Johannes H. Proost

Performance of an Iterative Two-stage Bayesian Technique for Population Pharmacokinetic Analysis of Rich Data Sets

PURPOSE To test the suitability of an Iterative Two-Stage Bayesian (ITSB) technique for population pharmacokinetic analysis of rich data sets, and to compare ITSB with Standard Two-Stage (STS) analysis and nonlinear Mixed Effect Modeling (MEM). MATERIALS AND METHODS Data from a clinical study with rapacuronium and data generated by Monte Carlo simulation were analyzed by an ITSB technique described in literature, with some modifications, by STS, and by MEM (using NONMEM). The results were evaluated by comparing the mean error (accuracy) and root mean squared error (precision) of the estimated parameter values, their interindividual standard deviation, correlation coefficients, and residual standard deviation. In addition, the influence of initial estimates, number of subjects, number of measurements, and level of residual error on the performance of ITSB were investigated. RESULTS ITSB yielded best results, and provided precise and virtually unbiased estimates of the population parameter means, interindividual variability, and residual standard deviation. The accuracy and precision of STS was poor, whereas ITSB performed better than MEM. CONCLUSIONS ITSB is a suitable technique for population pharmacokinetic analysis of rich data sets, and in the presented data set it is superior to STS and MEM.

Interaction Between Nitrous Oxide, Sevoflurane, and Opioids: A Response Surface Approach

Background:The interaction of sevoflurane and opioids can be described by response surface modeling using the hierarchical model. We expanded this for combined administration of sevoflurane, opioids, and 66 vol.% nitrous oxide (N2O), using historical data on the motor and hemodynamic responsiveness to incision, the minimal alveolar concentration, and minimal alveolar concentration to block autonomic reflexes to nociceptive stimuli, respectively. Methods:Four potential actions of 66 vol.% N2O were postulated: (1) N2O is equivalent to A ng/ml of fentanyl (additive); (2) N2O reduces C50 of fentanyl by factor B; (3) N2O is equivalent to X vol.% of sevoflurane (additive); (4) N2O reduces C50 of sevoflurane by factor Y. These four actions, and all combinations, were fitted on the data using NONMEM (version VI, Icon Development Solutions, Ellicott City, MD), assuming identical interaction parameters (A, B, X, Y) for movement and sympathetic responses. Results:Sixty-six volume percentage nitrous oxide evokes an additive effect corresponding to 0.27 ng/ml fentanyl (A) with an additive effect corresponding to 0.54 vol.% sevoflurane (X). Parameters B and Y did not improve the fit. Conclusion:The effect of nitrous oxide can be incorporated into the hierarchical interaction model with a simple extension. The model can be used to predict the probability of movement and sympathetic responses during sevoflurane anesthesia taking into account interactions with opioids and 66 vol.% N2O.

Pharmacokinetics and anti-HIV-1 efficacy of negatively charged human serum albumins in mice

Negatively charged albumins (NCAs, with the prototypes succinylated human serum albumin (Suc-HSA) and aconitylated human serum albumin (Aco-HSA)), modified proteins with a potent anti-human immunodeficiency virus type 1 (anti-HIV-1) activity in vitro, were studied for their pharmacokinetic behaviour in mice and their in vivo anti-HIV-1 efficacy in an HIV-1 infection model in mice. In contrast to the saturation kinetics found in rats, intravenous injections of 10-300 mg/kg for both NCAs showed a linear correlation between the area under the curve (AUC) and the dose. The elimination t1/2 was 25 and 30 min for Suc-HSA and Aco-HSA, respectively. Preinjections of an excess of formaldehyde-treated albumin (Form-HSA) resulted in plasma levels that were 3- and 4-fold higher for Aco-HSA and Suc-HSA, respectively. These data indicate that elimination is at least partly (scavenger) receptor-mediated. Organ distribution studies 10 min after injection showed an accumulation in liver (Suc-HSA 17.3 +/- 6.6% of the dose; Aco-HSA 20.9 +/- 2.3%) and lungs (Suc-HSA 12.7 +/- 10.5%; Aco-HSA 16.0 +/- 13.6). Intraperitoneal injection of 300 mg/kg Suc-HSA resulted in a final bioavailability of about 0.45. Suc-HSA was also evaluated for its in vivo neutralizing capacity in a human-to-mouse chimeric model for HIV-1 infection. Intraperitoneal injections of 300 and 3 mg/kg Suc-HSA, given 15-30 min before the mice were challenged with the virus, sufficed to protect these mice against infection with the HIV-1 IIIB strain.

Pharmacokinetic and pharmacodynamic interactions in anaesthesia. A review of current knowledge and how it can be used to optimize anaesthetic drug administration

This review describes the basics of pharmacokinetic and pharmacodynamic drug interactions and methodological points of particular interest when designing drug interaction studies. It also provides an overview of the available literature concerning interactions, with emphasis on graphic representation of interactions using isoboles and response surface models. It gives examples on how to transform this knowledge into clinically and educationally applicable (bedside) tools.

Probability to tolerate laryngoscopy and noxious stimulation response index as general indicators of the anaesthetic potency of sevoflurane, propofol, and remifentanil

BACKGROUND The probability to tolerate laryngoscopy (PTOL) and its derivative, the noxious stimulation response index (NSRI), have been proposed as measures of potency of a propofol-remifentanil drug combination. This study aims at developing a triple drug interaction model to estimate the combined potency of sevoflurane, propofol, and remifentanil in terms of PTOL. We compare the predictive performance of PTOL and the NSRI with various anaesthetic depth monitors. METHODS Data from three previous studies (n=120) were pooled and reanalysed. Movement response after laryngoscopy was observed with different combinations of propofol-remifentanil, sevoflurane-propofol, and sevoflurane-remifentanil. A triple interaction model to estimate PTOL was developed. The NSRI was derived from PTOL. The ability of PTOL and the NSRI to predict observed tolerance of laryngoscopy (TOL) was compared with the following other measures: (i) effect-site concentrations of sevoflurane, propofol, and remifentanil (CeSEVO, CePROP, and CeREMI); (ii) bispectral index; (iii) two measures of spectral entropy; (iv) composite variability index; and (v) surgical pleth index. RESULTS Sevoflurane and propofol interact additively, whereas remifentanil interacts in a strongly synergistic manner. The effect-site concentrations of sevoflurane and propofol at a PTOL of 50% (Ce50; se) were 2.59 (0.13) vol % and 7.58 (0.49) µg ml(-1). A CeREMI of 1.36 (0.15) ng ml(-1) reduced the Ce50 of sevoflurane and propofol by 50%. The common slope factor was 5.22 (0.52). The PTOL and NSRI predict the movement response to laryngoscopy best. CONCLUSIONS The triple interaction model estimates the potency of any combination of sevoflurane, propofol, and remifentanil expressed as either PTOL or NSRI.

Decreased number of acetylcholine receptors is the mechanism that alters the time course of muscle relaxants in myasthenia gravis: a study in a rat model

Background: In myasthenic patients, the time course of action of non‐depolarizing neuromuscular blocking agents is prolonged and the sensitivity is increased. We used our antegrade perfused rat peroneal nerve anterior tibialis muscle model to investigate if this altered time course of effect and sensitivity can be explained by the decreased acetylcholine receptor concentration that is caused by the disease. Methods: Functional acetylcholine receptors were reduced by administration of α‐bungarotoxin or by injecting monoclonal antibodies against rat acetylcholine receptors (experimental autoimmune myasthenia gravis). After induction of anaesthesia, the model was set up and perfusion of the tibialis anterior muscle with blood was started. After stabilization of the twitch, rocuronium or pancuronium were infused until 90% block was obtained. Twitch data and infusion data were recorded and used to calculate the time course of effect and potency. Results: The potency of neuromuscular blocking agents was increased and the offset of the neuromuscular block was prolonged in both the α‐bungarotoxin groups and the experimental autoimmune myasthenia gravis groups compared to controls. Conclusion: This study shows that the increased sensitivity to neuromuscular‐blocking agents in myasthenia gravis can be accounted for by a decreased number of acetylcholine receptors. It also shows that the antegrade perfused rat peroneal nerve anterior tibialis muscle model is a suitable model to study the effects of myasthenia gravis on the time course of effect of neuromuscular blocking agents.

Structure-Pharmacokinetic and Pharmacodynamic Relationships of Steroidal Neuromuscular Blocking Agents

In anesthesiology there is still a need for a short-acting non-depolarizing neuromuscular blocking agent (NMBA) for intubation, replacing the depolarizing agent suxamethonium. In order to find a rational basis for the development of new short-acting NMBA’s, it is essential to know the factors governing the time course of action of this class of drugs.

Pharmacokinetic-Pharmacodynamic Modelling of Anaesthetic Drugs

The aim of pharmacokinetic–pharmacodynamic (PKPD) modelling is to be able to predict the time course of clinical effect resulting from different drug administration regimens and to predict the influence of various factors such as body weight, age, gender, underlying pathology and co-medication, on the clinical effect.

Twitch Potentiation Influences the Time Course of Twitch Depression in Muscle Relaxant Studies: A Pharmacokinetic-Pharmacodynamic Explanation

The time course of twitch depression following neuromuscular blocking agent (NMBA) administration is influenced by the duration of control neuromuscular monitoring (twitch stabilization). The physiological mechanism for this interaction is not known. During twitch stabilization twitch response often increases to a plateau, this is known as twitch potentiation or the staircase phenomenon. Since twitch potentiation contributes to the observed twitch response it may also influence the time course of twitch depression following NMBA administration. Our objective was to estimate the degree that twitch potentiation influences the time course of twitch depression following NMBA administration under conditions typical for muscle relaxation studies. We used previousy described pharmacokinetic-pharmacodynamic (PK-PD) and twitch potentiation models to simulate twitch data. Simulations consisted of twitch stabilization followed by a NMBA bolus dose and subsequent onset and recovery from muscle relaxation. Twitch data were analyzed for onset and recovery characteristics and the results compared to clinical muscle relaxation studies in existing literature. We found that twitch potentiation likely plays a minor role in shortened onset time and increased duration of twitch depression observed with long periods of twitch stabilization.