Influence of Different Fat Emulsion-Based Intravenous Formulations on the Pharmacokinetics and Pharmacodynamics of Propofol

Purpose. The influence of different intravenous formulations on the pharmacokinetics and pharmacodynamics of propofol was investigated using the effect on the EEG (11.5-30 Hz) as pharmacodynamic endpoint. Methods. Propofol was administered as an intravenous bolus infusion (30 mg/kg in 5 min) or as a continuous infusion (150 mg/kg in 5 hours) in chronically instrumented male rats. Propofol was formulated as a 1% emulsion in an Intralipid 10%^®-like fat emulsion (Diprivan-10^®, D) or as a 1%- or 6% emulsion in Lipofundin^® MCT/LCT-10% (Pl% and P6%, respectively). EEG was recorded continuously and arterial blood samples were collected serially for the determination of propofol concentrations using HPLC. Results. Following bolus infusion, the pharmacokinetics of the various propofol emulsions could adequately be described by a two-compart-mental pharmacokinetic model. The average values for clearance (Cl), volume of distribution at steady-state (V_d,ss) and terminal half-life (t_{1/2, 2}) were 107 ± 4 ml/min/kg, 1.38 ± 0.06 l/kg and 16 ± 1 min, respectively (mean ± S.E., n = 22). No significant differences were observed between the three propofol formulations. After continuous infusion these values were 112 ± 11 ml/min/kg, 5.19 ± 0.41 l/kg and 45 ± 3 min, respectively (mean±S.E., n = 20) with again no statistically significant differences between the three propofol formulations. Comparison between the bolus- and the continuous infusion revealed a statistically significant difference for both V_d,ss and t_{1/2, 2} (p < 0.05), whereas Cl remained unchanged. In all treatment groups infusion of propofol resulted in a burst-suppression type of EEG. A profound hysteresis loop was observed between blood concentrations and EEG effect for all formulations. The hysteresis was minimized by a semi-parametric method and resulted in a biphasic concentration-effect relationship of propofol that was described non-parametrically. For P6% a larger rate constant onset of drug effect (t,_{1/2, keo}) was observed compared to the other propofol formulations (p<0.05). Conclusions. The pharmacokinetics and pharmacodynamics of propofol are not affected by to a large extent the type of emulsion nor by the concentration of propofol in the intravenous formulation.     

Propofol pharmacokinetics in young healthy Indian subjects

Objectives:

To analyze population pharmacokinetics of Propofol in Indian patients after single bolus dose of Propofol using WINNONLIN program.

Materials and Methods:

Population pharmacokinetics of Propofol was investigated in Indian subjects in 26 elective surgical patients (14 males and 12 females) following single bolus dose of 2 mg/kg propofol. A total of 364 samples were estimated by High Performance Liquid Chromatography and pharmacokinetic parameters were derived using WINNONLIN (5.2). The effect of demographic characters of the study population on pharmacokinetic parameters was investigated.

Results:

Three-compartment model was used to describe the pharmacokinetic data of Propofol in Indian subjects. Initial volume of distribution (V1) clearance (Cl) and steady state volume of distribution (Vd_ss) was 13.5 ± 3.3 l, 1.08 ± 0.42 l/min, and 77.69 ± 48.0 l, respectively. Body weight best described the volume of central compartment (V1) as well as elimination clearance (P<0.01).

Conclusion:

Pharmacokinetics of Propofol in young healthy Indian subjects show lower volume of distribution and clearance as compared with most of the western data. Body weight best describes the V1, Vd_ss, and Clearance in this group.KEY WORDS: Anesthetics, propofol, pharmacokinetics, volume of distribution     

A Novel,Lipid-Free Nanodispersion Formulation of Propofol and Its Characterization

No HeadingPurpose. Propofol is a widely used anesthetic agent with highly desirable fast on and off effects. It is currently formulated as lipid emulsions, which are known to support microbial growth. In this study, a novel, lipid-free nanodispersion formulation of propofol was characterized.Methods. The formulation was evaluated for its physical and chemical stability, in vitro compatibility with red blood cells, and its antimicrobial effectiveness. In vivo pharmacokinetic and pharmacodynamic properties of the formulation were evaluated in rats.Results. Our data suggest that this lipid-free formulation is physically and chemically stable. Compared to the commercial emulsion formulation Diprivan, it causes less hemolysis with red blood cells and has improved antimicrobial activity. In addition, the lipid-free formulation demonstrates similar pharmacological effects to Diprivan in rats.Conclusions. This novel, lipid-free formulation exhibits improved in vitro properties without compromising in vivo effects, therefore representing a promising new alternative for propofol.     

The pharmacokinetics of propofol in laboratory animals

1. The pharmacokinetics of propofol in an emulsion formulation (‘Diprivan’) have been studied after single bolus doses to rats, dogs, rabbits and pigs, and after single and multiple infusions to dogs. Venous blood propofol concentrations were determined by h.p.l.c. with u.v. or fluorescence detection. Curve fitting was performed using ELSFIT.

2. The distribution of propofol in blood and its plasma protein binding have been studied in rat, dog, rabbit and man. Protein binding was high (96-98%), and in most species propofol showed appreciable association with the formed elements of blood.

3. Where an adequate sampling period was employed the pharmacokinetics of propofol were best described by a three-compartment open ‘mammillary’ model. Propofol was distributed into a large initial volume (1-21/kg) and extensively redistributed (V_ss=2-10 x body weight) in all species. Clearance of propofol by all species was rapid, ranging from about 30-80ml/kg per min in rats, dogs and pigs to about 340ml/kg per min in rabbits.     

Pharmacokinetics and pharmacodynamics of a new reformulated microemulsion and the long-chain triglyceride emulsion of propofol in beagle dogs

Background and purpose:

Microemulsion propofol was developed to eliminate lipid solvent-related adverse events of long-chain triglyceride emulsion (LCT) propofol. We compared dose proportionality, pharmacokinetic and pharmacodynamic characteristics of both formulations.

Experimental approach:

The study was a randomized, two-period and crossover design with 7-day wash-out period. Microemulsion and LCT propofol were administered by zero-order infusion (0.75, 1.00 and 1.25 mg·kg⁻¹·min⁻¹) for 20 min in 30 beagle dogs (male/female = 5/5 for each rate). Arterial samples were collected at preset intervals. The electroencephalographic approximate entropy (ApEn) was used as a measure of propofol effect. Dose proportionality, pharmacokinetic and pharmacodynamic bioequivalence were evaluated by non-compartmental analyses. Population analysis was performed using nonlinear mixed effects modelling.

Key results:

Both formulations showed dose proportionality at the applied dose range. The ratios of geometric means of AUC_last and AUC_inf between both formulations were acceptable for bioequivalence, whereas that of C_max was not. The pharmacodynamic bioequivalence was indicated by the arithmetic means of AAC (areas above the ApEn time curves) and E₀ (baseline ApEn)–E_max (maximally decreased ApEn) between both formulations. The pharmacokinetics of both formulations were best described by three compartment models. Body weight was a significant covariate for V₁ of both formulations and sex for k₂₁ of microemulsion propofol. The blood-brain equilibration rate constants (k_e0, min⁻¹) were 0.476 and 0.696 for microemulsion and LCT propofol respectively.

Conclusions and implications:

Microemulsion propofol was pharmacodynamically bioequivalent to LCT propofol although pharmacokinetic bioequivalence was incomplete, and demonstrated linear pharmacokinetics at the applied dose ranges.     

Individual differences in pharmacokinetics and pharmacodynamics of anesthetic agent propofol with regard to CYP2B6 and UGT1A9 genotype and patient age

Propofol (2,6-diisopropylphenol) is administered intravenously for induction and maintenance of anesthesia; however, cases of progressive myocardial failure (propofol syndrome) related to the use of propofol have been reported. In the present study, the individual differences in pharmacokinetics and/or pharmacodynamics of propofol were investigated in patients who were genotyped for CYP2B6 and UGT1A9. Fifty-one patients treated with propofol in St. Marianna University Hospital were recruited for this study and provided written informed consent. The following parameters were analyzed: awakening time as a pharmacodynamic parameter, duration of propofol infusion, drug concentration in plasma after treatment, genotypes of CYP2B6 and UGT1A9, and age (42-84 years, mean of 65 years). Propofol was rapidly cleared from the blood of the subjects as a result of distribution and elimination. The awakening time after stopping propofol infusion was significantly correlated with the duration of infusion and the maximum concentration of propofol in these subjects. The maximum plasma concentration of propofol after normalizing with the duration of infusion was affected by the CYP2B6 G516T variant (related to impaired function) and was significantly affected by a propofol risk index score that incorporated CYP2B6 G516T and UGT1A9 I399C>T (high expression) genotypes and advanced age. These results provide important information indicating that the genotypes of the two enzymes studied and advanced age are combinative determinant factors of the pharmacokinetics and/or pharmacodynamics of propofol.     

Pharmacokinetics and pharmacodynamics of propofol 6% SAZN versus propofol 1% SAZN and Diprivan-10 for short-term sedation following coronary artery bypass surgery

Objective: A new formulation of propofol 6% in Lipofundin MCT/LCT 10% (propofol 6% SAZN) has been developed in order to reduce the fat, emulsifier and volume load that is given during prolonged infusions of propofol. The pharmacokinetics, pharmacodynamics and safety characteristics of propofol 6% SAZN were investigated during a short-term infusion and compared with the commercially available product propofol 1% in Intralipid 10% (Diprivan-10) and propofol 1% in Lipofundin MCT/LCT 10% (propofol 1% SAZN). Methods: In a randomised double-blind study, 24 male patients received a 5-h infusion of propofol at the rate of 1 mg/kg/h for sedation in the immediate postoperative period following coronary artery bypass surgery. Results: The average pharmacokinetic parameter estimates of clearance (Cl), volume of distribution at steady state (V_d,ss), elimination half-life (t _1/2,β) and distribution half-life (t _1/2,α) observed in the three groups were 28 ± 1.1 ml/kg/min, 1.8 ± 0.12 l/kg, 94 ± 4.1 min and 3.1 ± 0.26 min, respectively (mean ± SEM, n=24) and no significant differences were noted between the three formulations (P > 0.05). In one patient receiving propofol 6% SAZN, in two patients receiving propofol 1% SAZN and in three patients receiving Diprivan-10, the level of sedation was inadequate and additional sedative medication had to be given. In all other 18 patients, the level of sedation was adequate. The mean propofol concentration in these six inadequately sedated patients was lower than the adequately sedated patients (P=0.015). The serum triglyceride concentrations were not significantly different between the groups studied. No adverse events occurred in any of the patients. Conclusions: The pharmacokinetics, pharmacodynamics and safety characteristics of propofol 6% SAZN are in good agreement with those of the 1% formulations. Propofol 6% SAZN therefore provides a useful alternative to the commercially available 1% formulation for short-term sedation in the intensive care unit. Expected advantages in long-term sedation of the 6% over 1% formulation are the subject of an ongoing study. Received: 11 June 1999 / Accepted in revised form: 23 December 1999     

Pharmacokinetics, induction of anaesthesia and safety characteristics of Propofol 6% SAZN vs Propofol 1% SAZN and Diprivan®-10 after bolus injection

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(R) 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(R) 10%, Diprivan-10) and propofol 1% in Lipofundin(R) 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-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-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 (Vd,ss ), elimination half-life (t1/2,z ) and distribution half-life (t1/2, lambda2) observed in the three groups were 32+/-1.5 ml kg-1 min-1, 2. 0+/-0.18 l kg-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 (t1/2,lambda1 ) 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 dose of propofol of 2.1+/-0.06 mg kg-1 (mean+/-s.e. mean, n=24). The percentage of patients reporting any pain on injection did not vary between the formulations and was 17% for the three groups. No postoperative phlebitis or other venous sequelae of the vein used for injection occurred in any of the patients at recovery of anaesthesia nor after 24 h. CONCLUSIONS: From the above results, we conclude that the alteration of the type of emulsion and the higher concentration of propofol in the new parenteral formulation of propofol does not affect the pharmacokinetics and induction characteristics of propofol, compared with the currently available product. Propofol 6% SAZN can be administered safely and has the advantage of a reduction of the load of fat and emulsifier which may be preferable when long term administration of propofol is required.     

Effects of propofol (intravenous propofol emulsion) on cell membranes measured by electrofusion and electroporation

The influence of propofol (CAS 2078-54-8 (intravenous propofol emulsion) on cell membrane properties was investigated in vitro with techniques of cell electrofusion and cell electroporation. Human lymphoma cells and plant protoplasts were chosen as a model system. Propofol (intravenous propofol emulsion) decreased the electrofusion yield of the cells and their membrane permeability. A 50% decrease in relative electrofusion was observed in human lymphoma cells in the presence of about 0.05 mmol/l propofol (intravenous propofol emulsion) and in plant protoplasts in the presence of about 0.1 mmol/l. The fusion of human lymphoma cells was inhibited to 100% at concentrations higher than 0.2 mmol/l propofol and 0.4 mmol/l intravenous propofol emulsion. The membrane permeability of human lymphoma cells decreased by the factor of two with increasing propofol concentrations up to about 0.1 mmol/l. The effects of electroporation were highly reversible. Propofol (intravenous propofol emulsion) was more effective than tetracaine. These sensitive techniques are suitable for the investigation of interactions between anesthetic drugs and the cell membrane.     

Fospropofol disodium,a water-soluble prodrug of the intravenous anesthetic propofol (2,6-diisopropylphenol)

Background: Today, propofol or 2,6-diisopropylphenol is the anesthetic mainly used for monitored anesthetic care sedation and during intravenous anesthesia. The formulation, a lipid macroemulsion, shows several disadvantages. Therefore, during the past years considerable scientific effort has been undertaken to find either a better formulation or a prodrug of propofol. Fospropofol is the first propofol prodrug that has been intensively studied in man. It has been licensed in 2008 by the FDA for monitored anesthetic care sedation. Objectives and methods: This review describes first published study results of fospropofol with regard to its pharmacokinetics/pharmacodynamics, drug safety, tolerability and drug side effects. Using a Medline search all published articles and abstracts containing the words fospropofol or GPI 15715 were included. Results and conclusion: As the impact of an errorness drug assay for propofol liberated from fospropofol is not exactly defined, no clear conclusions can be drawn from the first published pharmacokinetic/pharmacodynamic studies. Fospropofol was well tolerated in the first two clinical studies and no serious side effects were reported. After characterization of the true pharmacokinetic/pharmacodynamics profile, fospropofol, an aqueous solution, has the potential to favorably compare with benzodiazepines for procedural sedation and also may be used for long-term sedation and intravenous anesthesia.     

新型麻醉药——异丙酚及其制剂的研究进展

综述了新型在麻醉药－异丙酚及其制剂的国内外研究进展，主要包括异丙酚的理化性质，，制剂进展，分析方法，药动学，药效学及临床使用情况，作用机理等方面的研究结果。     

Physical properties and stability of two emulsion formulations of propofol

We have compared the physical properties of two commercial emulsion formulations of the intravenous anaesthetic propofol, (Diprivan, AstraZeneca, and Propofol Intravenous Emulsion, Gensia Sicor Pharmaceuticals) which appear to differ primarily in the additive content and formulation pH. Diprivan contains disodium edetate and has a pH of 7-8.5, while the Gensia product contains sodium metabisulphite and is formulated to a pH of 4.5-6.4. The average zeta potential of Diprivan at pH 8 was -50 mV while that of the Gensia product at pH 4-5 was -40 mV. This information suggests that the physical stability of Propofol Intravenous Emulsion should be lower than that of Diprivan. Three random batches of both products were subjected to a range of stability tests, including shaking, thermal cycling, and freeze-thaw cycling, and the emulsion droplet size distribution was then assessed by dynamic light scattering, light diffraction, and electrical and optical zone sensing. Both emulsions initially showed narrow submicrometre particle size distributions. An increased level of droplets larger than 5 microm could be detected in Propofol Intravenous Emulsion after as little as 4 h shaking (300 strokes/min at room temperature) and visible free oil could be detected after 8-12 h shaking. In contrast, Diprivan showed no increase in the large droplet count after shaking for times up to 16 h. A similar difference in the emulsions was found after one freeze-thaw cycle, with Propofol Intravenous Emulsion exhibiting extensive coalescence, while that of Diprivan was at the limits of detection. We conclude that these two products have different physical stability characteristics, and that this may in part be due to the reduced zeta potential in Propofol Intravenous Emulsion compared to that of Diprivan.     

Acute and Chronic Drug Problems Responsible for Emergency Hospital Admissions: An Analysis of Complaint and Response

Abstract

Propofol is a widely used general anaesthetic with multisite mechanisms and especially ultrashort activation of certain central GABA-A receptors. Since its introduction into the market in the mid 1980s this is the seventh report on propofol dependence in the literature. The present case shows for the first time that craving for propofol can be quite intense and able to induce addictive behaviour.     

ICU患者并联输注多种药物致静脉导管堵塞的体外药物配伍研究

目的:探讨1例ICU患者采用三通阀输液器并联输注多种静脉药物致导管堵塞的原因,为临床药师重点关注ICU患者静脉联用多种药物的安全性提供实践参考。方法:取患者同时在用的4种药物:氯化钾注射液、丙泊酚中/长链脂肪乳注射液、间羟胺注射液和地佐辛注射液,进行体外药物配伍试验,经整体混合及分别混合(丙泊酚与其他3种药物分别配伍),在电子显微镜下观察配伍后不同时间段药液的变化情况。结果:4种药液混合后,丙泊酚由最初匀质的小粒径乳滴(0.43μm)逐渐聚集增大,稳定性下降,最大乳滴粒径为3.45μm。进一步分别配伍试验证明了丙泊酚与间羟胺配伍时,乳滴蓄积与融合速度最快,4h乳滴粒径达10.36μm,已超过毛细血管平均直径;与氯化钾配伍时,乳滴蓄积与融合速度居中;与地佐辛配伍时,蓄积与融合速度最慢。结论:丙泊酚与间羟胺存在严重的配伍禁忌,应避免同时使用;与其他药物配伍时,其稳定性也会不同程度下降,建议采用双腔或多腔静脉导管单独一路输注丙泊酚中/长链脂肪乳。     

Comparative canine pharmacokinetics-pharmacodynamics of fospropofol disodium injection, propofol emulsion, and cyclodextrin-enabled propofol solution following bolus parenteral administration

The pharmacokinetics and pharmacodynamics of fospropofol (FP) disodium injection, propofol emulsion (PE), and cyclodextrin-enabled propofol (CDP) solution following bolus parenteral administration in dogs was evaluated. Three healthy male beagle dogs were treated in a three-way cross-over study (14 day washout period) with 6 mg/kg propofol equivalents. Blood samples were collected predose and at 16 points postdose through 1440 min and analyzed for propofol and FP, when appropriate. From 5 min predose to 30 min postdose, brain electrical activity [electroencephalography (EEG)] was recorded and analyzed by power spectrum analysis techniques. Each formulation appeared to be well tolerated with transient discomfort observed in the PE and CDP animals and minor excitability in the FP animals prior to loss of consciousness. Blood propofol followed three-compartment pharmacokinetic behavior and derived parameters were not statistically different except for elimination half-life from the CDP formulation and onset, and duration of anesthesia from the FP formulation. The effect site concentrations at 50% the maximum EEG effect for the FP and CDP formulations were approximately one-half that of the PE formulation. Onset and duration of anesthesia are correlated with modeled effect site propofol concentrations. The implications of formulation on pain on injection and propofol activity are discussed.     

The pharmacokinetics of propofol in laboratory animals.

1. The pharmacokinetics of propofol in an emulsion formulation ('Diprivan') have been studied after single bolus doses to rats, dogs, rabbits and pigs, and after single and multiple infusions to dogs. Venous blood propofol concentrations were determined by h.p.l.c. with u.v. or fluorescence detection. Curve fitting was performed using ELSFIT. 2. The distribution of propofol in blood and its plasma protein binding have been studied in rat, dog, rabbit and man. Protein binding was high (96-98%), and in most species propofol showed appreciable association with the formed elements of blood. 3. Where an adequate sampling period was employed the pharmacokinetics of propofol were best described by a three-compartment open 'mammillary' model. Propofol was distributed into a large initial volume (1-21/kg) and extensively redistributed (Vss = 2-10 x body weight) in all species. Clearance of propofol by all species was rapid, ranging from about 30-80 ml/kg per min in rats, dogs and pigs to about 340 ml/kg per min in rabbits.     

蒿甲醚在兔体内的药代动力学

本文报道蒿甲醚在兔体内的药代动力学。静脉输注蒿甲醚脂肪乳剂(蒿甲醚80mg/kg)后,血药时间数据用NONLIN程序拟合曲线,符合线性二室开模型。药代动力学参数的平均(SD)为:t1/2(α和β)分别为0.144(0.077)h和0.896(0.371)h;k₂₁,k₁₀和k₁₂分别为1.235(0.705),4.143(1.370)和1.140(0.951)h^-1;V_c,V_d(area)和V_d(ss)分别为0.609(0.119),2.985(0.787)和1.054(0.202)L/kg;清除率为2.401(0.339)L·kg^-1·h。肌内注射油剂250mg/kg或125mg/kg,血药时间数据按矩量法计算,得吸收速率常数(Ka)为0.0377(0.0119)h^-1;吸收程度为36.14(18.39)%。     

Optical imaging of propofol‐induced central respiratory depression in medulla–spinal cord preparations from newborn rats

1. Propofol (2,6‐diisopropylphenol) is an intravenous anaesthetic used for the induction and maintenance of general anaesthesia; it also potently and dose‐dependently depresses respiration. The aim of the present study was to analyse propofol‐induced changes in spatiotemporal patterns of inspiratory‐related neural activity and to investigate the involvement of the GABA_A receptor by using an optical imaging technique. 2. The brain stems and spinal cords of 0–1‐day‐old Wistar rats were isolated and stained using a fluorescent voltage‐sensitive dye. Neuronal activity in the preparation was detected using an optical recording apparatus containing a charge‐coupled device (CCD)‐based camera. 3. Bath‐applied propofol (7.5 μmol/L) decreased the C4 burst rate to 45.9% of baseline. Although optical signals corresponding to membrane depolarization during the pre‐inspiratory phase in the parafacial region of the ventral medulla decreased to 28.7% of baseline following propofol application, those during the inspiratory phase in the caudal part of the rostral ventrolateral medulla did not. 4. The inhibitory effect of bath‐applied propofol was reversed by 2 μmol/L bicuculline. 5. Changes in optical signals corresponding to the population activity of pre‐inspiratory neurons were parallel to changes in the C4 burst rate. 6. The results suggest that propofol decreases the inspiratory burst rate by reducing the activity of pre‐inspiratory neurons and that GABA_A receptor activation plays a role in propofol‐induced central respiratory depression. These results are consistent with those of previous electrophysiological studies.     

Pharmacokinetics and pharmacodynamics following intravenous doses of azimilide dihydrochloride

Azimilide pharmacokinetics and pharmacodynamics were characterized in a safety and tolerance study of intravenously administered azimilide dihydrochloride. This was a parallel-group design (seven treatments), and 68 healthy volunteers received the drug. Single intravenous infusion doses (4.5 to 9 mg/kg) were administered over 60 minutes, and single 4.5 mg/kg intravenous infusion doses were also given over 15 or 30 minutes. Blood and urine specimens were collected and analyzed for azimilide and metabolites. QTc was measured as a marker of class III antiarrhythmic activity. Azimilide pharmacokinetics were dose proportional and did not differ among infusion rates. Azimilide pharmacodynamics did not differ among treatments. Mean Emax ranged from 23 to 28% delta QTc, with mean EC50 of 509 to 566 ng/mL. Peak circadian variation in QTc was equivalent to 14% of Emax. Rapid equilibration occurred between blood and the biophase. Unconfounded pharmacodynamic estimates required inclusion of circadian QTc variation in the pharmacodynamic model.