Is It Possible To Estimate the Parameters of the Sigmoid Emax Model with Truncated Data Typical of Clinical Studies?

1996 ◽  
Vol 85 (2) ◽  
pp. 232-239 ◽  
Author(s):  
Sandeep Dutta ◽  
Yoshiaki Matsumoto ◽  
William F. Ebling
Keyword(s):  
Clinical Studies ◽  
Truncated Data ◽  
Emax Model ◽  
Sigmoid Emax Model

Pharmacokinetics and Bioavailability of Inhaled Esketamine in Healthy Volunteers

2017 ◽  
Vol 127 (4) ◽  
pp. 675-683 ◽  
Author(s):  
Kelly Jonkman ◽  
Andreas Duma ◽  
Erik Olofsen ◽  
Thomas Henthorn ◽  
Monique van Velzen ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Pharmacokinetic Model ◽  
Substantial Reduction ◽  
Mixed Effects ◽  
Pulmonary Absorption ◽  
Reduced Dose ◽  
Emax Model ◽  
Dose Dependent ◽  
Absorption Pathways ◽  
Sigmoid Emax Model

Abstract Background Esketamine is traditionally administered via intravenous or intramuscular routes. In this study we developed a pharmacokinetic model of inhalation of nebulized esketamine with special emphasis on pulmonary absorption and bioavailability. Methods Three increasing doses of inhaled esketamine (dose escalation from 25 to 100 mg) were applied followed by a single intravenous dose (20 mg) in 19 healthy volunteers using a nebulizer system and arterial concentrations of esketamine and esnorketamine were obtained. A multicompartmental pharmacokinetic model was developed using population nonlinear mixed-effects analyses. Results The pharmacokinetic model consisted of three esketamine, two esnorketamine disposition and three metabolism compartments. The inhalation data were best described by adding two absorption pathways, an immediate and a slower pathway, with rate constant 0.05 ± 0.01 min–1 (median ± SE of the estimate). The amount of esketamine inhaled was reduced due to dose-independent and dose-dependent reduced bioavailability. The former was 70% ± 5%, and the latter was described by a sigmoid EMAX model characterized by the plasma concentration at which absorption was impaired by 50% (406 ± 46 ng/ml). Over the concentration range tested, up to 50% of inhaled esketamine is lost due to the reduced dose-independent and dose-dependent bioavailability. Conclusions We successfully modeled the inhalation of nebulized esketamine in healthy volunteers. Nebulized esketamine is inhaled with a substantial reduction in bioavailability. Although the reduction in dose-independent bioavailability is best explained by retention of drug and particle exhalation, the reduction in dose-dependent bioavailability is probably due to sedation-related loss of drug into the air.

scholarly journals Modeling the Effect of Sevoflurane on Corrected QT Prolongation

2010 ◽  
Vol 113 (4) ◽  
pp. 806-811 ◽  
Author(s):  
Dong Woo Han ◽  
Kyungsoo Park ◽  
Seong Bok Jang ◽  
Steven E. Kern
Keyword(s):  
Prediction Error ◽  
Interval Data ◽  
Coefficient Of Determination ◽  
Qtc Interval ◽  
Sevoflurane Anesthesia ◽  
Healthy Humans ◽  
Emax Model ◽  
Pharmacodynamic Analysis ◽  
End Tidal ◽  
Sigmoid Emax Model

Background Sevoflurane may prolong the corrected QT (QTc) interval in healthy humans when administered for induction and maintenance of anesthesia. Little information is available about the dose-response relationship of sevoflurane on the QTc interval. We performed a pharmacodynamic analysis of the relationship between end-tidal sevoflurane concentration (CET) and the QTc. Methods Twenty-one patients aged 20-50 yr were enrolled in this study. Sevoflurane concentrations were progressively increased and then decreased over 15 min at the start of anesthesia; CET and automated QT interval were recorded continuously. Pharmacodynamic analysis using a sigmoid Emax model was performed to assess the concentration-effect relationship. Results Maximal CET was 4.30 ± 0.33%. Measured baseline and maximally prolonged QTc interval values were 351.7 ± 15.4 ms and 397.8 ± 17.5 ms, respectively. During sevoflurane anesthesia, increased concentrations were correlated with prolonged QTc interval. Hysteresis between the CET and QTc interval were observed and accounted for in the model. Ce50 and ke0 were 2.5 ± 1.4 and 2.0 ± 1.0, respectively. The median prediction error, median absolute prediction error, and the coefficient of determination (R) were 0.02%, 0.75%, and 0.95, respectively. The effect-site concentration (Ce50) and QTc interval data fit to a sigmoid Emax model. Conclusions Among patients receiving sevoflurane for anesthesia, QTc interval changes correlate to anesthetic level. The Ce50 for significant QTc change is at clinically relevant levels of sevoflurane anesthesia.

Repurposing drugs for treatment of Mycobacterium abscessus: a view to a kill

2020 ◽  
Vol 75 (5) ◽  
pp. 1212-1217 ◽  
Author(s):  
Tawanda Gumbo ◽  
Kayle Cirrincione ◽  
Shashikant Srivastava
Keyword(s):  
Combination Therapy ◽  
Anticancer Agent ◽  
Drug Regimen ◽  
Current Treatment ◽  
Hollow Fibre ◽  
Mycobacterium Abscessus ◽  
Treatment Regimens ◽  
Emax Model ◽  
Combination Regimens ◽  
Sigmoid Emax Model

Abstract Background The current treatment regimens recommended for Mycobacterium abscessus subspecies abscessus (Mab) pulmonary disease are not effective. We identified 16 drugs with potential to build new regimens, translating to 560 possible three-drug combination regimens. Objectives To determine MICs and efficacy of drugs from different antibiotic classes for treatment against Mab, in order to winnow down the potential drugs for combination therapy to tractable numbers, for future use in hollow-fibre studies. Methods The MICs of levofloxacin, minocycline, meropenem, imipenem, tedizolid, bedaquiline, azithromycin, clarithromycin, amikacin, vancomycin, delafloxacin, tebipenem/avibactam and omadacycline were determined for 20 Mab isolates. In addition, concentration–response studies with tedizolid, bedaquiline, clarithromycin, amikacin, tebipenem/avibactam, cefdinir, faropenem, omadacycline and daunorubicin were performed and data were fitted to the inhibitory sigmoid Emax model. Efficacy was defined as maximal kill, expressed as cfu/mL kill below day 0 burden. Results The lowest MICs among the 13 antibiotics were of bedaquiline, tebipenem/avibactam and omadacycline. The antibiotics that killed Mab below the day 0 burden were the anticancer agent daunorubicin (3.36 log10 cfu/mL), cefdinir (1.85 log10 cfu/mL), faropenem (2.48 log10 cfu/mL) and tebipenem/avibactam (1.71 log10 cfu/mL kill). The EC50 values of these drugs were 11.67, 9.52, 48.2 and 0.33 mg/L, respectively, below peak concentrations of these drugs. Conclusions The low MICs and efficacy at clinically achievable concentrations mean that tebipenem/avibactam, daunorubicin, omadacycline and bedaquiline give a view of components of a three-drug regimen likely to effectively kill Mab. We propose pharmacokinetic/pharmacodynamic studies to identify such a regimen and the doses to be combined.

scholarly journals The validity of the sigmoid Emax model and efficiency concept in diuretic studies [letter]

1991 ◽  
Vol 31 (2) ◽  
pp. 210-211 ◽  
Author(s):  
G. Alvan ◽  
M. Hammarlund-Udenaes ◽  
B. Odlind
Keyword(s):  
Emax Model ◽  
Sigmoid Emax Model

scholarly journals Pharmacokinetics and Pharmacodynamics of Remimazolam (CNS 7056) after Continuous Infusion in Healthy Male Volunteers

2020 ◽  
Vol 132 (4) ◽  
pp. 652-666 ◽  
Author(s):  
Andreas Eisenried ◽  
Jürgen Schüttler ◽  
Marco Lerch ◽  
Harald Ihmsen ◽  
Christian Jeleazcov
Keyword(s):  
Frequency Band ◽  
Sedation Score ◽  
Healthy Male ◽  
Emax Model ◽  
Healthy Male Volunteers ◽  
Male Volunteers ◽  
Prediction Probability ◽  
Continuous Eeg ◽  
Narcotrend Index ◽  
Sigmoid Emax Model

Abstract Background Remimazolam (CNS 7056) is a new ultra-short acting benzodiazepine for IV sedation. This study aimed to investigate the electroencephalogram (EEG) pharmacodynamics of remimazolam infusion. Methods Twenty healthy male volunteers received remimazolam as continuous IV infusion of 5 mg/min for 5 min, 3 mg/min for the next 15 min, and 1 mg/min for further 15 min. Continuous EEG monitoring was performed by a neurophysiologic system with electrodes placed at F3, F4, C3, C4, O1, O2, Cz, and Fp1 (10/20 system) and using the Narcotrend Index. Sedation was assessed clinically by using the Modified Observer’s Assessment of Alertness and Sedation scale. Pharmacodynamic models were developed for selected EEG variables and Narcotrend Index. Results EEG changes during remimazolam infusion were characterized by an initial increase in beta frequency band and a late increase in delta frequency band. The EEG beta ratio showed a prediction probability of Modified Observer’s Assessment of Alertness and Sedation score of 0.79, and could be modeled successfully using a standard sigmoid Emax model. Narcotrend Index showed a prediction probability of Modified Observer’s Assessment of Alertness and Sedation score of 0.74. The time course of Narcotrend Index was described by an extended sigmoid Emax model with two sigmoid terms and different plasma–effect equilibration times. Conclusions Beta ratio was identified as a suitable EEG variable for monitoring remimazolam sedation. Narcotrend Index appeared less suitable than the beta ratio for monitoring the sedative effect if remimazolam is administered alone. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

scholarly journals Pharmacodynamic modeling of the in vivo interaction between cefotaxime and ofloxacin by using serum ultrafiltrate inhibitory titers.

1997 ◽  
Vol 41 (5) ◽  
pp. 1108-1114 ◽  
Author(s):  
D E Nix ◽  
J H Wilton ◽  
J Hyatt ◽  
J Thomas ◽  
L C Strenkoski-Nix ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Volume Of Distribution ◽  
Pharmacodynamic Modeling ◽  
Emax Model ◽  
Test Organisms ◽  
Total Body ◽  
Randomized Crossover Study ◽  
Sigmoid Emax Model

The pharmacokinetics (PK) and pharmacodynamics (PD) of cefotaxime and ofloxacin and of their combination were examined in a three-period randomized crossover study involving 12 healthy adults. The PK of cefotaxime and ofloxacin were modeled. PD was assessed from the predicted concentrations in serum and serum untrafiltrate inhibitory titers for 10 test organisms. An inhibitory sigmoid Emax model based on the probability of bacterial growth was used, where Emax = 1 and EC50 is the concentration resulting in a 50% probability of growth. The total body clearance (CL(T)) and volume of distribution at steady state (V(SS)) for cefotaxime were 0.236 liters/kg/h and 0.207 liters/kg, respectively, for the monotherapy and 0.231 liters/kg/h and 0.208 liters/kg for the combination therapy. Ofloxacin exhibited PK parameters of 0.143 liters/kg/h for CL(T) and 1.20 liters/kg for V(SS) following the monotherapy and of 0.141 liters/kg/h for CL(T) and 1.16 liters/kg for V(SS) following combination therapy. For the combination therapy, an interaction term, theta, defined the type and relative extent of interaction. The range of observed theta values (-0.033 to 0.067) is consistent with an additive PD interaction according to standards similar to those used for the in vitro fractional inhibitory concentration index.

scholarly journals Pharmacokinetic-Pharmacodynamic (PK-PD) Modeling of Effect of Naringenin and Its Surface Modified Nanocarriers on Associated and Core Behaviors of Autism Spectrum Disorders (ASD)

2019 ◽  
Vol 6 (02) ◽  
pp. e41-e49
Author(s):  
Ranjana Bhandari ◽  
Jyoti K. Paliwal ◽  
Anurag Kuhad
Keyword(s):  
Autism Spectrum Disorders ◽  
Social Interaction ◽  
Repetitive Behavior ◽  
Autism Spectrum ◽  
Maximum Effect ◽  
Model Parameters ◽  
Emax Model ◽  
Spectrum Disorders ◽  
The Relationship ◽  
Sigmoid Emax Model

AbstractThe pharmacokinetic and pharmacodynamic (PK-PD) model was developed to describe the relationship between plasma/brain concentration of naringenin and its nanocarriers with behavioral and biochemical alterations in a rat model of autism spectrum disorders (ASD). Behavioral parameters like sensorimotor dysfunction, hyperlocomotion, anxiety-like behavior, social interaction, and repetitive behavior were investigated by rotarod, actophotometer, open-field, reciprocal social interaction, and repetitive self-grooming test respectively. Naringenin was administered in doses (25, 50, and 100 mg/kg) and in the form of its uncoated and glutathione as well as tween 80–coated PLGA nanocarriers (25 mg/kg) thrice daily (8 hourly). Sigmoid Emax model was applied to study the relationship between the concentration of naringenin in plasma/brain and behavioral effects (in terms of sensorimotor dysfunction, locomotor activity, anxiety-like behavior, social interaction ability, repetitive behavior) as well as biochemical changes (plasma levels of TNF-α, MMP-9, and HSP-70, and Pgp at BBB). Model parameters such as Eo, Emax, and EC50 indicate that maximum effect occurred after administration of GSH-coated naringenin nanoparticles and the minimum effect occurred with the 25 mg/kg dose of unencapsulated naringenin. The R2 value of 0.99 and small Akaike information criterion indicate the goodness of fit of the model. The PK-PD modeling done by sigmoid Emax model showed a positive correlation between plasma/brain drug concentration and neuroinflammatory markers as well as behaviors consistent with the ASD phenotype.  

Clinical Studies in Human Strongyloidiasis

1950 ◽  
Vol 16 (4) ◽  
pp. 743-756 ◽  
Author(s):  
Charles A. Jones
Keyword(s):  
Clinical Studies

Experimental and Clinical Studies of Malleus Fixation

2006 ◽  
Vol 2006 ◽  
pp. 90-91
Author(s):  
M.M. Paparella
Keyword(s):  
Clinical Studies
Sign in / Sign up

Export Citation Format

Share Document