Drug effects on the CVS in conscious rats: separating cardiac output into heart rate and stroke volume using PKPD modelling.

BACKGROUND AND PURPOSE: Previously, a systems pharmacology model was developed characterizing drug effects on the interrelationship between mean arterial pressure (MAP), cardiac output (CO) and total peripheral resistance (TPR). The present investigation aims to (i) extend the previously developed model by parsing CO into heart rate (HR) and stroke volume (SV) and (ii) evaluate if the mechanism of action (MoA) of new compounds can be elucidated using only HR and MAP measurements. EXPERIMENTAL APPROACH: Cardiovascular effects of eight drugs with diverse MoAs (amiloride, amlodipine, atropine, enalapril, fasudil, hydrochlorothiazide, prazosin and propranolol) were characterized in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats following single administrations of a range of doses. Rats were instrumented with ascending aortic flow probes and aortic catheters/radiotransmitters for continuous recording of MAP, HR and CO throughout the experiments. Data were analysed in conjunction with independent information on the time course of the drug concentration following a mechanism-based pharmacokinetic-pharmacodynamic modelling approach. KEY RESULTS: The extended model, which quantified changes in TPR, HR and SV with negative feedback through MAP, adequately described the cardiovascular effects of the drugs while accounting for circadian variations and handling effects. CONCLUSIONS AND IMPLICATIONS: A systems pharmacology model characterizing the interrelationship between MAP, CO, HR, SV and TPR was obtained in hypertensive and normotensive rats. This extended model can quantify dynamic changes in the CVS and elucidate the MoA for novel compounds, with one site of action, using only HR and MAP measurements. Whether the model can be applied for compounds with a more complex MoA remains to be established.

PKPD modelling of the interrelationship between mean arterial BP, cardiac output and total peripheral resistance in conscious rats.

BACKGROUND AND PURPOSE: The homeostatic control of arterial BP is well understood with changes in BP resulting from changes in cardiac output (CO) and/or total peripheral resistance (TPR). A mechanism-based and quantitative analysis of drug effects on this interrelationship could provide a basis for the prediction of drug effects on BP. Hence, we aimed to develop a mechanism-based pharmacokinetic-pharmacodynamic (PKPD) model in rats that could be used to characterize the effects of cardiovascular drugs with different mechanisms of action (MoA) on the interrelationship between BP, CO and TPR. EXPERIMENTAL APPROACH: The cardiovascular effects of six drugs with diverse MoA, (amlodipine, fasudil, enalapril, propranolol, hydrochlorothiazide and prazosin) were characterized in spontaneously hypertensive rats. The rats were chronically instrumented with ascending aortic flow probes and/or aortic catheters/radiotransmitters for continuous recording of CO and/or BP. Data were analysed in conjunction with independent information on the time course of drug concentration using a mechanism-based PKPD modelling approach. KEY RESULTS: By simultaneous analysis of the effects of six different compounds, the dynamics of the interrelationship between BP, CO and TPR were quantified. System-specific parameters could be distinguished from drug-specific parameters indicating that the model developed is drug-independent. CONCLUSIONS AND IMPLICATIONS: A system-specific model characterizing the interrelationship between BP, CO and TPR was obtained, which can be used to quantify and predict the cardiovascular effects of a drug and to elucidate the MoA for novel compounds. Ultimately, the proposed PKPD model could be used to predict the effects of a particular drug on BP in humans based on preclinical data.

Individualized dosing with anesthetic agents.

The development of fundamental pharmacokinetics and pharmacodynamics concepts has enabled anesthesiologists to choose and dose anesthetic agents on a rational basis. The application of these concepts to a variety of clinical scenarios and patient populations makes it possible to individualize the dose, thereby decreasing the risk of complications. As more knowledge is gained about the sometimes profound differences in drug response, empirical dosing such as in milligrams per kilogram of total body weight is disappearing from the anesthesia specialty.

Pharmacokinetics and pharmacodynamics of intravenously administered anesthetic drugs: concepts and lessons for drug development.

The drugs used in the clinical practice of anesthesiology, specifically the intravenously administered compounds that create the hypnotic aspect (unconsciousness) and the analgesic aspect (opiates) of an anesthetic, provide important insights into principles that can be applied to drug development in general. Additionally, research involving these drugs and their therapeutic applications has advanced some of the fundamental principles of pharmacokinetic (PK) and pharmacodynamic (PD) modeling. This article reviews several examples of anesthetic drugs used in clinical pharmacology and points out how they provide insights into methods of applying these modeling concepts to modern drug development in general.

Defining depth of anesthesia.

In this chapter, drawn largely from the synthesis of material that we first presented in the sixth edition of Miller's Anesthesia, Chap 31 (Stanski and Shafer 2005; used by permission of the publisher), we have defined anesthetic depth as the probability of non-response to stimulation, calibrated against the strength of the stimulus, the difficulty of suppressing the response, and the drug-induced probability of non-responsiveness at defined effect site concentrations. This definition requires measurement of multiple different stimuli and responses at well-defined drug concentrations. There is no one stimulus and response measurement that will capture depth of anesthesia in a clinically or scientifically meaningful manner. The "clinical art" of anesthesia requires calibration of these observations of stimuli and responses (verbal responses, movement, tachycardia) against the dose and concentration of anesthetic drugs used to reduce the probability of response, constantly adjusting the administered dose to achieve the desired anesthetic depth. In our definition of "depth of anesthesia" we define the need for two components to create the anesthetic state: hypnosis created with drugs such as propofol or the inhalational anesthetics and analgesia created with the opioids or nitrous oxide. We demonstrate the scientific evidence that profound degrees of hypnosis in the absence of analgesia will not prevent the hemodynamic responses to profoundly noxious stimuli. Also, profound degrees of analgesia do not guarantee unconsciousness. However, the combination of hypnosis and analgesia suppresses hemodynamic response to noxious stimuli and guarantees unconsciousness.

Contribuciones de la anestesiología al desarrollo clínico de nuevos fármacos / Lessons learned ind rug development from anesthesia

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Pharmacodynamics of orally administered sustained- release hydromorphone in humans.

BACKGROUND: The disposition kinetics of hydromorphone generally necessitates oral administration every 4 h of the conventional immediate-release tablet to provide sustained pain relief. This trial examined time course and magnitude of analgesia to experimental pain after administration of sustained-release hydromorphone as compared with that after immediate-release hydromorphone or placebo. METHODS: Using a 4 x 4 Latin square double-blind design, 12 subjects were randomized to receive a single dose of 8, 16, and 32 mg sustained-release hydromorphone and placebo. The same subjects had received 8 mg immediate-release hydromorphone before this study. Using an electrical experimental pain paradigm, analgesic effects were assessed for up to 30 h after administration, and venous hydromorphone plasma concentrations were measured at corresponding times. RESULTS: The hydromorphone plasma concentration peaked significantly later (12.0 h [12.0--18.0] vs. 0.8 h [0.8--1.0]; median and interquartile range) but was maintained significantly longer at greater than 50% of peak concentration (22.7 +/- 8.2 h vs. 1.1 +/- 0.7 h; mean +/- SD) after sustained-release than after immediate-release hydromorphone. Similarly, sustained-release hydromorphone produced analgesic effects that peaked significantly later (9.0 h [9.0--12.0] vs. 1.5 h [1.0--2.0]) but were maintained significantly longer at greater than 50% of peak analgesic effect (13.3 +/- 6.3 h vs. 3.6 +/- 1.7 h). A statistically significant linear relation between the hydromorphone plasma concentration and the analgesic effect on painful stimuli existed. CONCLUSION: A single oral dose of a new sustained-release formulation of hydromorphone provided analgesia to experimental pain beyond 24 h of its administration.

Lumbar epidural morphine in humans and supraspinal analgesia to experimental heat pain.

BACKGROUND: Epidural administration of morphine is a common analgesic technique to manage pain. Morphine spreads from the epidural space to the cerebrospinal fluid and then rostrally, causing side effects mediated by the brain stem. However, data on the rostral spread of morphine-mediated analgesia are sparse. This study examined the rostral spread of analgesic effects on heat and electrical pain after epidural administration of morphine. METHODS: In a randomized, double-blinded, placebo-controlled, crossover study, 5 mg morphine or saline placebo were injected into the lumbar epidural space in nine healthy volunteers. Correct needle placement was confirmed with fluoroscopy. Analgesia to experimental nociceptive heat and electrical stimuli was measured at lumbar (L4), thoracic (T10), cervical (C2), and trigeminal (V2) levels before and 2, 5, 10, and 24 h after epidural injection. Plasma samples for assaying morphine concentrations were drawn before and after each analgesic evaluation. RESULTS: Epidural morphine significantly attenuated experimental heat pain at all dermatomes tested compared with saline placebo. Analgesic effects were significant at L4 after 2, 5, and 10 h, at T10 after 5, 10, and 24 h, and at V2 after 10 h. Electrical pain was attenuated at the lumbar and thoracic but not at the cervical dermatome. Analgesic effects were significant at L4 after 2, 5, and 10 h and at T10 after 5 and 10 h. Morphine plasma concentrations were below the detection limit (1 ng/ml) in eight of the nine subjects 10 h after epidural injection. CONCLUSIONS: Lumbar epidural injection of morphine attenuated cutaneous heat pain up to the trigeminal dermatome during a 24-h observation period. In a clinical context, this implies that some types of pain may be attenuated up to the supraspinal level after lumbar epidural administration of morphine.

Application of physiologic models to predict the influence of changes in body composition and blood flows on the pharmacokinetics of fentanyl and alfentanil in patients.

BACKGROUND: The influence of changes in the physiologic state of a patient on the disposition of fentanyl and alfentanil is poorly understood. The aims of this study were to determine whether physiologic pharmacokinetic models for fentanyl and alfentanil, based on data from rats, could predict plasma concentrations of these opioids in humans and to determine how changes in physiology would influence the predictions of their disposition. METHODS: The predictions of the models were tested against plasma concentration data from published pharmacokinetic studies. The influences of changes in body composition, cardiac output, and regional blood flows on the disposition of the opioids were simulated. RESULTS: The models could predict independently measured plasma concentrations of the opioids after short infusions in humans. Simulations then predicted that differences in body composition between men and women would have little influence on the pharmacokinetics of the opioids. Changes in cardiac output would affect drug redistribution, and consequently the early decay of the plasma concentrations, but not markedly influence rates of elimination. Further, the clearance of the opioids would decrease and their volumes of distribution increase with the age of the patient, but this would only marginally affect the early disposition of the drugs. Even large fluctuations in peripheral or hepatic blood flows would have modest effects on arterial plasma concentrations of the opioids, and sudden "postoperative" increases in peripheral blood flows would cause minor secondary plasma concentration peaks. CONCLUSIONS: The ability of the physiologic models to predict plasma concentrations of fentanyl and alfentanil in humans was confirmed. When changes in physiologic condition were simulated, effects on the pharmacokinetics of the opioids with possible implications for dosing were obtained only if cardiac output was varied over a wide range.

Computer simulation of the effects of alterations in blood flows and body composition on thiopental pharmacokinetics in humans.

BACKGROUND: Understanding the influence of physiological variables on thiopental pharmacokinetics would enhance the scientific basis for the clinical usage of this anesthetic. METHODS: A physiological pharmacokinetic model for thiopental previously developed in rats was scaled to humans by substituting human values for tissue blood flows, tissue masses, and elimination clearance in place of respective rat values. The model was validated with published serum concentration data from 64 subjects. The model was simulated after intravenous thiopental administration, 250 mg, over 1 min, to predict arterial plasma concentrations under conditions of different cardiac outputs, degrees of obesity, gender, or age. RESULTS: The human pharmacokinetic model is characterized by a steady state volume of distribution of 2.2 l/kg, an elimination clearance of 0.22 l/min, and a terminal half-life of 9 h. Measured thiopental concentrations are predicted with an accuracy of 6 +/- 37% (SD). Greater peak arterial concentrations are predicted in subjects with a low versus a high cardiac output (3.1 and 9.4 l/min), and in subjects who are lean versus obese (56 and 135 kg). Acutely, obesity influences concentrations because it affects cardiac output. Prolonged changes are due to differences in fat mass. Changes with gender and age are relatively minor. CONCLUSIONS: The physiological pharmacokinetic model developed in rats predicts thiopental pharmacokinetics in humans. Differences in basal cardiac output may explain much of the variability in early thiopental disposition between subjects.

No effect of age on the dose requirement of thiopental in the rat.

With increasing human age (20-80 years), the electroencephalogram (EEG) dose requirement for the intravenous anesthetic thiopental decreases approximately 10% per decade of life. The goal of this study was to compare the dose required to attain isoelectric EEG in young (4-5 month) vs. aged (24-25-month) Fischer 344 rats. One second isoelectricity was found to be an endpoint where minimal cardiorespiratory depression occurred. The effects of age, infusion rate, and repeated administration were examined in nine young and nine old rodents. Thiopental dose requirement increased with increasing infusion rates. Repeated administration at two-day intervals did not demonstrate tolerance to thiopental. No difference in thiopental dose requirement was detected in the young vs. elderly rats. In a separate group of five young and five old rats, thiopental plasma, brain, heart, and CSF concentrations were measured when five seconds of EEG isoelectricity was achieved: no consistent differences were noted. The rat may not be an appropriate model to investigate acute age-related anesthetic effects in humans, because cardiovascular changes with age are dissimilar between species.

A comparison of spectral edge, delta power, and bispectral index as EEG measures of alfentanil, propofol, and midazolam drug effect.

BACKGROUND: The effects of anesthetic drugs on electroencephalograms (EEG) have been studied to develop the EEG as a measure of anesthetic depth. Bispectral analysis is a new quantitative technique that measures the consistency of the phase and power relationships and returns a single measure, the bispectral index. The purpose of this study was to compare the performance of the bispectral index, version 1.1, with other spectral analysis EEG measures of drug effect for three commonly used anesthetic drugs. METHODS: The EEG waveforms from 31 adults receiving infusions of alfentanil, propofol, or midazolam were analyzed. The time course of spectral edge (SE95), relative power in delta band, and bispectral index were related to the estimated effect-site concentration with use of a sigmoidal Emax model to estimate the potency (IC50) and the plasma effect-site equilibration rate constant (Ke0) for each measure. The performance of the fitting was assessed by the coefficient of correlation between predicted and observed effect. RESULTS: Alfentanil induced a high-amplitude low-frequency EEG response. Propofol induced a biphasic response. At low concentrations, both frequency and amplitude increased. When the concentration increased, the EEG slowed and the amplitude decreased. High concentration produced burst suppression. Midazolam increased EEG frequency and amplitude. Bispectral index, SE95, and delta power yield similar estimates of IC50 and ke0. Except for alfentanil, the performance of the modeling with the bispectral index was as good that with SE95 or delta power. CONCLUSION: Bispectral analysis can be used as a measure of the EEG effects of anesthetic drugs.

Pharmacokinetic-pharmacodynamic characterization of the cardiovascular, hypnotic, EEG and ventilatory responses to dexmedetomidine in the rat.

This study characterizes the pharmacokinetic-pharmacodynamic (PK-PD) relationships of the cardiovascular, EEG, hypnotic and ventilatory effects of the alpha-2 adrenergic agonist dexmedetomidine in rats. Dexmedetomidine was administered by a single rapid infusion (n = 6) and by an infusion regimen of gradually increasing rate (n = 8). HR, mean arterial pressure (MAP) and EEG signals were recorded continuously, as was the time at which the rats woke up spontaneously from drug-induced sleep, a measure of hypnosis. Arterial concentrations of dexmedetomidine and blood gases were determined regularly. A sigmoidal Emax model was used to describe the HR, MAP and EEG concentration-effect relationships, with the EEG effect (activity in 0.5-3.5-Hz frequency band) linked to an effect-site model. The PK of dexmedetomidine could be described by a two-compartment model, with similar PK parameters for both infusion regimens. Plasma protein binding was 84.1[0.7]%. Because of complex cardiovascular homeostatic reflex mechanisms, HR and MAP could only be analyzed during gradually increasing infusions. The maximal decrease in HR was 35(2)%, and the maximal increase in MAP was 37(2)%. For both infusion regimens, similar PD parameters were found for the EEG and the hypnotic measure. These data suggest the absence of active metabolites or tolerance of the EEG and hypnotic effects. Judging on the basis of concentrations of dexmedetomidine (mean (S.E. M.)), HR decrease was the most sensitive response [EC50 of 0.65(0. 09) ng/ml], followed by increase in MAP [EC50 of 2.01(0.14) ng/ml], change in EEG activity [EC50 of 2.24(0.16) ng/ml] and the hypnotic measure [Cwake-up of 2.64(0.10) ng/ml]. Ventilatory effects were minor.

Characterization and validation of a pharmacokinetic model for controlled-release oxycodone.

1. Oxycodone is a strong opioid agonist that is currently available in immediate-release (IR) formulations for the treatment of moderate to severe pain. Recently, controlled-release (CR) oxycodone tablets were developed to provide the benefits of twice-a-day dosing to patients treated with oxycodone. The purpose of this investigation was to develop and validate a pharmacokinetic model for CR oxycodone tablets in comparison with IR oxycodone solution. 2. Twenty-four normal male volunteers were enrolled in a single-dose, randomized, analytically blinded, two-way crossover study designed to compare the pharmacokinetics of two 10 mg CR oxycodone tablets with 20 mg IR oxycodone oral solution. Pharmacokinetic models describing the oxycodone plasma concentration vs time profiles of CR tablets and IR solution were derived using NONMEM version IV. The predictive performance of the models was assessed by comparison of predicted oxycodone plasma concentrations with actual oxycodone plasma concentrations observed in a separate group of 21 volunteers who received repeated doses of IR and CR oxycodone for 4 days. 3. The unit impulse disposition function of oxycodone was best described by a one-compartment model. Absorption rate of the IR solution was best described by a mono-exponential model with a lag time, whereas absorption rate of the CR tablet was best described using a bi-exponential model. The absorption profile of the CR tablets was characterized by a rapid absorption component (t1/2abs = 37 min) accounting for 38% of the available dose and a slow absorption phase (t1/2abs = 6.2 h) accounting for 62% of the available dose. Two 10 mg tablets of oral CR oxycodone hydrochloride were 102.7% bioavailable relative to 20 mg of IR oxycodone hydrochloride oral solution. The population model derived after administration of a single dose accurately predicted both the mean and range of oxycodone concentrations observed during 4 days of repeated dosing. The mean prediction error was 2.7% with a coefficient of variation of 54%. 4. The absorption characteristics of CR oxycodone tablets should allow effective plasma concentrations of oxycodone to be reached quickly and for effective concentrations to be maintained for a longer period after dosing compared with the IR oral solution. The CR dosage form has pharmacokinetic characteristics that permit 12 hourly dosing.

Population pharmacodynamic model for ketorolac analgesia.

OBJECTIVE: To derive a population pharmacokinetic-pharmacodynamic model that characterizes the distribution of pain relief scores and remedication times observed in patients receiving intramuscular ketorolac for the treatment of moderate to severe postoperative pain. BACKGROUND: The data analysis approach deals with the complexities of analyzing analgesic trial data: (1) repeated measurements, (2) ordered categorical response variables, and (3) nonrandom censoring because the patients can take a rescue medication if their pain relief is insufficient. METHODS: Patients (n = 522) received a single oral or intramuscular administration of placebo or a single intramuscular dose of 10, 30, 60, or 90 mg ketorolac for postoperative pain relief. Pain relief was measured periodically with use of a five-category ordinal scale up to 6 hours after dosing. In this period, 288 patients received additional medication because of insufficient pain relief. Pharmacokinetic data was available for 85 subjects. Models were fitted to the data with the NONMEM program. RESULTS: The pharmacokinetic data was best described by a two-compartment model with first-order absorption. Pain relief was found to be a function of drug concentration (Emax model), time (waxing and waning of placebo effect), and an individual random effect. The drug concentration at half-maximal effect (EC50) and the first-order rate constant (keo) half-life for pain relief were 0.37 mg/L and 24 minutes. The probability of remedication was found to be a function of the observed level of pain relief and was found to increase with time. Monte Carlo simulations showed that adequate pain relief was achieved in 50% of the patients at 41, 27, 23, and 21 minutes after 10, 30, 60, or 90 mg of intramuscular ketorolac. Adequate pain relief was maintained up to 6 hours in 50%, 70%, 78%, and 81% of patients after these four doses. Only 25% of the patients achieved adequate pain relief with placebo. CONCLUSIONS: A population pharmacokinetic-pharmacodynamic model for the analgesic efficacy of intramuscular ketorolac was derived. The simulated relationship between dose, time, and percentage of patients with adequate pain relief suggested that 30 mg intramuscular ketorolac was the optimal initial dose for postoperative pain relief.

Thiopental uncouples hippocampal and cortical synchronized electroencephalographic activity.

BACKGROUND: Thiopental produces a concentration-dependent continuum of effects on the cortical electroencephalogram (EEG) that has been linked to behavioral measures of anesthetic depth. The complexity of the response, however, limits a clear insight into the neurophysiologic actions of thiopental. The current study investigated thiopental actions on cortical EEG and hippocampal electrical activity, to determine whether similar effects occur on both structures and to compare synchronized activity between these structures. METHODS: Thiopental was administered intravenously via an implanted catheter in freely moving rats. Arterial blood oxygen/carbon dioxide concentration, thiopental concentrations, and temperature were monitored and controlled. Neocortical EEG was recorded from implanted dural surface electrodes and hippocampal neuron electrical activity was recorded from stereotaxically placed microelectrodes. Pharmacokinetic models were used to determine effect site concentrations. RESULTS: Thiopental produced an increase in EEG frequency and amplitude at low concentrations (15-20 micrograms/ml total plasma, approximately 10 microM unbound), which produced a loss of righting reflex. This was followed by a frequency decrease and burst suppression activity at higher concentrations (50-80 micrograms/ml, approximately 60 microM), which produced a loss of tail pinch and corneal reflexes. Higher concentrations of thiopental ( > 60 micrograms/ml) uncoupled synchronized burst discharges recorded in hippocampus and cortex. Isoelectric EEG activity was associated with concentrations of 70-90 micrograms/ml (approximately 80 microM) and a deep level of anesthesia; motor reflexes were abolished, although cardiovascular reflexes remained. In all frequency bands, similar concentration-EEG effect relationships were observed for cortical and hippocampal signals, only differing in the magnitude of response. A reversed progression of effects was observed on recovery. CONCLUSIONS: The results confirm earlier findings in humans and animals and demonstrate that both the hippocampus and neocortex exhibit burst suppression and isoelectric activity during thiopental anesthesia. Thiopental-induced synchronized burst activity was depressed by progressively higher concentrations. The lost synchronization suggests a depression of synaptic coupling between cortical structures contributes to anesthesia.

Comparative absorption kinetics of intramuscular midazolam and diazepam.

PURPOSE: This study investigates the rate and extent of absorption following intramuscular injection of midazolam and diazepam. METHODS: Four healthy male volunteers were recruited in this randomized three-way cross-over study. On one occasion each subject received simultaneous im injections of 5 mg midazolam and 10 mg diazepam in separate deltoid muscles. On two other separate occasions each subject received an iv infusion of 7.5 mg midazolam and 30 mg diazepam over five minutes. Frequent arterial blood samples were collected for up to two hours and venous blood samples were collected for up to 24 hours for midazolam and ten days for diazepam. A gas chromatography assay was used to determine the plasma concentrations of midazolam and diazepam. The im absorption profiles were estimated using constrained least-squares deconvolution. RESULTS: There were substantial intersubject variabilities in the estimated pharmacokinetic parameters (volume and clearances) of intravenous midazolam and diazepam. The mean (+/-sd) time to peak plasma concentration (Cmax) was shorter for im midazolam (17.5 +/- 6.5 min) relative to diazepam (33.8 +/- 7.5 min). The mean (+sd) time to peak absorption rate was also shorter for midazolam (9 +/- 2 vs 13.8 +/- 7.5 min). The peak rate of absorption was identical (0.18 mg. min-1) and bioavailability was 1.0 for both drugs. CONCLUSIONS: We conclude that midazolam has more rapid absorption than diazepam following im administration.