Comparative pharmacodynamic modeling of desflurane, sevoflurane and isoflurane

Background  

We compared dose–response curves of the hypnotic effects of desflurane, sevoflurane and isoflurane. In addition, we analyzed the k_e0 values of the different anesthetics. The EEG parameters Bispectral index (BIS, Aspect Medical Systems, Natick, MA, version XP) and Narcotrend index (MonitorTechnik, Bad Bramstedt, Germany, version 4.0) were used as measures of the pharmacodynamic effect.     

The Correlation of the Bispectral Index with Propofol Effect Site Concentrations is not Altered by Epochs Indicated as Artefact-Loaded by Narcotrend

Objective. Artefact detection is an essential feature of automatic EEG monitoring systems used in anaesthesia. Clinical experience indicates that Narcotrend monitoring (MonitorTechnik, Bad Bramstedt, Germany, version 4.0) excludes more EEG epochs because of artefacts than bispectral index monitoring (BIS, Aspect Medical Systems, Newton, MA, version XP). Whether this increased exclusion of epochs is justified has not been investigated yet. Methods. Eighteen adult patients undergoing radical prostatectomy were investigated. Induction of anaesthesia was performed with a fentanyl bolus and a propofol infusion. Additionally, following intubation patients received 15 ml bupivacaine 0.5% epidurally. After a waiting period of 45 min depth of anaesthesia was varied two times by increasing and decreasing propofol concentrations. Narcotrend index, BIS values and calculated propofol effect site concentrations were automatically recorded at intervals of 5 s. We tested the hypothesis whether exclusion of artefacts detected by the Narcotrend monitor would possibly improve the prediction probability of the BIS monitor, justifying the necessity of artefact suppression. Results. Simulated propofol effect site concentrations ranged from 2 μ g/ml to 6 μ g/ml. The Narcotrend monitor excluded a significantly higher percentage of epochs because of artefact detection (12.6 ± 1.0%) than the BIS monitor (0.4 ± 0.1%). The performance of BIS as an indicator of predicted propofol effect site concentrations did not differ when including (P _K = 0.86 ± 0.05) or excluding (P _K = 0.85 ± 0.04) the data pairs where Narcotrend monitor but not BIS monitor indicated an artefact. Artefacts were evenly distributed over the investigated range of propofol effect site concentrations. Conclusion. Exclusion of data pairs that were detected as artefacts by Narcotrend but not by BIS did not change the performance of bispectral index as an indicator of propofol effect site concentration. Ellerkmann RK, Kreuer S, Wilhelm W, Wenningmann I, Roepcke H, Hoeft A, Bruhn J. The correlation of the bispectral index with propofol effect site concentrations is not altered by epochs indicated as artefactloaded by narcotrend     

Correlation Of Bispectral Index With Glasgow Coma Score In Mild And Moderate Head Injuries

Background Bispectral Index (BIS) derived from electroencephalogram (EEG) is primarily developed to monitor the depth of unconsciousness. Recent evidence suggests that BIS may also help in the detection of cerebral ischemia and prognostication of outcome of traumatic brain injury (TBI). The present study was designed to investigate the correlation between Glasgow Coma Score (GCS) and BIS in mild and moderate head injury.Methods In 29 patients with mild (GCS 13–15) and moderate (GCS 9–12) head injuries who underwent craniotomy, GCS and BIS were measured before surgery, after surgery and once a day for the first 10 days.Results A significant correlation was found between GCS and BIS in the data sets from all the patients (r = 0.67; p < 0.001). Mean BIS values increased with increasing GCS scores. However, the scatter of BIS values for any GCS score was high limiting the value of BIS in predicting GCS. Mean BIS values were significantly different between mild and moderate head injuries [65.7 ± 16.1 vs. 85.7 ± 6.1, p = 0.006].Conclusion In patients with mild and moderate head injury, significant correlation exists between GCS and BIS. But the high degree of scatter of BIS values for any given GCS score limits its use as a monitor of depth of coma in TBI. Further studies are required to understand the relation between BIS algorithm and cerebral electrical activity following TBI to define the role of BIS as an electrophysiological correlate of consciousness in TBI.The study was conducted with institutional resources only and no external funding was received.Paul DB, Rao GSU. Correlation of bispectral index with glasgow coma score in mild and moderate head injuries.     

Investigation of PK–PD drug–drug interaction between acenocoumarol and amoxicillin plus clavulanic acid

A pharmacokinetic–pharmacodynamic (PK–PD) drug–drug interaction between acenocoumarol and amoxicillin + clavulanic acid antibiotic was assessed in eight healthy volunteers, using a population PK–PD) model. Each subject received at day 1 a single dose of 8 mg of acenocoumarol. Then 1 g of amoxicillin + 250 mg of clavulanic acid was given from days 3 to 9. On day 8, each subject received a single dose of 8 mg of acenocoumarol concomitantly with the antibiotic combination. Eleven blood samples were taken during 48 h following each acenocoumarol administration. Acenocoumarol plasma concentrations and prothrombin time were measured at each sampling time. We first identified the structural PK model by pooling data from this trial with individual data from other acenocoumarol PK trials. An indirect response model was used to fit PD data. Models were built using a non-linear mixed effect modelling approach with nonmem software. Covariates were tested on PK and PD parameters, including antibiotic treatment. Acenocoumarol PK data were fitted by a two-compartment, first-order input model with log normal inter-individual variability. Weight and antibiotic treatment were found to improve significantly the fit of PK data with a 15% decrease in acenocoumarol clearance with concomitant antibiotics ( P  < 0.05). An indirect response model was successfully applied to the PK–PD data of acenocoumarol. No covariate, including antibiotic treatment effect, significantly affected PT. Drug–drug interaction was demonstrated at the PK level, without any PD corollary.     

Monte Carlo simulation for evaluation of the efficacy of carbapenems and new quinolones against ESBL-producing Escherichia coli

Extended-spectrum β-lactamase (ESBL)-producing bacteria are known to be resistant to penicillins, cephalosporins, and monobactams because of their substrate specificity, and these bacteria are sensitive only to a narrow range of antimicrobial agents. The present study was undertaken to evaluate the efficacy of carbapenems and the new quinolones against ESBL-producing Escherichia coli, using a Monte Carlo simulation based on the pharmacokinetic/pharmacodynamic (PK/PD) theory. The time above MIC (TAM, %) served as the PK/PD parameter for carbapenems, with the target level set at 40%. The AUC/MIC served as the PK/PD parameter for the new quinolones, with the target level set at more than 125. In the analysis of drug sensitivity, the MIC50 of all carbapenems other than imipenem was low (0.03 μg/ml), while the MIC50 of the new quinolones was higher (1–2 μg/ml). The probability of achieving the PK/PD target with carba penems after two doses at the usual dose level, as determined by the Monte Carlo simulation, was high for each of the carbapenems tested (99.0% for biapenem, 99.60% for meropenem, and 95.03% for doripenem), except for imipenem. Among the new quinolones, the highest probability of achieving the PK/PD target was obtained with pazufloxacin (42.90%). Thus, the results of the present study have revealed that carbapenems are effective at the regular dose and can be used as the first-choice antibiotics for ESBL-producing E. coli because the resistance ratios for carbapenems are low compared to those of the new quinolones.     

Pharmacokinetic-pharmacodynamic study of apomorphine's effect on growth hormone secretion in healthy subjects

Apomorphine (APO) stimulates growth hormone (GH) release via dopamine D2 receptors (DRD2). There is no specific study assessing the relationship between APO pharmacokinetic (PK) and the pharmacodynamic (PD) response e.g. GH release. The objective of the study is the PK-PD modelling of APO in healthy subjects. This is a randomized crossover study with s.c. administration of 5, 10, and 20 micro g/kg of APO in 18 healthy subjects. APO concentrations were modelled according to both a bi-compartmental model with zero-order absorption and a bi-compartmental model with first-order absorption. PK-PD relationship was modelled in accordance with the Emax Hill equation using plasma concentrations of APO calculated according to the bi-compartmental model with zero-order absorption. Modelled parameters were very similar to the experimental parameters. PK of APO was linear and there was no significant difference between the tested doses for AUC0--> infinity and Cmax (normalised to the dose 1 micro g/kg), t1/2alpha and t1/2beta. These parameters expressed as mean (CV%: SD/mean) were: 17.2 (26.9) ng/mL.min, 0.26 (33.3) ng/mL, 17.1 (54.2) and 45.2 (20.6) min, respectively (n = 53). An anticlockwise hysteresis loop (effect function of APO plasma concentration) appeared for each dose and each subject. The predicted and measured GH concentrations for all subjects and times were similar whatever the dose (P > 0.27). Emax values were 246 (121), 180 (107), 205 (139) ng/mL, respectively, and EC50 were 0.98 (48.1), 1.70 (62.3), 3.67 (65.2) ng/mL, respectively at dose 5, 10, and 20 micro g/kg (P < 10-4). APO and GH concentrations were predicted with good accuracy using bi-compartmental with zero-order absorption PK model and sigmoid Emax PD model, respectively.     

Lamotrigine pharmacokinetic/pharmacodynamic modelling in rats

The aim of this study was to perform a pharmacokinetic/pharmacodynamic (PK/PD) modelling of lamotrigine following its acute administration to rats. Adult male Wistar rats were given 10 mg/kg of lamotrigine intraperitoneally. Plasma and brain samples were obtained at predetermined times over 120 h post-dose and analysed by liquid chromatography. The anticonvulsant profile against maximal electroshock seizure stimulation was determined over 48 h after dosing. As a linear relationship between lamotrigine plasma and brain profiles was observed, only the plasma data set was used to establish the PK/PD relationship. To fit the effect-time course of lamotrigine, the PK/PD simultaneous fitting link model was used: the pharmacokinetic parameters and dosing information were used in the one-compartment first-order model to predict concentrations, which were then used to model the pharmacodynamic data with the sigmoid Emax model, in order to estimate all the parameters simultaneously. The following parameters were obtained: Vd = 2.00 L/kg, k(abs) = 8.50 h(-1), k(el) = 0.025 h(-1), k(e0) = 3.75 h(-1), Emax = 100.0% (fixed), EC50 = 3.44 mg/L and gamma = 8.64. From these results, it can be stated that lamotrigine is extensively distributed through the body, its plasma elimination half-life is around 28 h and a lamotrigine plasma concentration of 3.44 mg/L is enough to protect 50% of the animals. When compared with humans, the plasma concentrations achieved with this dose were within the therapeutic concentration range that had been proposed for epileptic patients. With the present PK/PD modelling it was possible to fit simultaneously the time-courses of the plasma levels and the anticonvulsant effect of lamotrigine, providing information not only about the pharmacokinetics of lamotrigine in the rat but also about its anticonvulsant response over time. As this approach can be easily applied to other drugs, it becomes a useful tool for an explanatory comparison between lamotrigine and other antiepileptic drugs.     

The effect of desflurane versus propofol on regional cerebral oxygenation in the sitting position for shoulder arthroscopy

The sitting position may cause significant hemodynamic instability and cerebral hypoperfusion. We investigated the effects of desflurane and propofol on regional cerebral oxygenation (rSO₂) in the sitting position during arthroscopic shoulder surgery. Forty patients undergoing arthroscopic shoulder surgery in the sitting position were randomly allocated to the desflurane group (n = 20) or the propofol group (n = 20). Anesthetic agents were maintained and adjusted with the effect-site concentration of propofol (2–3.5 μg/ml) or desflurane (4–7 vol%) to obtain a bispectral index (BIS) of 40–50. The hemodynamic variables, end-tidal carbon dioxide tension (ETCO₂) and rSO₂ were measured and evaluated. There were no differences in BIS, hemodynamic variables and ETCO₂ between the groups. The rSO₂ values in the desflurane group were higher compared to the propofol group at 3, 5, 7 and 9 min after the sitting position (P = 0.031, 0.047, 0.025 and 0.034, respectively). However, it decreased significantly from the baseline values at 3, 5, 7 and 9 min after the sitting position in both groups (P < 0.001). The change in rSO₂ across time was not significantly different between the groups (P = 0.183). The incidence of rSO₂ <75 % of the baseline values after the sitting position was similar between the groups (0 and 10 % in the desflurane and propofol group, respectively, P = 0.487). When anesthetized patients were raised to the sitting position, desflurane preserved cerebral oxygenation better than propofol at equipotent concentrations in terms of BIS. However, both anesthetics were associated with significant decrease in the rSO₂ values during the sitting position.     

The effects of the extent of spinal block on the BIS score and regional cerebral oxygen saturation in elderly patients: A prospective,randomized, and double-blinded study

Backgrounds Patients may become sedated with␣spinal anesthesia; however, the effect of the extent of␣spinal block on the Bispectral index (BIS), a processed electroencephalographic variable, has not been fully investigated. We evaluated the influence of the extent of spinal block on BIS values and on regional cerebral oxygen saturation (rSO₂) in elderly patients. Methods A prospective, randomized, double-blinded study was performed in 55 ASA II patients undergoing urological surgery. The patients were randomly allocated into one of two groups to receive 2.7 ml of 0.5% hyperbaric bupivacaine or 1.5 ml, and then divided into two groups according to level of spinal blockade: high spinal group (Th6 and above) or low spinal group (Th12 and below). Systolic blood pressure (SBP), heart rate (HR), cardiac output (CO), stroke volume (SV), BIS values, and rSO₂ were measured for 30 min. CO and SV were evaluated using impedance cardiograph methods. Results The level of spinal blockade was Th4.7 ± 1.0 in high spinal group (n = 20) and L2.5 ± 2.2 in low spinal group (n = 20). High spinal anesthesia produced a significant decrease in SBP (p < 0.01) and SV (p < 0.01), but had no effect on CO. High spinal anesthesia significantly decreased BIS values (p < 0.01) without affecting rSO₂. There was relationship between level of spinal blockade and BIS values (r = 0.566). In contrast, no changes in above parameters were found in low spinal group. Conclusions This study provides evidence that the extent of spinal block may have significant influence on BIS values without affecting rSO₂ in elderly patients. A part of the present study was presented at the Annual Meeting of the Japan Society of Anesthesiologists, June 02–04, 2005 at Kobe, Japan. Nishikawa K,Hagiwara R, Nakamura K, Ishizeki J, Kubo K, Saito S, Goto F. The effects of the extent of spinal block on the BIS score and regional cerebral oxygen saturation in elderly patients: A prospective, randomized, and double-blinded study.     

Relationship between the clinical efficacy and AUC/MIC of intravenous ciprofloxacin in Japanese patients with intraabdominal infections

The efficacy of fluoroquinolones (FQs) correlates with the pharmacokinetic/pharmacodynamic (PK–PD) parameter, AUC/MIC. To our knowledge, however, no prospective studies have reported the relationship between FQ efficacy and PK–PD parameters in intraabdominal infection; therefore, we prospectively investigated the relationship between the efficacy of intravenous ciprofloxacin (CPFX IV) and PK–PD parameters. The study included 16 patients diagnosed with peritonitis between 2006 and 2008: 14 patients infected with a single organism and 2 patients infected with more than one organism. Each patient was treated with CPFX IV (300 mg twice daily). The response rate was 56 % (9 responders and 7 non-responders). Non-responders were infected with Escherichia coli, Pseudomonas aeruginosa, and Bacteroides fragilis (6 patients were infected with a single organism and 1 with more than one organism). Plasma drug concentrations were measured 1 h and 2 or 4 h after administration of CPFX IV. AUC for 24 h (AUC_0–24)/MIC values was calculated. The range of AUC_0–24/MIC values in responders [95.3–3628.4 (geometric mean, 521.6)] was significantly different from that in non-responders [7.0–45.2 (geometric mean, 16.5)] (p = 0.001). The target AUC/MIC value of CPFX IV would be considered to be 45–95 in patients with peritonitis.     

Neuroactive steroids differ in potency but not in intrinsic efficacy at the GABA(A) receptor in vivo

The objective of the present investigation was to characterize the in vivo EEG effects of (synthetic) neuroactive steroids on the basis of a recently proposed mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model. After intravenous administration, the time course of the EEG effect of pregnanolone, 2beta-3alpha-5alpha-3-hydroxy-2-(2,2-dimethylmorpholin-4-yl)-pregnan-11,20-dione (ORG 21465), 2beta-3alpha-5alpha-21-chloro-3-hydroxy-2-(4-morpholinyl)-pregnan-20-one (ORG 20599), and alphaxalone was determined in conjunction with plasma concentrations in rats. For each neuroactive steroid the PK/PD correlation was described on the basis of a two-compartment pharmacokinetic model with an effect compartment to account for hysteresis. The observed concentration EEG effect relationships were biphasic and characterized with a mechanism-based pharmacodynamic model, which is based on a separation between the receptor activation process and the stimulus-response relationship. A single unique biphasic stimulus-response relationship could be identified for all neuroactive steroids, which was successfully described by a parabolic function. The receptor activation process was described by a hyperbolic function. Estimates for the maximum activation (e(PD)) were similar for the different neuroactive steroids but values of the potency estimate (K(PD)) ranged from 157 +/- 16 ng. ml(-1) for pregnanolone, 221 +/- 83 ng. ml(-1) for ORG 20599, and 483 +/- 42 ng. ml(-1) for alphaxalone to 1619 +/- 208 ng. ml(-1) for ORG 21465. A statistically significant correlation was observed between the in vivo potency and the IC(50) in an in vitro [(35)S]t-butylbicyclophosphorothionate binding assay (r = 0.91). It is concluded that the new PK/PD model constitutes a new mechanism-based approach to the quantification of the effects of (synthetic) neuroactive steroids in vivo effects. The results show that the neuroactive steroids differ in potency but not in intrinsic efficacy at the GABA(A) receptor in vivo.     

Response Entropy Is More Reactive Than Bispectral Index During Laparoscopic Gastric Banding

Objective. There is a potential use for spectral entropy or bispectral index (BIS) for controlling level of anesthesia, but it is not known how these EEG monitors relate during steady state anesthesia. We compared Response Entropy (RE) and BIS during anesthesia for laparoscopic gastric banding with RE targeted to 45. Methods. Forty patients undergoing laparoscopic gastric banding were randomly assigned to receive either fentanyl or dexmedetomidine infusion, with desflurane concentration adjusted to maintain RE at 45. During anesthesia the average RE and BIS was determined in each patient and the RE-BIS difference plotted as a function of RE every 10 seconds. Fifteen of 40 patients showed activation of RE above 60 during surgery. In these patients RE, BIS and the electromyogram (EMG) were evaluated for the period 10 minutes before and including the peak change in RE. Results. In fentanyl and dexmedetomidine treated patients the average RE was 44–47 with no statistical difference between anesthesia groups or between RE and BIS. In each patient there was a linear relationship between the RE-BIS difference and RE during anesthesia. RE and BIS were similar at a level of 41–44 and RE showed a greater range at higher and lower values compared to BIS. When RE activation was identified during surgery in 15 patients, it was associated with an increase in BIS and EMG. Conclusion. Within the range of 41–44, RE and BIS are equal but the gain of RE is 0.5 greater than BIS with deeper or lighter anesthesia. This is not likely due to increased smoothing with BIS. Identifying periods of RE activation show that BIS, EMG and RE increase together.Feld J, Hoffman WE Park H. Response entropy is more reactive than bispectral index during laparoscopic gastric banding.     

Simultaneous modeling of abciximab plasma concentrations and ex vivo pharmacodynamics in patients undergoing coronary angioplasty

An integrated structural pharmacokinetic/pharmacodynamic (PK/PD) model was developed for the glycoprotein IIb/IIIa antagonist abciximab administered to patients undergoing percutaneous transluminal coronary angioplasty. PK/PD data, in the form of plasma abciximab concentrations and ex vivo platelet aggregation in the presence of 20 microM adenosine diphosphate, were obtained from two previously conducted clinical studies. Study 1 consisted of patients who were given abciximab as a single intravenous injection of 0.25 mg/kg (n = 32). Patients in study 2 received an identical bolus dose, followed by a 36-h infusion at 0.125 microg/kg/min (n = 15). The PK component of the final model included drug-receptor binding, nonspecific distribution, and linear systemic clearance, whereas the PD module assumed that ex vivo dynamics were controlled by free plasma drug concentration. Mean PK/PD data from both studies were fitted simultaneously using nonlinear regression. PK profiles from both studies show rapidly decreasing plasma abciximab concentrations at early time points, but with extended terminal disposition phases. The maximum effect (Emax = 83.6%) was achieved rapidly and gradually returned to baseline values, although inhibition could be measured long after abciximab concentrations dropped below the detection limit. The final model well described the resulting PK/PD profiles and allowed for parameter estimation with relatively small coefficients of variation. Simulations were conducted to assess predicted receptor-occupancy and effects of selected parameters on PK/PD profiles. Models such as the one developed in this study demonstrate how drug binding to pharmacological targets may influence the PK of certain drugs and also provide a suitable paradigm for defining the PK/PD relationships of similar compounds.     

Comparison of Narcotrend Index,Bispectral Index,spectral and entropy parameters during induction of propofol-remifentanil anaesthesia

Objective This study investigated the suitability of various electroencephalogram (EEG) parameters to describe anaesthetic drug effects in propofol-remifentanil anaesthesia. The investigated parameters were the Narcotrend^? Index (NI), the Bispectral Index^TM (BIS^TM), and standard spectral and entropy parameters. Additionally, it was investigated whether the effect of a fixed dosage of propofol on the attained depth of hypnosis during induction of anaesthesia is different in male and female patients. Methods Standardized inductions of anaesthesia in 10 male and 10 female patients (ASA status I or II, 15–75 years) were analysed. All patients received 4 mg propofol/kg over 6 min followed by 4 mg/kg/h. For analgesia, patients received 0.3 μg/kg/min remifentanil starting 2 min before propofol application. For EEG monitoring, the Narcotrend and the Aspect A-2000 Bispectral Index monitor were used simultaneously. Data from start of propofol injection until 1 min after the end of the induction period (420 s) were used for statistical analysis. EEG parameters were evaluated every 10 s. Results The Narcotrend^? Index and the Bispectral Index^TM had the highest mean correlations with the calculated propofol effect-site concentration and were able to distinguish stages from the awake state or the near awake state and stages of deep hypnosis. On the Narcotrend scale, more data points are available for levels of anaesthesia with relevance for maintenance of anaesthesia. The BIS values at the first occurrence of burst suppression were significantly higher than the corresponding NI values. During induction of anaesthesia, the same dosages of propofol (per kg body weight) given to men and women did not show different effects on the EEG. Conclusions NI and BIS are superior to␣spectral and entropy parameters in describing changes of propofol concentration during induction of propofol-remifentanil anaesthesia. Drs. U. Grouven, A. Schultz and B. Schultz are members of the research group that developed the classification algorithms implemented in the EEG monitor Narcotrend. Schultz A, Siedenberg M, Grouven U, Kneif T, Schultz B. Comparison of Narcotrend Index, Bispectral Index, spectral and entropy parameters during induction of propofol-remifentanil anaesthesia.     

Clinical pharmacological approach for balancing the use of daptomycin and linezolid in comparison with that of vancomycin in the treatment of MRSA-related infections

Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most challenging bacterial pathogens responsible for severe infections among hospitalized patients. In recent years there is increasing evidence that the clinical efficacy of vancomycin is progressively decreasing. Although daptomycin and linezolid are valuable alternatives to vancomycin for the treatment of MRSA-related bloodstream infections and pneumonia, respectively, a great deal of debate exists about their role in daily clinical practice due to cost-effectiveness issues. In this article we put into perspective the importance of pharmacokinetic/pharmacodynamic (PK/PD) considerations based on recent experimental and clinical data to argue whether they could be helpful in identifying clinical conditions in which these agents could be advantageous as compared to vancomycin.     

Pharmacokinetic/pharmacodynamic relationship of danofloxacin against Mannheimia haemolytica in a tissue-cage model in calves

OBJECTIVE: To evaluate an experimental model of the pharmacokinetic/pharmacodynamic (PK/PD) relationship of danofloxacin against Mannheimia haemolytica infection, using subcutaneously implanted tissue cages in calves. METHODS: Tissue cages implanted subcutaneously in calves were infected with M. haemolytica and different concentration-time profiles of danofloxacin were simulated. Drug concentrations and bacterial counts were monitored over time and various PK/PD parameters calculated. RESULTS: By using different types of cage and various doses, a range of PK/PD indices were simulated. The PK/PD index that best predicted the antimicrobial effect was the AUC/MIC ratio. The magnitude of this index needed for near-maximum effect (80%), assessed using the area under the bacterial kill curve to 48 h, was 244 h. CONCLUSIONS: The model described enabled different concentration-time profiles to be simulated, and PK/PD interactions to be studied in the presence of the host's defences. The validity of this model needs to be confirmed by clinical studies, but the results suggest that it may be a useful intermediary step between in vitro and clinical studies.     

Blood concentrations are better predictors of chioroquine poisoning severity than plasma concentrations: a prospective study with modeling of the concentration/effect relationships

Introduction. Chloroquine causes rare but life-threatening toxicity. The prognostic value of plasma chloroquine concentrations in acute poisonings remains poorly investigated. We investigated the hypothesis that blood chloroquine concentrations better predicted chloroquine poisoning severity than plasma concentrations. Methods. A prospective study of consecutive chloroquine poisonings admitted to an intensive care unit from 2003 to 2007 was performed with simultaneous measurements of blood and plasma chloroquine (chloroquine and desethylchloroquine) concentrations. A population pharmacokinetic–pharmacodynamic model described epinephrine infusion rate, our surrogate marker of cardiovascular toxicity, as function of blood or plasma chloroquine concentrations. Results. Forty-four patients [29F/15M, 33 years (25–41), median (25–75th percentile), 34% with cardiac arrest] were included. Management included mechanical ventilation (80%), 8.4% sodium bicarbonate (66%), epinephrine [73%, maximal rate: 2.8 mg/h (0.8–5.0)], and extracorporeal life support (16%). Seven patients died. Blood [6.7 mg/L (4.0–13.0)] and plasma [1.5 mg/L (1.2–2.9)] chloroquine concentrations were weakly, although significantly correlated (r = 0.66, p < 0.0001, Spearman test). Admission chloroquine concentrations correlated with the reported ingested dose (r = 0.70 for blood vs. 0.48 for plasma), QRS duration (r = 0.82 vs. 0.64), lactate concentrations (r = 0.63 vs. 0.47), and epinephrine infusion rates (r = 0.70 vs. 0.62). Chloroquine concentrations differed significantly between patients with and without cardiac arrest (p = 0.0002 for blood vs. 0.02 for plasma). A one-compartment pharmacokinetic (PK) model adequately described blood chloroquine concentrations. An effect compartment linked to the blood compartment adequately described plasma chloroquine concentrations. Using a sigmoidal E_max pharmacodynamic (PD) model, epinephrine infusion rate was better predicted with blood than plasma concentrations (p < 0.01), suggesting that time-course of blood concentrations is a better prognostic value than plasma concentrations. Conclusion. Immediate and serial measurements of blood chloroquine concentrations are better than plasma for predicting cardiovascular severity of chloroquine poisonings.     

In vitro pharmacodynamics of rapid versus continuous infusion of amphotericin B deoxycholate against Candida species in the presence of human serum albumin

BACKGROUND: Recent open label studies have suggested that dosing amphotericin B (AMB) by continuous infusion (CI) may reduce drug-associated infusion reactions and nephrotoxicity. In vitro and in vivo pharmacodynamic (PD) data, however, do not consistently support the concept of CI dosing based on the concentration-dependent activity of this agent and in vitro studies with AMB rarely account for the drug's high degree of protein binding. Therefore, we compared the PD activity of simulated continuous versus rapid infusion strategies of AMB in killing of AMB-susceptible and -resistant Candida species using an in vitro pharmacodynamic model. METHODS: Time-kill curves were performed with Candida albicans (Etest MIC 0.38 mg/L) and Candida lusitaniae (MIC 1.5 mg/L) at AMB concentrations between 0 and 16 mg/L in the absence and presence of 4 and 8% human serum albumin (HSA). A one-compartment in vitro pharmacodynamic model was used to simulate the steady-state PK parameters of bolus and CI AMB. RESULTS: The fungicidal activity of AMB was attenuated by the presence of HSA for both Candida species tested. The EC50 for each isolate significantly increased in the presence of 4% HSA (P<0.05), and fungicidal activity was completely abated for C. lusitaniae when HSA concentrations were increased to 8%. No substantial differences in the rate or extent of AMB killing were observed between rapid infusion or CI dosing and neither regimen produced fungicidal activity in the presence of HSA. CONCLUSIONS: The presence of HSA changes the in vitro PD of AMB. In our model, CI and rapid infusion dosing of AMB exhibited similar activity when attempts were made to correct for protein binding that is likely to occur in vivo.