitivity and signal attenuation with distance of MFC sensors were compared with those of commercially available sensors. Although noticeably less sensitive than the commercial sensors, the MFC sensors still had an acceptable operating range. Furthermore, a series of compressive carbon fiber coupon tests were monitored in parallel using both an MFC sensor and a commercially available sensor for comparison. The results showed good agreement of AE trends recorded by both sensors

Pharmacometrics in Australasia — twenty years of population approach group of Australia and New Zealand

In February 2019, the Population Approach Group of Australia and New Zealand (PAGANZ) celebrated 20 years of providing education, mentoring, and support to the Australasian pharmacometrics community. This article provides insight into the history of this group and its operations to the present date

Population pharmacokinetics of tacrolimus in pediatric liver transplantation: Early posttranplantation clearance

Background: Tacrolimus is an immunosuppressant with a narrow therapeutic window, with considerable pharmacokinetic variability. Getting sufficient concentrations in pediatric liver transplantation is imperative, but it has proven difficult in the immediate posttransplantation period in particular. A predictive pharmacokinetic model could be the basis for development of a novel initial dose schedule, and therapeutic drug monitoring with Bayesian methodology