Population pharmacokinetics of oxycodone in plasma and cerebrospinal fluid after epidural and intravenous administration

Objectives: To establish the first plasma and cerebrospinal fluid (CSF) oxycodone population pharmacokinetic (PopPK) model after epidural (EPI) and intravenous (IV) oxycodone administration.

Methods: The study was conducted with 30 female subjects undergoing elective gynecological surgery with epidural analgesia. A parallel single dose of EPI oxycodone with IV placebo (EPI group; n = 18) or IV oxycodone with EPI placebo (IV group; n = 12) was administered. An epidural catheter for drug administration was placed at T12/L1 and a spinal catheter for CSF sampling at L3/4. Plasma and CSF for oxycodone analysis were frequently collected. A PopPK model was built using the NONMEM software package.

Results: Plasma and CSF oxycodone concentrations were evaluated using separate central plasma and CSF compartments and separate peripheral plasma and CSF compartments. Epidural space served as a depot compartment with transfer to both the plasma and CSF central compartments. The population parameters for plasma clearance and apparent distribution volumes for central and peripheral compartments for plasma and CSF were 37.4 L/h, 90.2 L, 68.9 L, 0.035 L (fixed based on literature), and 0.039 L, respectively.

Conclusion: A PopPK model was developed and found to precisely and accurately describe oxycodone time-concentration data in plasma and CSF.     

Towards human ex vivo organ perfusion models to elucidate drug pharmacokinetics in health and disease

Abstract

To predict the absorption, distribution, metabolism and excretion (ADME) profile of candidate drugs a variety of preclinical models can be applied. The ADME and toxicological behavior of newly developed drugs are often investigated prior to assessment in humans, which is associated with long time-lines and high costs. Therefore, good predictions of ADME profiles earlier in the drug development process are very valuable. Good prediction of intestinal absorption and renal and biliary excretion remain especially difficult, as there is an interplay of active transport and metabolism involved. To study these processes, including enterohepatic circulation, ex vivo tissue models are highly relevant and can be regarded as the bridge between in vitro and in vivo models. In this review the current in vitro, in vivo and in more detail ex vivo models for studying pharmacokinetics in health and disease are discussed. Additionally, we propose novel models, i.e., perfused whole-organs, which we envision will generate valuable pharmacokinetic information in the future due to improved translation to the in vivo situation. These machine-perfused organ models will be particularly interesting in combination with biomarkers for assessing the functionality of transporter and CYP450 proteins.     

Pharmacokinetic considerations for pediatric patients receiving analgesia in the intensive care unit; targeting postoperative,ECMO and hypothermia patients

Introduction: Adequate postoperative analgesia in pediatric patients in the intensive care unit (ICU) matters, since untreated pain is associated with negative outcomes. Compared to routine postoperative patients, children undergoing hypothermia (HT) or extracorporeal membrane oxygenation (ECMO), or recovering after cardiac surgery likely display non-maturational differences in pharmacokinetics (PK) and pharmacodynamics (PD). These differences warrant additional dosing recommendations to optimize pain treatment.

Areas covered: Specific populations within the ICU will be discussed with respect to expected variations in PK and PD for various analgesics. We hereby move beyond maturational changes and focus on why PK/PD may be different in children undergoing HT, ECMO or cardiac surgery. We provide a stepwise manner to develop PK-based dosing regimens using population PK approaches in these populations.

Expert opinion: A one-dose to size-fits-all for analgesia is suboptimal, but for several commonly used analgesics the impact of HT, ECMO or cardiac surgery on average PK parameters in children is not yet sufficiently known. Parameters considering both maturational and non-maturational covariates are important to develop population PK-based dosing advices as part of a strategy to optimize pain treatment.     

Simultaneous Pharmacokinetic Modeling of Gentamicin,Tobramycin and Vancomycin Clearance from Neonates to Adults: Towards a Semi-physiological Function for Maturation in Glomerular Filtration

Purpose

Since glomerular filtration rate (GFR) is responsible for the elimination of a large number of water-soluble drugs, the aim of this study was to develop a semi-physiological function for GFR maturation from neonates to adults.

Methods

In the pharmacokinetic analysis (NONMEM VI) based on data of gentamicin, tobramycin and vancomycin collected in 1,760 patients (age 1 day–18 years, bodyweight 415 g–85 kg), a distinction was made between drug-specific and system-specific information. Since the maturational model for clearance is considered to contain system-specific information on the developmental changes in GFR, one GFR maturational function was derived for all three drugs.

Results

Simultaneous analysis of these three drugs showed that maturation of GFR mediated clearance from preterm neonates to adults was best described by a bodyweight-dependent exponent (BDE) function with an exponent varying from 1.4 in neonates to 1.0 in adults (Cl_GFR?=?Cl_drug*(BW/4 kg)^BDE with BDE?=?2.23*BW^?0.065). Population clearance values (Cl_drug) for gentamicin, tobramycin and vancomycin were 0.21, 0.28 and 0.39 L/h for a full term neonate of 4 kg, respectively.

Discussion

Based on an integrated analysis of gentamicin, tobramycin and vancomycin, a semi-physiological function for GFR mediated clearance was derived that can potentially be used to establish evidence based dosing regimens of renally excreted drugs in children.     

The utility of online panel surveys versus computer-assisted interviews in obtaining substance-use prevalence estimates in the Netherlands

Aims   Rather than using the traditional, costly method of personal interviews in a general population sample, substance-use prevalence rates can be derived more conveniently from data collected among members of an online access panel. To examine the utility of this method, we compared the outcomes of an online survey with those obtained with the computer-assisted personal interviews (CAPI) method.
Design   Data were gathered from a large sample of online panellists and in a two-stage stratified sample of the Dutch population using the CAPI method.
Setting   The Netherlands.
Participants   The online sample comprised 57 125 Dutch online panellists (15–64 years) of Survey Sampling International LLC (SSI), and the CAPI cohort 7204 respondents (15–64 years).
Measurements   All participants answered identical questions about their use of alcohol, cannabis, ecstasy, cocaine and performance-enhancing drugs. The CAPI respondents were asked additionally about internet access and online panel membership. Both data sets were weighted statistically according to the distribution of demographic characteristics of the general Dutch population.
Findings   Response rates were 35.5% ( n  = 20 282) for the online panel cohort and 62.7% ( n  = 4516) for the CAPI cohort. The data showed almost consistently lower substance-use prevalence rates for the CAPI respondents. Although the observed differences could be due to bias in both data sets, coverage and non-response bias were higher in the online panel survey.
Conclusions   Despite its economic advantage, the online panel survey showed stronger non-response and coverage bias than the CAPI survey, leading to less reliable estimates of substance use in the general population.     

Pharmacokinetics and Pharmacodynamics of Midazolam and Metabolites in Nonventilated Infants after Craniofacial Surgery

Background: Because information on the optimal dose of midazolam for sedation of nonventilated infants after major surgery is scant, a population pharmacokinetic and pharmacodynamic model is developed for this specific group.

Methods: Twenty-four of the 53 evaluated infants (aged 3-24 months) admitted to the Pediatric Surgery Intensive Care Unit, who required sedation judged necessary on the basis of the COMFORT-Behavior score and were randomly assigned to receive midazolam, were included in the analysis. Bispectral Index values were recorded concordantly. Population pharmacokinetic and pharmacodynamic modeling was performed using NONMEM V (GloboMax LLC, Hanover, MD).

Results: For midazolam, total clearance was 0.157 l/min, central volume was 3.8 l, peripheral volume was 30.2 l, and intercompartmental clearance was 0.30 l/min. Assuming 60% conversion of midazolam to 1-OH-midazolam, the volume of distribution for 1-OH-midazolam and 1-OH-midazolamglucuronide was 6.7 and 1.7 l, and clearance was 0.21 and 0.047 l/min, respectively. Depth of sedation using COMFORT-Behavior could adequately be described by a baseline, postanesthesia effect (Emax model) and midazolam effect (Emax model).The midazolam concentration at half maximum effect was 0.58 [mu]m with a high interindividual variability of 89%. Using the Bispectral Index, in 57% of the infants the effect of midazolam could not be characterized.     

Back care instructions in physical therapy: a trend analysis of individualized back care programs

BACKGROUND AND PURPOSE: The treatment of people with low back pain often includes giving a variety of instructions about back care. The objective of our study was to explore the content and sequence of these instructions. SUBJECTS: Our database contained information on 1,151 therapy sessions for 132 patients who were treated by 21 therapists. METHODS: Hierarchical linear modeling was used to establish trends in instructions during the course of treatment. Instructions were measured by means of a registration form. RESULTS: Pain management instructions were given at the start of treatment and then decreased in later sessions. Instructions about taking care of the back in daily activities followed the same course. Exercise instructions were introduced after the start of treatment and were spread evenly across the visits. The number of recommendations about general fitness decreased during treatment. CONCLUSION AND DISCUSSION: The majority of back care instructions were spread evenly across therapy visits. Relatively little variation in instructions among patients was seen, which may indicate a lack of individualization of the back care programs.     

Special approaches for safe handling of disabled children in The Netherlands.

This article illustrates the manner in which care providers and lawmakers in The Netherlands are addressing safe patient handling of disabled children. Standardization of ergonomic practices for safe patient handling of children requires tailored solutions at both the ward and the individual patient level. Elements such as physical contact versus device-assisted transfer, healing environment, and nonverbal (or haptonomic) communication should all be taken into accountfor a program to be successful. Experience from The Netherlands has shown that consideration of these factors, national guidelines, and the presence of ergocoaches can all help to ensure the success of ergonomic interventions, thereby reducing the possibility of direct caregiver injuries.