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

Population pharmacodynamic modeling using the sigmoid E-max model : influence of inter-individual variability on the steepness of the concentration-effect relationship : a simulation study

The relationship between the concentration of a drug and its pharmacological effect is often described by empirical mathematical models. We investigated the relationship between the steepness of the concentration-effect relationship and inter-individual variability (IIV) of the parameters of the sigmoid E-max model, using the similarity between the sigmoid E-max model and the cumulative log-normal distribution. In addition, it is investigated whether IIV in the model parameters can be estimated accurately by population modeling. Multiple data sets, consisting of 40 individuals with 4 binary observations in each individual, were simulated with varying values for the model parameters and their IIV. The data sets were analyzed using Excel Solver and NONMEM. An empirical equation (Eq. (11)) was derived describing the steepness of the population-predicted concentration-effect profile (gamma*) as a function of gamma and IIV in C50 and gamma, and was validated for both binary and continuous data. The tested study design is not suited to estimate the IIV in C50 and gamma with reasonable precision. Using a naive pooling procedure, the population estimates gamma* are significantly lower than the value of gamma used for simulation. The steepness of the population-predicted concentration-effect relationship (gamma*) is less than that of the individuals (gamma). Using gamma*, the population-predicted drug effect represents the drug effect, for binary data the probability of drug effect, at a given concentration for an arbitrary individual

A response surface model approach for continuous measures of hypnotic and analgesic effect during sevoflurane-remifentanil interaction: quantifying the pharmacodynamic shift evoked by stimulation

Background: The authors studied the interaction between sevoflurane and remifentanil on bispectral index (BIS), state entropy (SE), response entropy (RE), Composite Variability Index, and Surgical Pleth Index, by using a response surface methodology. The authors also studied the influence of stimulation on this interaction. Methods: Forty patients received combined concentrations of remifentanil (0 to 12 ng/ml) and sevoflurane (0.5 to 3.5 vol%) according to a crisscross design (160 concentration pairs). During pseudo–steady-state anesthesia, the pharmacodynamic measures were obtained before and after a series of noxious and nonnoxious stimulations. For the “prestimulation” and “poststimulation” BIS, SE, RE, Composite Variability Index, and Surgical Pleth Index, interaction models were applied to find the best fit, by using NONMEM 7.2.0. (Icon Development Solutions, Hanover, MD). Results: The authors found an additive interaction between sevoflurane and remifentanil on BIS, SE, and RE. For Composite Variability Index, a moderate synergism was found. The comparison of pre- and poststimulation data revealed a shift of C50SEVO for BIS, SE, and RE, with a consistent increase of 0.3 vol%. The Surgical Pleth Index data did not result in plausible parameter estimates, neither before nor after stimulation. Conclusions: By combining pre- and poststimulation data, interaction models for BIS, SE, and RE demonstrate a consistent influence of “stimulation” on the pharmacodynamic relationship between sevoflurane and remifentanil. Significant population variability exists for Composite Variability Index and Surgical Pleth Index

Comparison of haemodynamic- and electroencephalographic-monitored effects evoked by four combinations of effect-site concentrations of propofol and remifentanil, yielding a predicted tolerance to laryngoscopy of 90%

This prospective study evaluates haemodynamic and electroencephalographic effects observed when administering four combinations of effect-site concentrations of propofol (Ce-PROP) and remifentanil (Ce-REMI), all yielding a single predicted probability of tolerance of laryngoscopy of 90% (P-TOL = 90%) according to the Bouillon interaction model. We aimed to identify combinations of Ce-PROP and Ce-REMI along a single isobole of P-TOL that result in favourable hypnotic and haemodynamic conditions. This knowledge could be of advantage in the development of drug advisory monitoring technology. 80 patients (18-90 years of age, ASA I-III) were randomized into four groups and titrated towards Ce-PROP (Schnider model, ug.ml(-1)) and Ce-REMI (Minto model, ng.ml(-1)) of respectively 8.6 and 1, 5.9 and 2, 3.6 and 4 and 2.0 and 8. After eleven minutes of equilibration, baseline measurements of haemodynamic endpoints and bispectral index were compared with three minutes of responsiveness measurements after laryngoscopy. Before laryngoscopy, bispectral index differed significantly (p < 0.0001) between groups in concordance with Ce-PROP. Heart rate decreased with increasing Ce-REMI (p = 0.001). The haemodynamic and arousal responses evoked by laryngoscopy were not significantly different between groups, but Ce-PROP = 3.6 mu g.ml(-1) and Ce-REMI = 4 ng.ml(-1) evoked the lowest median value for increment HR and increment SAP after laryngoscopy. This study provides clinical insight on the haemodynamic and hypnotic consequences, when a model based predicted P-TOL is used as a target for combined effect-site controlled target- controlled infusion of propofol and remifentanil. Heart rate and bispectral index were significantly different between groups despite a theoretical equipotency for P-TOL, suggesting that each component of the anaesthetic state (immobility, analgesia, and hypnotic drug effect) should be considered as independent neurophysiological and pharmacological phenomena. However, claims of (in)accuracy of the predicted P-TOL must be considered preliminary because larger numbers of observations are required for that goal

Pharmacokinetic-pharmacodynamic modeling of severity levels of extrapyramidal side effects with markov elements

A major problem in the treatment of schizophrenic patients with current antipsychotic drugs, mainly acting as dopamine-2 receptor antagonists, is the occurrence of side effects such as extrapyramidal symptoms (EPS). Meta-analyses of summary data of EPS occurrence, and receptor occupancies inferred from mean plasma concentrations, have shown the incidence of EPS to rise when receptor occupancy is above ~80%. In this analysis, individual longitudinal EPS data from 2,630 patients participating in one of seven different trials and treated with haloperidol, paliperidone, ziprasidone, olanzapine, JNJ-37822681, or placebo were analyzed using a continuous time probability model with Markov elements. The developed pharmacokinetic-pharmacodynamic model describes the longitudinal changes of spontaneously reported EPS-related adverse events and their severity levels rated by clinicians. Individual steady-state concentrations and occupancy levels were found to be predictors for EPS. The results confirm 80% occupancy as a level of increased EPS occurrence rates, also at the individual level.CPT: Pharmacometrics & Systems Pharmacology (2012) 1, e1; doi:10.1038/psp.2012.9; advance online publication 26 September 2012

An Isolated, Antegrade, Perfused, Peroneal Nerve Anterior Tibialis Muscle Model in the Rat A Novel Model Developed to Study the Factors Governing the Time Course of Action of Neuromuscular Blocking Agents

Background: A model of an antegrade, perfused, isolated rat peroneal nerve anterior tibial muscle was developed to study potentially important factors governing the time course of action of (nondepolarizing) neuromuscular blocking agents such as concentration, blood flow, and temperature. The model allows observation of the effects of selective changes in these factors. Methods: The authors isolated the anterior tibial muscle and cannulated the anterior tibial artery and vein, providing a way for single-pass perfusion with blood from a donor rat. A force transducer was connected to the tibialis anterior muscle and a stimulator was connected to the tibial nerve. The influence of intrinsic potency (EC 90 ) and muscle blood flow rate on the time course of pancuronium and rocuronium was investigated. Results: The model remained stable for at least 4 h with respect to twitch height, muscle structure and function, and blood chemistry. Doubling the muscle-blood flow resulted in a significantly faster onset and offset for both pancuronium and rocuronium. Trebling the intrinsic potency (EC 90 ) was not associated with significant changes in the time course of action of the relaxants. Conclusion: The authors developed and validated a model that allows us to study biophase kinetics of neuromuscular blocking agents in the anterior tibial muscle of the rat. In this model, muscle-blood flow rather than EC 90 appears to predominantly determine the onset and offset time of nondepolarizing muscle relaxants

Biological Activity of CXCL8 Forms Generated by Alternative Cleavage of the Signal Peptide or by Aminopeptidase-Mediated Truncation

Posttranslational modification of chemokines is one of the mechanisms that regulate leukocyte migration during inflammation. Multiple natural NH(2)-terminally truncated forms of the major human neutrophil attractant interleukin-8 or CXCL8 have been identified. Although differential activity was reported for some CXCL8 forms, no biological data are available for others.status: publishe

Long-term exposure to circulating platinum is associated with late effects of treatment in testicular cancer survivors

BACKGROUND: The success of cisplatin-based (Platinol, Bristol-Myers Squibb Company, New York, NY, USA) chemotherapy for testicular cancer comes at the price of long-term and late effects related to healthy tissue damage. We assessed and modelled serum platinum (Pt) decay after chemotherapy and determined relationships between long-term circulating Pt levels and known late effects. PATIENTS AND METHODS: In 99 testicular cancer survivors, treated with cisplatin-based chemotherapy, serum and 24-h urine samples were collected during follow-up (1–13 years after treatment). To build a population pharmacokinetic model, measured Pt data were simultaneously analysed, together with cisplatin dose, age, weight and height using the NONMEM software. Based on this model, area under the curve between 1 and 3 years after treatment (Pt AUC(1–3 years)) was calculated for each patient. Predicted long-term Pt exposure was related to renal function and to late effects of treatment assessed median 9 (3–15) years after chemotherapy. RESULTS: Decay of Pt was best described by a two-compartment model. Mean terminal T(1/2) was 3.7 (range 2.5–5.2) years. Pt AUC(1–3 years) correlated with cumulative cisplatin dose, and creatinine clearance before and 1 year after treatment. Patients with paraesthesia had higher Pt AUC(1–3 years) (30.9 versus 27.0 µg/l month) compared with those without paraesthesia (P = 0.021). Patients with hypogonadism, elevated LDL-cholesterol levels or hypertension also had higher Pt AUC(1–3 years). CONCLUSIONS: Renal function before and after cisplatin treatment is an important determinant of long-term Pt exposure. Known long-term effects of testicular cancer treatment, such as paraesthesia, hypogonadism, hypercholesterolaemia and hypertension, are associated with long-term circulating Pt exposure

Cathelicidin-BF, a Snake Cathelicidin-Derived Antimicrobial Peptide, Could Be an Excellent Therapeutic Agent for Acne Vulgaris

Cathelicidins are a family of antimicrobial peptides acting as multifunctional effector molecules in innate immunity. Cathelicidin-BF has been purified from the snake venoms of Bungarus fasciatus and it is the first identified cathelicidin antimicrobial peptide in reptiles. In this study, cathelicidin-BF was found exerting strong antibacterial activities against Propionibacterium acnes. Its minimal inhibitory concentration against two strains of P. acnes was 4.7 µg/ml. Cathelicidin-BF also effectively killed other microorganisms including Staphylococcus epidermidis, which was possible pathogen for acne vulgaris. Cathelicidin-BF significantly inhibited pro-inflammatory factors secretion in human monocytic cells and P. acnes-induced O2.− production of human HaCaT keratinocyte cells. Observed by scanning electron microscopy, the surfaces of the treated pathogens underwent obvious morphological changes compared with the untreated controls, suggesting that this antimicrobial peptide exerts its action by disrupting membranes of microorganisms. The efficacy of cathelicidin-BF gel topical administering was evaluated in experimental mice skin colonization model. In vivo anti-inflammatory effects of cathelicidin-BF were confirmed by relieving P. acnes-induced mice ear swelling and granulomatous inflammation. The anti-inflammatory effects combined with potent antimicrobial activities and O2.− production inhibition activities of cathelicidin-BF indicate its potential as a novel therapeutic option for acne vulgaris