Clinical Decision Support Tools: The Evolution of a Revolution.

Dashboard systems for clinical decision support integrate data from multiple sources. These systems, the newest in a long line of dose calculators and other decision support tools, utilize Bayesian approaches to fully individualize dosing using information gathered through therapeutic drug monitoring. In the treatment of inflammatory bowel disease patients with infliximab, dashboards may reduce therapeutic failures and treatment costs. The history and future development of modern Bayesian dashboard systems is described.

Interactive Pharmacometric Applications Using R and the Shiny Package.

Interactive applications, developed using Shiny for the R programming language, have the potential to revolutionize the sharing and communication of pharmacometric model simulations. Shiny allows customization of the application's user-interface to provide an elegant environment for displaying user-input controls and simulation output-where the latter simultaneously updates with changing input. The flexible nature of the R language makes simulations of population variability possible thus promoting the combination of Shiny with R in model visualization.

Semiphysiologically Based Pharmacokinetic Model of Leflunomide Disposition in Rheumatoid Arthritis Patients.

A semiphysiologically based pharmacokinetic (semi-PBPK) population model was used to evaluate the influence of enterohepatic recycling and protein binding, as well as the effect of genetic variability in CYP1A2, CYP2C19, and ABCG2, on the large interindividual variability of teriflunomide (active metabolite) concentrations following leflunomide administration in rheumatoid arthritis (RA) patients. The model was developed with total and free teriflunomide concentrations determined in RA patients taking leflunomide, as well as mean teriflunomide concentrations following the administration of leflunomide or teriflunomide extracted from the literature. Once developed, the 15-compartment model was able to predict total and free teriflunomide concentrations and was used to screen demographic and genotypic covariates, of which only fat-free mass and liver function (ALT) improved prediction. This approach effectively evaluated the effects of multiple covariates on both total and free teriflunomide concentrations, which have only been explored previously through simplistic one-compartment models for total teriflunomide.

The rheumatoid arthritis susceptibility polymorphism PTPN22 C1858T is not associated with leflunomide response or toxicity.

WHAT IS KNOWN AND OBJECTIVE: A common polymorphism (C1858T) in the gene that encodes the protein tyrosine phosphatase non-receptor type 22 (PTPN22) is associated with altered T-cell responses and increased susceptibility to rheumatoid arthritis (RA) and other autoimmune diseases. Teriflunomide, the active metabolite of leflunomide, reduces T-cell responses through inhibition of tyrosine kinase p56LCK. We examined a potential association between PTPN22 genotype and response or toxicity to leflunomide in Caucasian RA patients taking leflunomide in combination with other disease-modifying antirheumatic drugs (DMARDs). METHODS: Patients enrolled in the Royal Adelaide Hospital RA inception cohort and taking leflunomide were eligible for inclusion. Participants were followed for 12 months after leflunomide initiation or until either another DMARD was added or leflunomide was ceased. Clinical response according to change in 28-joint Disease Activity Score (DAS28) and cessation due to toxicity were assessed. RESULTS AND DISCUSSION: A total of 94 participants were included in the study, 75 of whom carried the CC genotype, 18 the CT, whereas one individual carried the TT genotype. Over the first 12 months of leflunomide treatment, there was no statistically significant relationship between carrying the T allele and change in DAS28 (-0·84 vs. -1·15, P = 0·446) nor with cessation of leflunomide treatment due to side effects (P = 0·433). These results indicate that PTPN22 C1858T genotype has no effect on response or toxicity outcomes in leflunomide-treated RA patients. WHAT IS NEW AND CONCLUSION: This is the first study to evaluate the biologically plausible hypothesis that PTPN22 genotype might be a predictor of response/toxicity to leflunomide therapy. Despite this, PTPN22 genotype was not associated with leflunomide response or toxicity in patients with RA.

Basic concepts in population modeling, simulation, and model-based drug development: part 3-introduction to pharmacodynamic modeling methods.

Population pharmacodynamic (PD) models describe the time course of drug effects, relating exposure to response, and providing a more robust understanding of drug action than single assessments. PD models can test alternative dose regimens through simulation, allowing for informed assessment of potential dose regimens and study designs. This is the third paper in a three-part series, providing an introduction into methods for developing and evaluating population PD models. Example files are available in the Supplementary Data.

Pharmacokinetics of oxycodone after subcutaneous administration in a critically ill population compared with a healthy cohort.

This study aimed to characterise and compare the absorption pharmacokinetics of a single subcutaneous dose of oxycodone in critically ill patients and healthy subjects. Blood samples taken at intervals from two minutes to eight hours after a subcutaneous dose of oxycodone in patients (5 mg) and healthy volunteers (10 mg) were assayed using high performance liquid chromatography. Data were analysed using a non-compartmental approach and presented as mean (SD). Parameters were corrected for dose differences between the groups assuming linear kinetics. Ten patients (eight male, two female) and seven healthy male subjects were included. Maximum venous concentration and area under the concentration curve were approximately two-fold lower in the patient group for an equivalent dose, suggesting either reduced bioavailability or increased clearance: maximum venous concentration 0.14 ± 0.06 vs 0.05 ± 0.02 µg/ml (P <0.0001); area under the concentration curve 19.50 ± 9.15 vs 9.72 ± 2.71 µg/ml/minute (P <0.001) respectively. However, time to maximum venous concentration and mean residence time were not different, suggesting similar absorption rates: time to maximum venous concentration 22.10 ± 18.0 vs 20.50 ± 16.10 minutes (P=0.81); mean residence time 353 ± 191 vs 291 ± 80 minutes (P=0.26). Kinetic parameters were less variable in patients than in volunteers. The patients therefore had reduced exposure to subcutaneous oxycodone. This warrants further model-based analysis and experimentation. Dose regimens for subcutaneous oxycodone developed in healthy volunteers cannot be directly translated to critically ill patients.

Basic concepts in population modeling, simulation, and model-based drug development.

Modeling is an important tool in drug development; population modeling is a complex process requiring robust underlying procedures for ensuring clean data, appropriate computing platforms, adequate resources, and effective communication. Although requiring an investment in resources, it can save time and money by providing a platform for integrating all information gathered on new therapeutic agents. This article provides a brief overview of aspects of modeling and simulation as applied to many areas in drug development.CPT: Pharmacometrics & Systems Pharmacology (2012) 1, e6; doi:10.1038/psp.2012.4; advance online publication 26 September 2012.

Pharmacokinetics and pharmacodynamics of the short-acting sedative CNS 7056 in sheep.

BACKGROUND: CNS 7056 is a new short-acting esterase-metabolized benzodiazepine. We report the first pharmacokinetic (PK) and pharmacodynamic (PD) study of CNS 7056 and its inactive metabolite CNS 7054 in sheep. METHODS: The stability of CNS 7056 in blood samples was examined ex vivo. Six sheep were prepared with physiological instrumentation, and were given doses of 0.37, 0.74, and 1.47 mg kg(-1) (2 min infusion) of CNS 7056 in alternating order on separate days. RESULTS: CNS 7056 was degraded in warm whole sheep blood (23% over 2 h), but not in plasma or blood stored on ice. Using non-compartmental analysis (NCA), CNS 7056 had a mean (sd) clearance of 4.52 (0.96) litre min(-1) and a terminal half-life of 21.3 (10.9) min. There was a rapid conversion of CNS 7056 to its metabolite CNS 7054, which had a terminal half-life of 22.5 (3.4) min. The arterial kinetics of CNS 7056 could be described by a three-compartment model, with volumes of 1.9, 3.9, and 79 litre, a clearance of 4.2 litre min(-1), and inter-compartmental clearances of 2.85 and 1.44 litre min(-1), while the metabolite could be described by a two-compartment model. Cardiac output was an important covariate. Sedation as measured by the alpha power band of the EEG showed rapid onset and offset. The t(1/2,)(k)(e0) for sedation was 1.78 min, and the EC(50) was 0.10 µg ml(-1). CONCLUSIONS: CNS 7056 has PK-PD properties compatible with its potential human use as a short-acting i.v. sedative.

Comparison of the sedative properties of CNS 7056, midazolam, and propofol in sheep.

BACKGROUND: CNS 7056 is an esterase-metabolized benzodiazepine sedative currently under development. Its short duration of action would suggest a clinical role similar to midazolam or propofol. METHODS: The effect of a range of doses of CNS 7056, midazolam, and propofol on depth of sedation, the respiratory system, and the cardiovascular system was studied in chronically instrumented sheep (n=5 or 6). The low, medium, and high doses of CNS 7056, midazolam, and propofol were 0.37, 0.74, and 1.47 mg kg(-1); 0.05, 0.1, and 0.2 mg kg(-1); and 1, 2, and 4 mg kg(-1), respectively. RESULTS: CNS 7056 produced substantial sedation with rapid onset and offset for all doses, with duration rather than depth of sedation increasing with the dose. The lower doses of midazolam had minimal sedative effect; increasing the dose produced variable but longer term sedation. Sedation from propofol was comparable with that of CNS 7056 for the medium and high doses only. The high doses produced approximately 20 min of sedation. All three drugs produced dose-dependent respiratory (e.g. reductions in arterial oxygen tension) and cardiovascular depression (e.g. reductions in mean arterial pressure). For CNS 7056, midazolam, and propofol, the magnitude of the cardiovascular and respiratory depression was proportional to the depth of sedation achieved for any given drug or dose. For all three drugs, the respiratory and cardiovascular depression was not of sufficient magnitude to endanger the animals. CONCLUSIONS: CNS 7056 is a powerful and short-acting anaesthetic in sheep with respiratory and cardiovascular effects consistent with its sedative/anaesthetic qualities.

Blood-brain distribution of morphine-6-glucuronide in sheep.

BACKGROUND AND PURPOSE: At present there are few data regarding the rate and extent of brain-blood partitioning of the opioid active metabolite of morphine, morphine-6-glucuronide (M6G). In this study the cerebral kinetics of M6G were determined, after a short-term intravenous infusion, in chronically instrumented conscious sheep. EXPERIMENTAL APPROACH: Five sheep received an intravenous infusion of M6G 2.2 mg kg(-1) over a four-minute period. Non-linear mixed-effects analysis, with hybrid physiologically based kinetic models, was used to estimate cerebral kinetics from the arterio-sagittal sinus concentration gradients and cerebral blood flow measurements. KEY RESULTS: A membrane limited model was selected as the final model. The blood-brain equilibration of M6G was relatively slow (time to reach 50% equilibration of the deep compartment 5.8 min), with low membrane permeability (PS, population mean, 2.5 ml min(-1)) from the initial compartment (V1, 13.7 ml) to a small deep distribution volume (V2) of 18.4 ml. There was some between-animal variability (%CV) in the initial distribution volume (29%), but this was not identified for PS or V2. CONCLUSION AND IMPLICATIONS: Pharmacokinetic modelling of M6G showed a delayed equilibration between brain and blood of a nature that is primarily limited by permeability across the blood-brain-barrier, in accordance with its physico-chemical properties.

Countercurrent compartmental models describe hind limb skeletal muscle helium kinetics at resting and low blood flows in sheep.

AIMS: This study evaluated the relative importance of perfusion and diffusion mechanisms in compartmental models of blood : tissue helium exchange in a predominantly skeletal muscle tissue bed in the sheep hind limb. Helium has different physiochemical properties from previously studied gases and is a common diluent gas in underwater diving where decompression schedules are based on theoretical models of inert gas kinetics. METHODS: Helium kinetics across skeletal muscle were determined during and after 20 min of helium inhalation, at separate resting and low steady-states of femoral vein blood flow in six sheep under isoflurane anaesthesia. Helium concentrations in arterial and femoral vein blood were determined using gas chromatographic analysis and femoral vein blood flow was monitored continuously. Parameters and model selection criteria of various perfusion-limited or perfusion-diffusion compartmental models of skeletal muscle were estimated by simultaneous fitting of the models to the femoral vein helium concentrations for both blood flow states. RESULTS: A model comprising two parallel perfusion-limited compartment models fitted the data well but required a 51-fold difference in relative compartment perfusion that did not seem physiologically plausible. Models that allowed a countercurrent diffusion exchange of helium between arterial and venous vessels outside of the tissue compartments provided better overall fit of the data and credible parameter estimates. CONCLUSIONS: These results suggest a role of arterial-venous diffusion in blood : tissue helium equilibration in skeletal muscle.

Recirculatory model of fentanyl disposition with the brain as the target organ.

BACKGROUND: The factors affecting the concentrations of fentanyl in the brain after intravenous administration have not been completely quantified. METHODS: A model integrating the role of brain, lung and systemic kinetics was developed based on data from conscious instrumented sheep. Brain kinetics were inferred from arterio-sagittal sinus concentration gradients and cerebral blood flow, and lung kinetics from the pulmonary artery-aortic gradient and cardiac output. The best models of the lung and brain were incorporated into a recirculatory model of the whole-body disposition of fentanyl. The validity of the model structure was tested by its ability to describe published data on the effect of hypo-, normo- and hypercarbia on the blood and brain concentrations of fentanyl in anaesthetized dogs. RESULTS: The cerebral kinetics of fentanyl were consistent with partial membrane limitation: the time to 50% equilibration with arterial blood was 10.0 min. Lung kinetics had two distinct components: a shallow compartment that was 50% equilibrated with blood in 0.72 min, and a loss term probably representing sequestration. Despite its simplicity, the recirculatory model was an adequate description of the sheep data. The dog data could be described if cerebral blood flow and cardiac output in the model were allowed to differ between hypo-, normo- and hypercarbic states. The required flow changes were in good agreement with the known effect of these states in the dog. CONCLUSIONS: A recirculatory model with the brain as a target organ defined the quantitative relationship between the brain concentrations of fentanyl and the circulatory state.

Comparison of the analgesic effects of xylazine in sheep via three different administration routes.

OBJECTIVE: To examine the influence of administration route on the analgesic effects of identical doses of xylazine in sheep. A prospective, linear, randomised laboratory study. PROCEDURE: The analgesic response to the administration of 2.5 mg of the alpha2 agonist xylazine either intravenously, intramuscularly or subcutaneously was assessed using an analgesia testing method based upon a learned response to a painful electrical stimulus. RESULTS: Intravenous administration achieved the most rapid onset and highest peak analgesic values of all administration methods, but was characterised by a shorter duration of action (25 min). Intramuscular and subcutaneous administration resulted in a longer duration of action (40 min) and a greater total analgesic response. CONCLUSION: For the routine management of acute pain, intramuscular administration provided the best combination of onset, duration and total analgesic response of the routes examined. The absence of adverse side effects, such as sedation, normally associated with the administration of alpha2 agonists should also encourage the use of this method as a simple and effective means of providing significant analgesia in the sheep.

The two-compartment recirculatory pharmacokinetic model--an introduction to recirculatory pharmacokinetic concepts.

BACKGROUND: Some limitations of traditional ("mamillary") compartmental pharmacokinetic models of anaesthetic related drugs arise from representing the blood as a central compartment. Recirculatory pharmacokinetic models overcome these limitations. It is proposed that the simplest recirculatory model has only two compartments, and that understanding the properties of this model is a useful introduction to recirculatory pharmacokinetic concepts. METHODS: The compartments of the model are the lungs and the remainder of the body. The traditional rate constants (e.g. k12 and k21) are replaced by terms that include cardiac output. Drug infusion is into the lung compartment, and drug clearance is from the "body" compartment. The "total" drug concentrations can be thought of as the sum of the first-pass and recirculated drug concentrations at any time. Equations for both first-pass and total drug concentrations in arterial and mixed venous blood are presented. The effects of cardiac output and injection time on these concentrations were analysed. RESULTS: The first-pass arterial concentrations were shown to make a significant contribution to the total concentrations for high-clearance drugs and/or bolus drug administration. There was an inverse relationship between these first-pass concentrations and cardiac output, and a direct relationship with bolus injection rate. Thus, the total arterial concentrations are affected by these factors in these circumstances. CONCLUSIONS: The two-compartment recirculatory model is the simplest tool available for elaborating recirculatory pharmacokinetic concepts. The recirculatory approach may provide a conceptual framework of drug disposition that better matches the clinical experience of anaesthetists.

The effect of infusions of adrenaline, noradrenaline and dopamine on cerebral autoregulation under isoflurane anaesthesia in an ovine model.

The effects of infusions of adrenaline, noradrenaline and dopamine on cerebral autoregulation under steady-state isoflurane anaesthesia were compared with the awake state. Six studies each were conducted in two cohorts of adult ewes: awake sheep and those anaesthetized with 2% isoflurane anaesthesia. In random order, each animal received ramped infusions of adrenaline, noradrenaline (0-40 micrograms/min) and dopamine (0-40 micrograms/kg/min). Cerebral blood flow was measured continuously from changes in Doppler velocities in the sagittal sinus. Autoregulation was determined by linear regression analysis between cerebral blood flow and mean arterial pressure. Isoflurane did not significantly alter cerebral blood flow relative to pre-anaesthesia values (P > 0.05). All three catecholamines significantly and equivalently increased MAP from baseline in a dose dependent manner in both the awake and isoflurane cohorts. Although adrenaline significantly increased cerebral blood flow from baseline in the awake cohort (P < 0.01), none of the catecholamines significantly increased cerebral blood flow during isoflurane anaesthesia. No significant differences were demonstrated between the slopes and intercepts of regression lines for adrenaline, noradrenaline and dopamine within either cohort (ANCOVA). Inter-cohort comparisons between the two autoregulation curves demonstrated no significant difference between the slopes of the autoregulation curves for the awake (pooled slope = 0.39) and isoflurane cohorts (pooled slope = 0.28) (P > 0.05). Over a specific dose range, systemic hypertension induced by adrenaline, noradrenaline and dopamine did not significantly increase cerebral blood flow under 2% isoflurane anaesthesia. The concomitant administration of isoflurane and the catecholamines was not associated with altered autoregulatory function compared to the awake state.

Cerebral and lung kinetics of morphine in conscious sheep after short intravenous infusions.

BACKGROUND: The analgesic effects of morphine are delayed relative to its concentration in blood. The rate of equilibration of morphine between blood and brain may contribute to this delay, but the kinetics of this process have not been modelled. This was determined in conscious instrumented sheep. The lung kinetics of morphine were also determined given their importance in defining systemic kinetics after i.v. bolus administration. METHODS: Sheep were given short i.v. infusions of morphine (30 mg over 4 min). Cerebral kinetics were inferred from arterio-sagittal sinus concentration gradients and cerebral blood flow, and lung kinetics from the pulmonary artery-aortic gradient and cardiac output. These data were fitted to flow- and membrane-limited models of the kinetics in each organ. RESULTS: Morphine had minimal cardiovascular effects, did not alter cerebral blood flow and caused insignificant respiratory depression. Lung kinetics were best described by a single distribution volume (2036 ml) with a first-order loss (1370 ml min(-1)), which was attributed to deep distribution. The cerebral kinetics of morphine were characterized by a significant permeability barrier. Permeability across the barrier (7.44 ml min(-1)) was estimated with good precision, and was approximately one-fifth of the nominal cerebral blood flow. The distribution volume of morphine in the brain was estimated with less precision, but was described by a brain:blood partition coefficient of approximately 1.4. The time required for 50% equilibration between brain and blood concentrations was approximately 10.3 min. CONCLUSION: The cerebral equilibration of morphine was relatively slow, and was characterized by significant membrane limitation.

The cerebrovascular effects of adrenaline, noradrenaline and dopamine infusions under propofol and isoflurane anaesthesia in sheep.

Infusions of catecholamines are frequently administered to patients receiving propofol or isoflurane anaesthesia. Interactions between these drugs may affect regional circulations, such as the brain. The aim of this animal (sheep) study was to determine the effects of ramped infusions of adrenaline, noradrenaline (10, 20, 40 micrograms/min) and dopamine (10, 20, 40 micrograms/kg/min) on cerebral blood flow (CBF), intracranial pressure (ICP), cerebrovascular resistance (CVR) and cerebral metabolic rate for oxygen (CMRO2). These measurements were made under awake physiological conditions, and during continuous propofol (15 mg/min) or 2% isoflurane anaesthesia. All three catecholamines significantly and equivalently increased mean arterial pressure from baseline in a dose-dependent manner in the three cohorts (P < 0.001). In the awake cohort (n = 8), dopamine (P < 0.01) significantly increased CBF from baseline whilst adrenaline and noradrenaline did not (P > 0.05). Under propofol (n = 6) and isoflurane (n = 6), all three catecholamines significantly increased CBF (P < 0.001). Dopamine caused the greatest increase in CBF, and was associated with significant increases in ICP (awake: P < 0.001; propofol P < 0.05; isoflurane P < 0.001) and CVR (isoflurane P < 0.05). No significant changes in CMRO2 were demonstrated. Under propofol and isoflurane anaesthesia, the cerebrovascular effects of catecholamines were significantly different from the awake, physiological state, with dopamine demonstrating the most pronounced effects, particularly under propofol. Dopamine-induced hyperaemia was associated with other cerebrovascular changes. In the presence of an equivalent effect on mean arterial pressure, the exaggerated cerebrovascular effects under anaesthesia appear to be centrally mediated, possibly induced by propofol- or isoflurane-dependent changes in blood-brain barrier permeability, thereby causing a direct influence on the cerebral vasculature.