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In acute and chronic pain, the objective of pharmacokinetic--pharmacodynamic (PKPD) modeling is the development and application of mathematical models to describe and/or predict the time course of the pharmacokinetics (PK) and pharmacodynamics (PD) of analgesic agents and link PK to PD. Performing population PKPD modeling using nonlinear mixed effects modeling allows, apart from the estimation of fixed effects (the PK and PD model estimates), the quantification of random effects as within- and between-subject variability. Effect-compartment models and mechanism-based biophase distribution models that incorporate drug-association and -dissociation kinetics are applied in PKPD modeling of pain treatment. Mechanism-based models enable the quantification of the rate-limiting factors in drug effect owing to drug distribution versus receptor kinetics (since receptor kinetics are nonlinear they are discernable from the linear effect-compartment kinetics). It is a helpful technique in understanding the complex behavior of specific analgesics, such as buprenorphine, but also morphine and its active metabolite morphine-6-glucuronide, especially with respect to the reversal of opioid-induced side effects, most importantly life-threatening respiratory depression. One approach in chronic pain studies is the application of mixture models. Mixture models do not necessarily need to take PK data into account and allow the objective differentiation of measured responses to analgesics into specific response subgroups, and as such, may play an important role in analyzing Phase I and II analgesia studies. Appropriate application of PKPD modeling leads to the improvement of current therapeutics with respect to dose design and outcome, understanding the interaction of analgesics within complex chronic pain disease processes and may play an important role in drug development. In the current article, novel observations using the aforementioned techniques on opioids, NSAIDs, epidural analgesia, ketamine and GABA-ergic drugs in acute and chronic pain are discussed. [ABSTRACT FROM AUTHOR]

Abstract: Aims: Pharmacological treatment of chronic (neuropathic) pain is often disappointing. In order to enhance our insight in the complex interaction between analgesic drug and chronic pain relief, we performed a pharmacokinetic–pharmacodynamic (PK–PD) modeling study on the effect of S(+)-ketamine on pain scores in Complex Regional Pain Syndrome type 1 (CRPS-1) patients. Methods: Sixty CRPS-1 patients were randomly allocated to received a 100-h infusion of S(+)-ketamine or placebo. The drug infusion rate was slowly increased from 5mg/h (per 70kg) to 20mg/h based upon the effect/side effect profile. Pain scores and drug blood samples were obtained during the treatment phase and pain scores were further obtained weekly for another 11weeks. A population PK–PD model was developed to analyze the S(+)-ketamine-pain data. Results: Plasma concentrations of S(+)-ketamine and its metabolite decreased rapidly upon the termination of S(+)-ketamine infusion. The chance for an analgesic effect from ketamine and placebo treatment was 67±10% and 23±9% (population value±SE), respectively. The pain data were well described by the PK–PD model with parameters C 50 =10.5±4.8ng/ml (95% ci 4.37–21.2ng/ml) and t½ for onset/offset=10.9±4.0days (5.3–20.5days). Discussion: Long-term S(+)-ketamine treatment is effective in causing pain relief in CRPS-1 patients with analgesia outlasting the treatment period by 50days. These data suggest that ketamine initiated a cascade of events, including desensitization of excitatory receptor systems in the central nervous system, which persisted but slowly abated when ketamine molecules were no longer present. [Copyright &y& Elsevier]

The article focuses on respiratory depression due to the use of opioids such as morphine, fentanyl and methadone. It states that despite the effectiveness of opioids as agents to alleviate pain during surgical operations, fatalities are still reported. It says that naloxone infusion is the treatment for opioid-induced respiratory depression however, its usage may lead to critical loss of analgesia resulting to difficulties in patient care. It mentions that pharmacodynamics and pharmacokinetics of opioids should be taken as important considerations in the treatment of respiratory depression. The actions of opioids against immune cells such as microglia and astrocytes as basis for drug development are also discussed.

To investigate the effect of cardiac output and liver blood flow on propofol concentrations in critically ill patients in the intensive care unit. Five medical/surgical critically ill patients were enrolled in this preliminary study. Liver blood flow was measured using sorbitol. The cardiac output was measured by bolus thermodilution. NONMEM ver. V was applied for propofol pharmacokinetic analysis. The clearance of propofol was positively influenced by the liver blood flow ( P < 0.005), whereas no significant correlation between cardiac output and propofol clearance was found. A correlation between liver blood flow and cardiac output or cardiac index could not be assumed in this patient group. Liver blood flow is a more predictive indicator than cardiac output for propofol clearance in critically ill patients when the techniques of hepatic sorbitol clearance and bolus thermodilution, respectively, are used. Further study is needed to determine the role played by liver blood flow and cardiac output on the pharmacokinetics of highly extracted drugs in order to reduce the observed high interindividual variabilities in response in critically ill patients. [ABSTRACT FROM AUTHOR]

Allometric equations have proven useful for the extrapolation of animal data to determine pharmacokinetic parameters in man. It has been proposed that these equations are also applicable over the human size range including the paediatric population. The aim of this work was to study the relationship between various pharmacokinetic parameters for propofol and body weight using data from rats, children and adults. Furthermore, the utility of allometric scaling is evaluated by the prediction of propofol concentrations in humans based on data obtained in the rat.The relationship between the pharmacokinetic parameters of propofol obtained in rats, children and adults was analyzed by plotting the logarithmically transformed parameters against the corresponding logarithmically transformed body weights. In addition, based on allometric equations, pharmacokinetic parameters obtained in rats were scaled to humans. These parameters were used to simulate propofol concentrations in long-term sedated critically ill patients using NONMEM. Simulated concentrations were then compared with actually observed concentrations in humans.The relationship between pharmacokinetic parameters of propofol from rats, children and adults was in good agreement with those from the literature on allometric modelling. For clearance, intercompartmental clearance, central volume of distribution and peripheral volume of distribution, the power parameters were 0.78, 0.73, 0.98 and 1.1, respectively, andr2 values for the linear correlations were 0.990, 0.983, 0.977 and 0.994, respectively. On the basis of data obtained after a single bolus injection in the rat, adequate predictions of propofol concentrations in critically ill patients can be made using allometric equations, despite the long-term nature of the use of the drug, the large number of infusion changes per day and/or differences in state of health and age.For propofol, allometric scaling has proved to be valuable for cross species extrapolation. Furthermore, the use of the allometric equation between adults and children seems to be an adequate tool for the development of rational dosing schemes for children of varying body weights, and requires further study. [ABSTRACT FROM AUTHOR]

Background: Ketamine has cardiac excitatory side-effects. Currently, data on the effects of ketamine and metabolite concentrations on cardiac output are scarce. We therefore developed a pharmacodynamic model derived from data from a randomised clinical trial. The current study is part of a larger clinical study evaluating the potential mitigating effect of sodium nitroprusside on the psychedelic effects of ketamine.Methods: Twenty healthy male subjects received escalating esketamine and racemic ketamine doses in combination with either placebo or sodium nitroprusside on four visits: (i) esketamine and placebo, (ii) esketamine and sodium nitroprusside, (iii) racemic ketamine and placebo, and (iv) racemic ketamine and sodium nitroprusside. During each visit, arterial blood samples were obtained and cardiac output was measured. Nonlinear mixed-effect modelling was used to analyse the cardiac output time-series data. Ketamine metabolites were added to the model in a sequential manner to evaluate the effects of metabolites.Results: A model including an S-ketamine and S-norketamine effect best described the data. Ketamine increased cardiac output, whereas modelling revealed that S-norketamine decreased cardiac output. No significant effects were detected for R-ketamine, metabolites other than S-norketamine, or sodium nitroprusside on cardiac output.Conclusions: S-Ketamine, but not R-ketamine, increased cardiac output in a dose-dependent manner. In contrast to S-ketamine, its metabolite S-norketamine reduced cardiac excitation in a dose-dependent manner.Clinical Trial Registration: Dutch Cochrane Center 5359. [ABSTRACT FROM AUTHOR]

Aims In order to avoid the potential for elevated serum lipid levels as a consequence of long term sedation with propofol, a formulation of propofol 6% in Lipofundin[sup ®] MCT/LCT 10% (Propofol 6% SAZN) has been developed. The pharmacokinetics, induction of anaesthesia and safety characteristics of this new formulation were investigated after bolus injection and were compared with the commercially available product (propofol 1% in Intralipid[sup ®] 10%, Diprivan[sup ®]-10) and propofol 1% in Lipofundin[sup ®] MCT/LCT 10% (Propofol 1% SAZN). Methods In a randomised double-blind study, 24 unpremedicated female patients received an induction dose of propofol of 2.5 mg kg[sup -1] over 60 s which was followed by standardized balanced anaesthesia. The patients were randomized to receive propofol as Propofol 6% SAZN, Propofol 1% SAZN or Diprivan[sup ®]-10. Results For all formulations the pharmacokinetics were adequately described by a tri-exponential equation, as the propofol concentrations collected early after the injection suggested an additional initial more rapid phase. The average values for clearance (CL), volume of distribution at steady-state (V[sub d,ss] ), elimination half-life (t[sub 1/2,z] ) and distribution half-life (t[sub 1/2,λ2]) observed in the three groups were 32±1.5 ml kg[sup -1] min[sup -1], 2.0±0.18 l kg[sup -1], 95±5.6 min and 3.4±0.20 min, respectively (mean±s.e.mean, n=24) and no significant differences were noted between the three formulations (P >0.05). The half-life of the additional initial distribution phase (t[sub 1/2,λ1] ) in all subjects ranged from 0.1 to 0.6 min. Anaesthesia was induced successfully and uneventfully in all cases, and the quality of induction was adequate in all 24 patients. The induction time did not vary between the three formulations and the average induction time observed in the three groups was 51±1.3 s which corresponded to an induction dos... [ABSTRACT FROM AUTHOR]

Background: Recent studies show activity of ketamine metabolites, such as hydroxynorketamine, in producing rapid relief of depression-related symptoms and analgesia. To improve our understanding of the pharmacokinetics of ketamine and metabolites norketamine, dehydronorketamine, and hydroxynorketamine, we developed a population pharmacokinetic model of ketamine and metabolites after i.v. administration of racemic ketamine and the S-isomer (esketamine). Pharmacokinetic data were derived from an RCT on the efficacy of sodium nitroprusside (SNP) in reducing the psychotomimetic side-effects of ketamine in human volunteers.Methods: Three increasing i.v. doses of esketamine and racemic ketamine were administered to 20 healthy volunteers, and arterial plasma samples were obtained for measurement of ketamine and metabolites. Subjects were randomised to receive esketamine/SNP, esketamine/placebo, racemic ketamine/SNP, and racemic ketamine/placebo on four separate occasions. The time-plasma concentration data of ketamine and metabolites were analysed using a population compartmental model approach.Results: The pharmacokinetics of ketamine and metabolites were adequately described by a seven-compartment model with two ketamine, norketamine, and hydroxynorketamine compartments and one dehydronorketamine compartment with metabolic compartments in-between ketamine and norketamine, and norketamine and dehydronorketamine main compartments. Significant differences were found between S- and R-ketamine enantiomer pharmacokinetics, with up to 50% lower clearances for the R-enantiomers, irrespective of formulation. Whilst SNP had a significant effect on ketamine clearances, simulations showed only minor effects of SNP on total ketamine pharmacokinetics.Conclusions: The model is of adequate quality for use in future pharmacokinetic and pharmacodynamic studies into the efficacy and side-effects of ketamine and metabolites.Clinical Trial Registration: Dutch Cochrane Center 5359. [ABSTRACT FROM AUTHOR]

Background: Opioids are potent painkillers but come with serious adverse effects ranging from addiction to potentially lethal respiratory depression. A variety of drugs with separate mechanisms of action are available to prevent or reverse opioid-induced respiratory depression (OIRD).Methods: The authors reviewed human studies on reversal of OIRD using models that describe and predict the time course of pharmacokinetics (PK) and pharmacodynamics (PD) of opioids and reversal agents and link PK to PD.Results: The PKPD models differ in their basic structure to capture the specific pharmacological mechanisms by which reversal agents interact with opioid effects on breathing. The effect of naloxone, a competitive opioid receptor antagonist, is described by the combined effect-compartment receptor-binding model to quantify rate limitation at the level of drug distribution and receptor kinetics. The effects of reversal agents that act through non-opioidergic pathways, such as ketamine and the experimental drug GAL021, are described by physiological models, in which stimulants act at CO2 chemosensitivity, CO2-independent ventilation, or both. The PKPD analyses show that although all reversal strategies may be effective under certain circumstances, there are conditions at which reversal is less efficacious and sometimes even impossible.Conclusions: Model-based drug development is needed to design an 'ideal' reversal agent-that is, one that is not influenced by opioid receptor kinetics, does not interfere with opioid analgesia, has a rapid onset of action with long-lasting effects, and is devoid of adverse effects. [ABSTRACT FROM AUTHOR]

The article focuses on a study which examined the effects of naloxone doses on morphine and morphine-6-glucuronide (M6G)-induced respiratory depression in healthy volunteers using a mechanism-based pharmacokinetic-pharmacodynamic modeling study. A total of 56 male and female volunteers were recruited for the study, 24 of which received morphine intravenously and 32 of which received M6G intravenously. The study observed that naloxone reversal of M6G-induced respiratory depression more slowly developed compared to the reversal of morphine's respiratory effect. It concluded that reversal of the opioid effect by naloxone is dependent on the receptor association-dissociation kinetics of the opioid which needs reversal.