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Article ; Online: Population pharmacokinetics/pharmacodynamics of anesthetics.

Olofsen, Erik / Dahan, Albert

The AAPS journal

2005 Volume 7, Issue 2, Page(s) E383–9

Abstract: In this article we review how population pharmacokinetic/pharmacodynamic (PD) modeling has evolved ...

Abstract	In this article we review how population pharmacokinetic/pharmacodynamic (PD) modeling has evolved in the specialty of anesthesiology, how anesthesiology benefited from the mixed-effects approach, and which features of modeling need careful attention. Key articles from the anesthesiology literature are selected to discuss the modeling of typical anesthesiological PD end points, such as level of consciousness and analgesia, interactions between hypnotics and analgesics, estimation with poor and sometimes rich data sets from populations of various sizes, covariate detection, covariances between random effects, and Bayesian forecasting.
MeSH term(s)	Anesthetics/pharmacokinetics ; Animals ; Humans ; Models, Biological ; Pharmacokinetics
Chemical Substances	Anesthetics
Language	English
Publishing date	2005-10-05
Publishing country	United States
Document type	Journal Article ; Review
ISSN	1550-7416
ISSN (online)	1550-7416
DOI	10.1208/aapsj070239
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Article ; Online: Population pharmacokinetic-pharmacodynamic model of subcutaneous bupivacaine in a novel extended-release microparticle formulation.

Storgaard, Ida Klitzing / Jensen, Elisabeth Kjær / Bøgevig, Søren / Balchen, Torben / Springborg, Anders Holten / Royal, Mike Allan / Møller, Kirsten / Werner, Mads Utke / Lund, Trine Meldgaard

Basic & clinical pharmacology & toxicology

2024 Volume 134, Issue 5, Page(s) 676–685

Abstract: The objective of this study was to develop a population pharmacokinetic-pharmacodynamic model ... threshold was used as a surrogate pharmacodynamic endpoint. Population pharmacokinetic ... The pharmacokinetics were best described by a two-compartment model with biphasic absorption as two parallel absorption ...

Abstract	The objective of this study was to develop a population pharmacokinetic-pharmacodynamic model of subcutaneously administered bupivacaine in a novel extended-release microparticle formulation for postoperative pain management. Bupivacaine was administered subcutaneously in the lower leg to 28 healthy male subjects in doses from 150 to 600 mg in a phase 1 randomized, placebo-controlled, double-blind, dose-ascending study with two different microparticle formulations, LIQ865A and LIQ865B. Warmth detection threshold was used as a surrogate pharmacodynamic endpoint. Population pharmacokinetic-pharmacodynamic models were fitted to plasma concentration-effect-time data using non-linear mixed-effects modelling. The pharmacokinetics were best described by a two-compartment model with biphasic absorption as two parallel absorption processes: a fast, zero-order process and a slower, first-order process with two transit compartments. The slow absorption process was found to be dose-dependent and rate-limiting for elimination at higher doses. Apparent bupivacaine clearance and the transit rate constant describing the slow absorption process both appeared to decrease with increasing doses following a power function with a shared covariate effect. The pharmacokinetic-pharmacodynamic relationship between plasma concentrations and effect was best described by a linear function. This model gives new insight into the pharmacokinetics and pharmacodynamics of microparticle formulations of bupivacaine and the biphasic absorption seen for several local anaesthetics.
MeSH term(s)	Humans ; Male ; Bupivacaine/pharmacology ; Models, Biological ; Double-Blind Method
Chemical Substances	Bupivacaine (Y8335394RO)
Language	English
Publishing date	2024-03-20
Publishing country	England
Document type	Randomized Controlled Trial ; Clinical Trial, Phase I ; Journal Article
ZDB-ID	2134679-3
ISSN	1742-7843 ; 1742-7835
ISSN (online)	1742-7843
ISSN	1742-7835
DOI	10.1111/bcpt.14004
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Article ; Online: Population pharmacokinetic and pharmacodynamic model of propofol externally validated in Korean elderly subjects.

Kim, Kyung Mi / Choi, Byung-Moon / Noh, Gyu-Jeong

Journal of pharmacokinetics and pharmacodynamics

2022 Volume 50, Issue 2, Page(s) 97–109

Abstract: ... of propofol for elderly subjects. A population PK-PD model was constructed using propofol plasma ... model) was assessed in a separate Korean elderly population and compared with that of the Eleveld model ... The Eleveld propofol pharmacokinetic (PK) model, which was developed based on a broad range ...

Abstract	The Eleveld propofol pharmacokinetic (PK) model, which was developed based on a broad range of populations, showed greater bias (- 27%) in elderly subjects in a previous validation study conducted by Vellinga and colleagues. We aimed to develop and externally validate a new PK-pharmacodynamic (PK-PD) model of propofol for elderly subjects. A population PK-PD model was constructed using propofol plasma concentrations and bispectral index (BIS) values that were obtained from 31 subjects aged 65 years older in previously published phase I studies. The predictive performance of the newly-developed PK-PD model (Choi model) was assessed in a separate Korean elderly population and compared with that of the Eleveld model. A three-compartment mammillary model using an allometric expression and a sigmoid E
MeSH term(s)	Humans ; Aged ; Propofol/pharmacokinetics ; Anesthetics, Intravenous/pharmacokinetics ; Models, Biological ; Republic of Korea
Chemical Substances	Propofol (YI7VU623SF) ; Anesthetics, Intravenous
Language	English
Publishing date	2022-12-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2041601-5
ISSN	1573-8744 ; 1567-567X
ISSN (online)	1573-8744
ISSN	1567-567X
DOI	10.1007/s10928-022-09836-6
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Article ; Online: General anesthesia in the pediatric population.

Cavuoto, Kara M / Rodriguez, Luis I / Tutiven, Jacqueline / Chang, Ta C

Current opinion in ophthalmology

2014 Volume 25, Issue 5, Page(s) 411–416

Abstract: ... neurodevelopmental delay; however, animal pharmacodynamics and pharmacokinetics do not directly correlate with human ... aware of current practices in pediatric anesthetic care, as well as the immediate- and long-term risks ... of general anesthetic exposure should be considered when recommending surgery, especially in light of the child's age ...

Abstract	Purpose of review: This article reviews the pertinent perioperative, intraoperative, and short- and long-term postoperative risks associated with general anesthesia in children undergoing ocular surgery. Recent findings: Animal studies suggest an association between general anesthesia and neurodevelopmental delay; however, animal pharmacodynamics and pharmacokinetics do not directly correlate with human metrics. Retrospective human studies present conflicting data. Further, prospective studies in humans are underway, with projected results available within the next 3-5 years. Summary: All surgeons should be aware of current practices in pediatric anesthetic care, as well as the immediate- and long-term risks of general anesthesia. Ophthalmologists with pediatric patients should be aware of the potentially life-threatening conditions associated with general anesthesia. Additionally, the relative lifelong risks and benefits of general anesthetic exposure should be considered when recommending surgery, especially in light of the child's age, health status, and necessity of multiple anesthetic events.
MeSH term(s)	Anesthesia, General/adverse effects ; Anesthesia, General/methods ; Animals ; Child ; Child, Preschool ; Developmental Disabilities/chemically induced ; Eye Diseases/surgery ; Humans ; Infant ; Intraoperative Complications ; Ophthalmology/methods ; Perioperative Care ; Postoperative Complications
Language	English
Publishing date	2014-09
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1049383-9
ISSN	1531-7021 ; 1040-8738
ISSN (online)	1531-7021
ISSN	1040-8738
DOI	10.1097/ICU.0000000000000088
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Zs.A 3047: Show issues

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Article ; Online: Pharmacokinetic-pharmacodynamic population modelling in paediatric anaesthesia and its clinical translation.

Morse, James D / Hannam, Jacqueline / Anderson, Brian J

Current opinion in anaesthesiology

2019 Volume 32, Issue 3, Page(s) 353–362

Abstract: ... pharmacokinetics and pharmacodynamics improve anaesthetic treatments and safety in diverse populations and clarify ... Purpose of review: Pharmacokinetic-pharmacodynamic (PKPD) population modelling has advanced adult ...

Abstract	Purpose of review: Pharmacokinetic-pharmacodynamic (PKPD) population modelling has advanced adult anaesthesia. Current literature was reviewed to discern use of this analytic technique for benefit in the perioperative management of children. Recent findings: Variability in drug response, selection of a dose that achieves a desired target concentration and optimizing sampling protocols for further studies are all facets of paediatric anaesthesia that have benefitted from modelling approaches. PKPD models have driven the maintenance dose rate in target-controlled infusion pumps used for total intravenous anaesthesia. Although many of the models used in these pumps were developed in adults, translation for paediatric use has followed, including subgroups, such as neonates and obese children. The use of drug effect measures (e.g. bispectral index) has improved the predictive performance of pharmacodynamic models. Simulation studies have facilitated an increase in safety by quantifying drug variability, and identifying where possible adverse drug events may occur. Summary: Modelling and simulation continue to have an important role optimizing drug use during anaesthesia. Models incorporating influential covariates that better describe drug pharmacokinetics and pharmacodynamics improve anaesthetic treatments and safety in diverse populations and clarify drug role and impact. Their use developing paediatric clinical studies improves trial conduct, often with fewer subjects required for study.
MeSH term(s)	Anesthesia/methods ; Anesthetics/pharmacology ; Child ; Humans ; Models, Biological
Chemical Substances	Anesthetics
Language	English
Publishing date	2019-05-02
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	645203-6
ISSN	1473-6500 ; 0952-7907
ISSN (online)	1473-6500
ISSN	0952-7907
DOI	10.1097/ACO.0000000000000725
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Zs.A 2564: Show issues

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Article ; Online: Population pharmacokinetic and pharmacodynamic model of propofol externally validated in children.

Choi, Byung-Moon / Lee, Hyun-Gu / Byon, Hyo-Jin / Lee, Soo-Han / Lee, Eun-Kyung / Kim, Hee-Soo / Noh, Gyu-Jeong

Journal of pharmacokinetics and pharmacodynamics

2015 Volume 42, Issue 2, Page(s) 163–177

Abstract: ... values were measured. Population pharmacokinetic and pharmacodynamic analysis was performed using ... of propofol obtained in a single population of children, by which propofol can be administered using a target ... nonlinear mixed effects modeling. External model validation was performed in a separate population ...

Abstract	There have been no pharmacokinetic parameters and blood-brain equilibration rate constant (k e0) of propofol obtained in a single population of children, by which propofol can be administered using a target effect-site concentration controlled infusion. Thirty-nine, American Society of Anesthesiologists Physical Status 1-2 children aged 2-12 years were given an intravenous bolus of propofol (3 mg kg(-1)), followed by infusion (200 µg kg(-1) min(-1)). Arterial drug concentrations and bispectral index (BIS) values were measured. Population pharmacokinetic and pharmacodynamic analysis was performed using nonlinear mixed effects modeling. External model validation was performed in a separate population of children. A two-compartment model and a sigmoid E max model directly linked by an effect compartment well described the time courses of propofol concentration and BIS. The estimates of parameters were: V 1 (L) = 1.69, V 2 (L) = 27.2 + 0.929 × (weight - 25), Cl (L min(-1)) = 0.893 × (weight/23.6)(0.966), Q (L min(-1)) = 1.3; E 0 = 76.9; E max = 35.4, Ce 50 (μg mL(-1)) = 3.47 - (0.095 × age) - (1.63 × mean infusion rate of remifentanil in µg kg(-1) min(-1)); γ = 2.1; and k e0 (min(-1)) = 0.371. Pooled biases (95 % CI) of the target effect-site concentration controlled infusion system of propofol was -20.2 % (-23.3 to -18.1 %) and pooled inaccuracy was 30.4 % (28.6-32.7 %). Pooled biases of BIS prediction was -6.8 % (-9.1 to -4.1 %) and pooled inaccuracies was 19.1 % (17.5-20.9 %).The altered weight-based dose requirements of propofol are well described pharmacokinetically, and pharmacodynamically. Predictive performances of the TCI system in this study were clinically acceptable.
MeSH term(s)	Anesthetics, Intravenous/administration & dosage ; Anesthetics, Intravenous/pharmacokinetics ; Brain/metabolism ; Child ; Child, Preschool ; Female ; Humans ; Infusions, Intravenous/methods ; Injections, Intravenous/methods ; Male ; Models, Biological ; Piperidines/administration & dosage ; Piperidines/pharmacokinetics ; Propofol/administration & dosage ; Propofol/pharmacokinetics
Chemical Substances	Anesthetics, Intravenous ; Piperidines ; remifentanil (P10582JYYK) ; Propofol (YI7VU623SF)
Language	English
Publishing date	2015-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2041601-5
ISSN	1573-8744 ; 1567-567X
ISSN (online)	1573-8744
ISSN	1567-567X
DOI	10.1007/s10928-015-9408-2
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Article: Unique Aspects of the Elderly Surgical Population: An Anesthesiologist's Perspective.

Yang, Relin / Wolfson, Matthew / Lewis, Michael C

Geriatric orthopaedic surgery & rehabilitation

2012 Volume 2, Issue 2, Page(s) 56–64

Abstract: ... experience. Alterations affect both the pharmacodynamics and pharmacokinetics of administered drugs. Elderly ... growth of the elderly surgical population. In this group, age-associated changes and decreased ... anesthetic management. Consequently, the importance of conducting a focused preoperative evaluation and ...

Abstract	Increasing life expectancies paired with age-related comorbidities have resulted in the continued growth of the elderly surgical population. In this group, age-associated changes and decreased physiological reserve impede the body's ability to maintain homeostasis during times of physiological stress, with a subsequent decrease in physiological reserve. This can lead to age-related physiological and cognitive dysfunction resulting in perioperative complications. Changes in the cardiovascular, pulmonary, nervous, hepatorenal, endocrine, skin, and soft tissue systems are discussed as they are connected to the perioperative experience. Alterations affect both the pharmacodynamics and pharmacokinetics of administered drugs. Elderly patients with coexisting diseases are at a greater risk for polypharmacy that can further complicate anesthetic management. Consequently, the importance of conducting a focused preoperative evaluation and identifying potential risk factors is strongly emphasized. Efforts to maintain intraoperative normothermia have been shown to be of great importance. Procedures to maintain stable body temperature throughout the perioperative period are presented. The choice of anesthetic technique, in regard to a regional versus general anesthetic approach, is debated widely in the literature. The type of anesthesia to be administered should be assessed on a case-by-case basis, with special consideration given to the health status of the patient, the type of operation being conducted, and the expertise of the anesthesiologist. Specifically addressed in this article are age-related cognitive issues such as postoperative cognitive dysfunction and postoperative delirium. Strategies are suggested for avoiding these pitfalls.
Language	English
Publishing date	2012-12-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	2589094-3
ISSN	2151-4593 ; 2151-4585
ISSN (online)	2151-4593
ISSN	2151-4585
DOI	10.1177/2151458510394606
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Article ; Online: Age progression from vicenarians (20-29 year) to nonagenarians (90-99 year) among a population pharmacokinetic/pharmacodynamic (PopPk-PD) covariate analysis of propofol-bispectral index (BIS) electroencephalography.

Dahaba, Ashraf A / Xiao, Zhaoyang / Zhu, Xiaoling / Dong, Hailong / Xiong, Lize / Rehak, Peter / Zelzer, Sieglinde / Wang, Kun / Reibnegger, Gilbert

Journal of pharmacokinetics and pharmacodynamics

2020 Volume 47, Issue 2, Page(s) 145–161

Abstract: Background: Pharmacokinetic/pharmacodynamic (PK/PD) modeling has made an enormous contribution ...

Abstract	Background: Pharmacokinetic/pharmacodynamic (PK/PD) modeling has made an enormous contribution to intravenous anesthesia. Because of their altered physiological, pharmacological and pathological aspects, titrating general anesthesia in the elderly is a challenging task. Methods: Eighty patients were consecutively enrolled divided by decades from vicenarians (20-29 year) to nonagenarians (90-99 year) into eight groups. Using target controlled infusion (TCI) and electroencephalographic (EEG)-derived bispectral index (BIS) we set propofol plasma concentration (C Results: Age was significant covariate for baseline BIS effect (E Conclusion: We quantified and graded EEG-BIS age-progression among different age groups divided by decades. We demonstrated deeper BIS values with decades' age progression. Our data has important implications for propofol dosing. The practical information for physicians in their daily clinical practice is using propofol C Clinical trial registry numbers: European Community Clinical Trials Database EudraCT (http://eudract.emea.eu) initial trial registration number: 2011-002847-81, and subsequently registered at www.clinicaltrials.gov; trial registration number: NCT02585284. Xijing Hospital of Fourth Military Medical University ethics committee approval number 20110707-4.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Aging/physiology ; Algorithms ; Anesthesia, Intravenous ; Anesthetics, Intravenous/administration & dosage ; Anesthetics, Intravenous/pharmacokinetics ; Anesthetics, Intravenous/pharmacology ; Computer Simulation ; Consciousness Monitors ; Electroencephalography/drug effects ; Female ; Humans ; Infusions, Intravenous ; Male ; Middle Aged ; Propofol/administration & dosage ; Propofol/pharmacokinetics ; Propofol/pharmacology ; Prospective Studies ; Reproducibility of Results ; Young Adult
Chemical Substances	Anesthetics, Intravenous ; Propofol (YI7VU623SF)
Language	English
Publishing date	2020-02-25
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2041601-5
ISSN	1573-8744 ; 1567-567X
ISSN (online)	1573-8744
ISSN	1567-567X
DOI	10.1007/s10928-020-09678-0
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Article ; Online: Population pharmacokinetic-pharmacodynamic model of propofol in adolescents undergoing scoliosis surgery with intraoperative wake-up test: a study using Bispectral index and composite auditory evoked potentials as pharmacodynamic endpoints.

Blussé van Oud-Alblas, Heleen J / Brill, Margreke J E / Peeters, Mariska Y M / Tibboel, Dick / Danhof, Meindert / Knibbe, Catherijne A J

BMC anesthesiology

2019 Volume 19, Issue 1, Page(s) 15

Abstract: Background: In adolescents limited data are available on the pharmacokinetics (PK) and ... pharmacodynamics (PD) of propofol. In this study we derived a PK-PD model for propofol in adolescents undergoing ... Conclusions: A population PKPD model for propofol in adolescents was developed that successfully described ...

Abstract	Background: In adolescents limited data are available on the pharmacokinetics (PK) and pharmacodynamics (PD) of propofol. In this study we derived a PK-PD model for propofol in adolescents undergoing idiopathic scoliosis surgery with an intraoperative wake-up test with reinduction of anesthesia using both Bispectral Index (BIS) and composite A-line ARX index (cAAI) as endpoints. Methods: Fourteen adolescents (9.8-20.1 years) were evaluated during standardized propofol-remifentanil anesthesia for idiopathic scoliosis surgery with an intraoperative wake-up test with reinduction of anesthesia. BIS and cAAI were continuously measured and blood samples collected. A propofol PKPD model was developed using NONMEM. Results: The time courses of propofol concentrations, BIS and cAAI values during anesthesia, intra-operative wakeup and reduction of anesthesia were best described by a two-compartment PK model linked to an inhibitory sigmoidal Emax PD model. For the sigmoidal Emax model, the propofol concentration at half maximum effect (EC Conclusions: A population PKPD model for propofol in adolescents was developed that successfully described the time course of propofol concentration, BIS and cAAI in individuals upon undergoing scoliosis surgery with intraoperative wake-up test and reinduction of anesthesia. Large differences were demonstrated between both monitors. This may imply that BIS and cAAI measure fundamentally different endpoints in the brain.
MeSH term(s)	Adolescent ; Anesthetics, Intravenous/administration & dosage ; Anesthetics, Intravenous/pharmacokinetics ; Anesthetics, Intravenous/pharmacology ; Child ; Consciousness Monitors ; Evoked Potentials, Auditory/physiology ; Female ; Humans ; Male ; Models, Biological ; Monitoring, Intraoperative/methods ; Propofol/administration & dosage ; Propofol/pharmacokinetics ; Propofol/pharmacology ; Remifentanil/administration & dosage ; Scoliosis/surgery ; Wakefulness/physiology ; Young Adult
Chemical Substances	Anesthetics, Intravenous ; Remifentanil (P10582JYYK) ; Propofol (YI7VU623SF)
Keywords	covid19
Language	English
Publishing date	2019-01-22
Publishing country	England
Document type	Journal Article
ZDB-ID	2091252-3
ISSN	1471-2253 ; 1471-2253
ISSN (online)	1471-2253
ISSN	1471-2253
DOI	10.1186/s12871-019-0684-z
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Article ; Online: Population pharmacokinetic-pharmacodynamic modeling and dosing simulation of propofol maintenance anesthesia in severely obese adolescents.

Chidambaran, Vidya / Venkatasubramanian, Raja / Sadhasivam, Senthilkumar / Esslinger, Hope / Cox, Shareen / Diepstraten, Jeroen / Fukuda, Tsuyoshi / Inge, Thomas / Knibbe, Catherijne A J / Vinks, Alexander A

Paediatric anaesthesia

2015 Volume 25, Issue 9, Page(s) 911–923

Abstract: ... of propofol clearance. This study was aimed at characterizing pharmacokinetics (PK) and pharmacodynamics (PD ... Background: Optimal dosing of propofol to maintain appropriate anesthetic depth is challenging ...

Abstract	Background: Optimal dosing of propofol to maintain appropriate anesthetic depth is challenging in severely obese (SO) adolescents. We previously reported that total body weight (TBW) is predictive of propofol clearance. This study was aimed at characterizing pharmacokinetics (PK) and pharmacodynamics (PD) of propofol in SO adolescents, using bispectral index (BIS), and toward developing PK/PD model-based dosing guidelines. Methods: A prospective PK/PD study was conducted in 26 SO children and adolescents aged 9-18 years (body mass index 31-69 kg·m(-2)), undergoing surgery with intravenous propofol anesthesia clinically titrated by providers blinded to BIS. BIS data and propofol infusion schemes were recorded. Venous blood samples collected during and after propofol infusion were assayed for propofol concentrations. A propofol PK/PD model was developed using NONMEM and model-based simulations were performed to determine propofol dosing regimens targeting BIS of 50 ± 10. Results: A three-compartment PK model linked to a sigmoidal inhibitory Emax PD model by a first-order rate constant, adequately described the propofol concentration (n = 375) and BIS (n = 3334) data. TBW was the most predictive covariate for propofol clearance [CL (l·min(-1) ) = 1.65 × (TBW/70)(0.75)]. An effect-site propofol concentration of 3.19 μg·ml(-1) was estimated for half-maximal effect, with no identifiable predictive covariates. The proposed maintenance dosing regimen targeted to a BIS of 50 ± 10, based on our PK/PD model, was able to predict desired propofol concentrations and BIS in a representative obese teen when used in conjunction with accepted PK/PD models for children/obese adults (PK:Eleveld/PD: Cortinez), further supporting evidence for the dosing based on TBW. Conclusion: This is the first study to describe the PK/PD of propofol in SO adolescents. The proposed maintenance dosing regimen for propofol uses TBW in an allometric function as a dosing scalar, with an exponent of 0.75. Our results suggest no relevant effect of obesity on the propofol concentration-BIS relationship.
MeSH term(s)	Adolescent ; Anesthetics, Intravenous/pharmacology ; Child ; Dose-Response Relationship, Drug ; Drug Dosage Calculations ; Electroencephalography/drug effects ; Female ; Humans ; Male ; Models, Biological ; Obesity/complications ; Obesity/surgery ; Propofol/pharmacology ; Prospective Studies
Chemical Substances	Anesthetics, Intravenous ; Propofol (YI7VU623SF)
Language	English
Publishing date	2015-05-13
Publishing country	France
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1086049-6
ISSN	1460-9592 ; 1155-5645
ISSN (online)	1460-9592
ISSN	1155-5645
DOI	10.1111/pan.12684
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