Assessing the efficiency of a pharmacokinetic-based algorithm for target-controlled infusion of ketamine in ponies

The objective of this study was to assess a pharmacokinetic algorithm to predict ketamine plasma concentration and drive a target-controlled infusion (TCI) in ponies. Firstly, the algorithm was used to simulate the course of ketamine enantiomers plasma concentrations after the administration of an intravenous bolus in six ponies based on individual pharmacokinetic parameters obtained from a previous experiment. Using the same pharmacokinetic parameters, a TCI of S-ketamine was then performed over 120 min to maintain a concentration of 1 microg/mL in plasma. The actual plasma concentrations of S-ketamine were measured from arterial samples using capillary electrophoresis. The performance of the simulation for the administration of a single bolus was very good. During the TCI, the S-ketamine plasma concentrations were maintained within the limit of acceptance (wobble and divergence <20%) at a median of 79% (IQR, 71-90) of the peak concentration reached after the initial bolus. However, in three ponies the steady concentrations were significantly higher than targeted. It is hypothesized that an inaccurate estimation of the volume of the central compartment is partly responsible for that difference. The algorithm allowed good predictions for the single bolus administration and an appropriate maintenance of constant plasma concentrations.

Use of linezolid in neonatal and pediatric inpatient facilities-results of a retrospective multicenter survey

The purpose of this investigation was to describe the use of linezolid in pediatric inpatient facilities. A retrospective multicenter survey including data from nine participating tertiary care pediatric inpatient facilities in Germany and Austria was undertaken. Data on 126 off-label linezolid treatment courses administered to 108 patients were documented. The survey comprises linezolid treatment in a broad spectrum of clinical indications to children of all age groups; the median age was 6.8 years (interquartile range 0.6-15.5 years; range 0.1-21.2 years; ten patients were older than 18 years of age but were treated in pediatric inpatient units). Of the 126 treatment courses, 27 (21%) were administered to preterm infants, 64 (51%) to pediatric oncology patients, and 5% to patients soon after liver transplantation. In 25%, the infection was related to a medical device. Linezolid iv treatment was started after intensive pre-treatment (up to 11 other antibiotics for a median duration of 14 days) and changed to enteral administration in only 4% of all iv courses. In 39 (53%) of 74 courses administered to children older than 1 week and younger than 12 years of age, the dose was not adjusted to age-related pharmacokinetic parameters. In only 17 courses (13%) was a pediatric infectious disease consultant involved in the clinical decision algorithm. Linezolid seemed to have contributed to a favorable outcome in 70% of all treatment courses in this survey. Although retrospective, this survey generates interesting data on the off-label use of linezolid and highlights several important clinical aspects in which the use of this rescue antibiotic in children might be improved.

Review of the fibrinolytic system: comparison of different antifibrinolytics used during cardiopulmonary bypass

Antifibrinolytic agents are often used in different clinical situations, especially in cardiac surgery. During several years, aprotinin was the drug of choice because more than antifibrinolytic properties, aprotinin offers a direct effect on kallikrein and inflammatory pathways. In 2008, The Blood Conservation Using Antifibrinolytics in a Randomized Trial (BART) initiated a discussion about real risks associated with aprotinin administration. Tranexamic acid and epsilon-aminocaproic acid appear to be interesting alternatives in our daily practice. The exact mechanism of action, the pharmacokinetic parameters, the efficacy, and the safety profile need to be clarified for lysine analogs. In this review, the different antifibrinolytics will be described with a special interest into the route of work, and recent patents. Current studies about the pharmacokinetic and the pharmacodynamic profile will be described, and finally the benefit-to-risk balance in patients undergoing cardiac surgery with cardiopulmonary bypass will be discussed.

Miotic action of tramadol is determined by CYP2D6 genotype

Polymorphic CYP2D6 is the enzyme that activates the opioid analgesic tramadol by O-demethylation to M1. Our objective was to determine the opioid effects measured by pupillary response to tramadol of CYP2D6 genotyped volunteers in relation to the disposition of tramadol and M1 in plasma. Tramadol displayed phenotypic pharmacokinetics and it was possible to identify PM subjects with >99% confidence from the metabolic ratio (MR) in a single blood sample taken between 2.5 and 24 h post-dose. Homozygous extensive metabolizers (EM) differed from poor metabolizers (PM), with an almost three-fold greater (P=0.0014) mean maximal pupillary constriction (Emax). Significant correlations between the AUC and Cmax values of M1 versus pupillary constriction were found. The corresponding correlations of pharmacokinetic parameters for tramadol itself were weaker and negative. The strongest correlations were for the single-point metabolic ratios at all sampling intervals versus the effects, with rs ranging from 0.85 to 0.89 (p0.01). It is concluded that the concept of dual opioid/non-opioid action of the drug, though considerably stronger in EMs, is valid for both EM and PM subjects. This is the theoretical basis for the frequent use and satisfactory efficacy of tramadol in clinical practice when given to genetically non-selected population.

Stereoselective pharmacokinetics of ketamine and norketamine after racemic ketamine or S-ketamine administration during isoflurane anaesthesia in Shetland ponies

BACKGROUND: The arterial pharmacokinetics of ketamine and norketamine enantiomers after racemic ketamine or S-ketamine i.v. administration were evaluated in seven gelding ponies in a crossover study (2-month interval). METHODS: Anaesthesia was induced with isoflurane in oxygen via a face-mask and then maintained at each pony's individual MAC. Racemic ketamine (2.2 mg kg(-1)) or S-ketamine (1.1 mg kg(-1)) was injected in the right jugular vein. Blood samples were collected from the right carotid artery before and at 1, 2, 4, 8, 16, 32, 64, and 128 min after ketamine administration. Ketamine and norketamine enantiomer plasma concentrations were determined by capillary electrophoresis. Individual R-ketamine and S-ketamine concentration vs time curves were analysed by non-linear least square regression two-compartment model analysis using PCNonlin. Plasma disposition curves for R-norketamine and S-norketamine were described by estimating AUC, C(max), and T(max). Pulse rate (PR), respiratory rate (R(f)), tidal volume (V(T)), minute volume ventilation (V(E)), end-tidal partial pressure of carbon dioxide (PE'(CO(2))), and mean arterial blood pressure (MAP) were also evaluated. RESULTS: The pharmacokinetic parameters of S- and R-ketamine administered in the racemic mixture or S-ketamine administered separately did not differ significantly. Statistically significant higher AUC and C(max) were found for S-norketamine compared with R-norketamine in the racemic group. Overall, R(f), V(E), PE'(CO(2)), and MAP were significantly higher in the racemic group, whereas PR was higher in the S-ketamine group. CONCLUSIONS: Norketamine enantiomers showed different pharmacokinetic profiles after single i.v. administration of racemic ketamine in ponies anaesthetised with isoflurane in oxygen (1 MAC). Cardiopulmonary variables require further investigation.

Influence of antibiotic dose, dosing interval, and duration of therapy on outcome in experimental pneumococcal meningitis in rabbits

We examined the influence of several pharmacokinetic parameters on cure rates in rabbits with experimental pneumococcal meningitis. When the duration of treatment was kept constant, cure rates improved as the individual dose of ampicillin was increased. On the other hand, when four doses of ampicillin at 60 mg/kg of body weight, producing peak concentrations in cerebrospinal fluid (CSF) of approximately 40 times the MBC, were administered at intervals of 24 instead of 4 h and the duration of therapy was thus prolonged from 12 to 72 h, cure rates also increased (85 versus 25%; P less than 0.01). These high cure rates were achieved even though bacterial titers in CSF 24 h after the first dose had reached levels similar to those present at the beginning of therapy. Cure in these animals was explained by the fact that the second ampicillin dose reduced bacterial titers in CSF significantly more than did the first dose (5.2 versus 2.5 log10 CFU/ml; P less than 0.02). The clinical relevance of these observations remains to be determined.

Population pharmacokinetics of sevoflurane in conjunction with the AnaConDa: toward target-controlled infusion of volatiles into the breathing system

BACKGROUND: The Anesthetic Conserving Device (AnaConDa) uncouples delivery of a volatile anesthetic (VA) from fresh gas flow (FGF) using a continuous infusion of liquid volatile into a modified heat-moisture exchanger capable of adsorbing VA during expiration and releasing adsorbed VA during inspiration. It combines the simplicity and responsiveness of high FGF with low agent expenditures. We performed in vitro characterization of the device before developing a population pharmacokinetic model for sevoflurane administration with the AnaConDa, and retrospectively testing its performance (internal validation). MATERIALS AND METHODS: Eighteen females and 20 males, aged 31-87, BMI 20-38, were included. The end-tidal concentrations were varied and recorded together with the VA infusion rates into the device, ventilation and demographic data. The concentration-time course of sevoflurane was described using linear differential equations, and the most suitable structural model and typical parameter values were identified. The individual pharmacokinetic parameters were obtained and tested for covariate relationships. Prediction errors were calculated. RESULTS: In vitro studies assessed the contribution of the device to the pharmacokinetic model. In vivo, the sevoflurane concentration-time courses on the patient side of the AnaConDa were adequately described with a two-compartment model. The population median absolute prediction error was 27% (interquartile range 13-45%). CONCLUSION: The predictive performance of the two-compartment model was similar to that of models accepted for TCI administration of intravenous anesthetics, supporting open-loop administration of sevoflurane with the AnaConDa. Further studies will focus on prospective testing and external validation of the model implemented in a target-controlled infusion device.

The pharmacokinetic profile of fesoterodine: similarities and differences to tolterodine

BACKGROUND: Fesoterodine is a new antimuscarinic agent developed for the treatment of overactive bladder. Fesoterodine itself is inactive and is rapidly and extensively converted by ubiquitous esterases to its principal active moiety, 5-hydroxymethyl tolterodine (5-HMT). 5-HMT is formed via biotransformation of both fesoterodine and tolterodine, albeit by different metabolising enzymes, viz. esterases and CYP2D6 respectively. Tolterodine is a potent muscarinic receptor antagonist and has been used for the treatment of overactive bladder for over ten years. The objective of this study was to establish the pharmacokinetic profile of fesoterodine and to highlight ist potential pharmacokinetic advantages over tolterodine. DESIGN: Single-centre, open-label, randomised, 4-way crossover study in a total of 24 healthy male volunteers. Single oral doses of 4, 8, or 12 mg fesoterodine were administered after an overnight fast. In addition, the 8 mg dose was also administered after a standard high-fat and high-calorie breakfast. Blood and urine samples for the analysis of 5-HMT were collected before and multiple times after drug administration for pharmacokinetic analysis. RESULTS: The mean peak plasma concentration (Cmax) of 5-HMT and the mean area under the time versus concentration curve (AUC) increased proportionally with the fesoterodine dose. These two parameters were some 2-fold higher in CYP2D6 poor metabolisers, whereas the time to peak plasma concentration (tmax) and half life (t1/2) were not influenced by the dose or the CYP2D6 metaboliser status. If fesoterodine was taken following a high-fat breakfast, we observed small increases in Cmax and AUC. In spite of these modest genetic influences and food effects on the pharmacokinetics of fesoterodine, the overall interindividual variability in Cmax levels was relatively little compared to previously published reports using tolterodine. CONCLUSIONS: Due to the esterase-mediated cytochrome P450-independent formation of 5-HMT and involvement of multiple metabolic and renal excretion pathways in the elimination of 5-HMT, the effects of patient-intrinsic and -extrinsic factors on the pharmacokinetics of fesoterodine are only modest, with some 2-fold higher 5-HMT exposure. Therefore, in contrast to tolterodine, no reduction of fesoterodine dosage is required under conditions of reduced elimination. In most cases of drug interaction or renal/hepatic impairment, the fesoterodine dose may be increased to 8 mg/day based on individual patients' response, or patients may be required to remain at the initial recommended dose of 4 mg/day.