9 results on '"Michael Gautrois"'
Search Results
2. Oxycodone Effect on Pupil Constriction in Recreational Opioid Users: A Pharmacokinetic/Pharmacodynamic Meta-Analysis Approach
- Author
-
Michael Gautrois, Jens Rengelshausen, Anna Dari, Stefan Buller, Hans-Jürgen Stahlberg, and Jan Freijer
- Subjects
Pupil constriction ,Pharmacology ,Models, Biological ,030226 pharmacology & pharmacy ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,medicine ,Humans ,Pharmacology (medical) ,Administration, Intranasal ,Pharmacokinetic pharmacodynamic ,business.industry ,Pupil ,Constriction ,Confidence interval ,Analgesics, Opioid ,Opioid ,Pharmacodynamics ,Meta-analysis ,business ,Oxycodone ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Understanding the effect of oxycodone pharmacokinetics (PK) on µ-opioid receptor binding benefits from an integrated approach to compiling the results of multiple studies. The current pharmacokinetic/pharmacodynamic (PK/PD) model analysis brings together various studies to support the interpretation of newly collected PK/PD data, putting the new results into the perspective of the full concentration-effect curve. A two-step modeling approach was applied to characterize the PK of oxycodone and its PK/PD relationship for the pupil diameter as a biomarker for µ-opioid receptor binding in recreational opioid users. First, a model-based meta-analysis (MBMA) was used to quantify the state-of-the-art knowledge from seven published studies, each of which contained part of the data needed for full characterization. Subsequently, the estimated parameters with uncertainty from the MBMA were used as prior information for a model developed on newly collected clinical data after intranasal administration in a clinical abuse potential trial. The inclusion of intravenous data in the MBMA showed that the PK of oxycodone can be described by a two-compartmental model, and allowed for the estimation of absolute bioavailability after intranasal and oral administration. A hysteresis loop was observed when plotting plasma concentrations and pupil constriction, which was approximated using an effect compartment. The totality of literature data enabled the identification of a Hill equation for the drug effect. The model with prior information fitted successfully to the newly collected data, where most parameter estimates had their confidence intervals overlapping with the prior distribution. The new data led to a slightly lower intranasal absorption rate constant, explaining the longer apparent half-life of oxycodone in the newly collected data. The PK/PD model parameters were confirmed by the new data, leading to the following estimates: half maximal inhibitory concentration (IC50) of 26.5 ng/mL, maximum pupil restriction of 66.0% from baseline, and a Hill factor of 1.05. The new data confirmed the PK profile and the PK/PD relationship identified using the MBMA, resulting in similar parameter estimates except for the intranasal absorption rate constant. The latter was lower than in the MBMA and explained the slightly longer apparent half-life of oxycodone in the newly collected data.
- Published
- 2021
- Full Text
- View/download PDF
3. Multiple Dose Pharmacokinetics of Tapentadol Oral Solution for the Treatment of Moderate to Severe Acute Pain in Children Aged 2 to7 Years
- Author
-
Renata, Jończyk, Christoph, Beuter, Beata, Bulawa, Stefan, Buller, Christoph, Eibl, Christian, Elling, Michael, Gautrois, Jens, Rengelshausen, Carsten, Schmidt, Guido, Thömmes, and Feras, Khalil
- Abstract
This prospective, open-label trial was conducted to fulfil a post-approval commitment made to the competent authorities to extend the indication of the strong opioid analgesic tapentadol hydrochloride oral solution (OS) to the pediatric population.The trial assessed the pharmacokinetic (PK) profile of tapentadol, tapentadol-O-glucuronide and tapentadol-O-sulfate after administration of multiple doses of tapentadol OS (1.25 mg tapentadol/kg bodyweight every 4 h for up to 72 h) in children aged 2 to7 years after a painful event that produces acute pain requiring treatment with a strong analgesic. The obtained PK data were integrated into a previously developed population PK (popPK) model based on single-dose data and then a model-based PK evaluation was performed. The primary trial endpoint was the area under the concentration-time curve at steady state for the dosing interval (AUCTen children received tapentadol OS; all completed the trial. Multiple administrations of the trial medication resulted in tapentadol serum concentrations within the concentration range predicted by the previously developed popPK model. The estimated model-based AUCThe findings confirm the linear and predictable PK profile of tapentadol hydrochloride. The good agreement between the observed data and the model predictions shows the value of modelling and simulations in the planning and analysis of pediatric clinical trials and the ability to utilize the established PK models to predict multiple dose exposure.
- Published
- 2022
4. Optimizing study design in LPS challenge studies for quantifying drug induced inhibition of TNFα response: Did we miss the prime time?
- Author
-
Julia Larsson, Edmund Hoppe, Michael Gautrois, Marija Cvijovic, and Mats Jirstrand
- Subjects
Lipopolysaccharides ,Research Design ,Tumor Necrosis Factor-alpha ,Pharmaceutical Science - Abstract
In this work we evaluate the study design of LPS challenge experiments used for quantification of drug induced inhibition of TNFα response and provide general guidelines of how to improve the study design. Analysis of model simulated data, using a recently published TNFα turnover model, as well as the optimal design tool PopED have been used to find the optimal values of three key study design variables - time delay between drug and LPS administration, LPS dose, and sampling time points - that in turn could make the resulting TNFα response data more informative. Our findings suggest that the current rule of thumb for choosing the time delay should be reconsidered, and that the placement of the measurements after maximal TNFα response are crucial for the quality of the experiment. Furthermore, a literature study summarizing a wide range of published LPS challenge studies is provided, giving a broader perspective of how LPS challenge studies are usually conducted both in a preclinical and clinical setting.
- Published
- 2022
- Full Text
- View/download PDF
5. Second-generation TNFa turnover model for improved analysis of test compound interventions in LPS challenge studies
- Author
-
Julia Larsson, Marija Cvijovic, Edmund Hoppe, Mats Jirstrand, Michael Gautrois, and Publica
- Subjects
Lipopolysaccharides ,Lipopolysaccharide ,Tumor Necrosis Factor-alpha ,Provocation test ,Anti-Inflammatory Agents ,Pharmaceutical Science ,Pharmacology ,chemistry.chemical_compound ,Pharmacokinetics ,chemistry ,In vivo ,Pharmacodynamics ,medicine ,Potency ,Humans ,Tumor necrosis factor alpha ,Roflumilast ,medicine.drug - Abstract
This study presents a non-linear mixed effects model describing tumour necrosis factor alpha (TNFα) release after lipopolysaccharide (LPS) provocations in absence or presence of anti-inflammatory test compounds. Inter-occasion variability and the pharmacokinetics of two test compounds have been added to this second-generation model, and the goal is to produce a framework of how to model TNFα response in LPS challenge studies in vivo and demonstrate its general applicability regardless of occasion or type of test compound. Model improvements based on experimental data were successfully implemented and provided a robust model for TNFα response after LPS provocation, as well as reliable estimates of the median pharmacodynamic parameters. The two test compounds, Test Compound A and roflumilast, showed 81.1% and 74.9% partial reduction of TNFα response, respectively, and the potency of Test Compound A was estimated to 0.166 µmol/L. Comparing this study with previously published work reveals that our model leads to biologically reasonable output, handles complex data pooled from different studies, and highlights the importance of accurately distinguishing the stimulatory effect of LPS from the inhibitory effect of the test compound.
- Published
- 2021
6. Clinical Pharmacokinetic Characteristics of Cebranopadol, a Novel First-in-Class Analgesic
- Author
-
Robert Nemeth, Elke Kleideiter, Michael Gautrois, Shaonan Wang, and Chiara Piana
- Subjects
0301 basic medicine ,Agonist ,Indoles ,medicine.drug_class ,Population ,Analgesic ,Administration, Oral ,Pharmacology ,Models, Biological ,Drug Administration Schedule ,03 medical and health sciences ,Clinical Trials, Phase II as Topic ,0302 clinical medicine ,Oral administration ,Humans ,Medicine ,Spiro Compounds ,Pharmacology (medical) ,Dosing ,education ,education.field_of_study ,Clinical Trials, Phase I as Topic ,Dose-Response Relationship, Drug ,business.industry ,Cebranopadol ,Chronic pain ,Correction ,medicine.disease ,Analgesics, Opioid ,Nociceptin receptor ,030104 developmental biology ,business ,030217 neurology & neurosurgery ,Half-Life - Abstract
Cebranopadol is a novel first-in-class analgesic acting as a nociceptin/orphanin FQ peptide and opioid peptide receptor agonist with central analgesic activity. It is currently in clinical development for the treatment of chronic pain conditions. This trial focuses on the clinical pharmacokinetic (PK) properties of cebranopadol after oral single- and multiple-dose administration. The basic PK properties of cebranopadol were assessed by means of noncompartmental methods in six phase I clinical trials in healthy subjects and patients. A population PK analysis included two further phase I and six phase II clinical trials. After oral administration of the immediate-release (IR) formulation, cebranopadol is characterized by a late time to reach maximum plasma concentration [C max] (4–6 h), a long half-value duration [HVD] (14–15 h), and a terminal phase half-life in the range of 62–96 h. After multiple once-daily dosing in patients, an operational half-life (the dosing interval resulting in an accumulation factor [AF] of 2) of 24 h was found to be the relevant factor to describe the multiple-dose PKs of cebranopadol. The time to reach steady state was approximately 2 weeks, the AF was approximately 2, and peak-trough fluctuation (PTF) was low (70–80%). Dose proportionality at steady state was shown for a broad dose range of cebranopadol 200–1600 µg. A two-compartment disposition model with two lagged transition compartments and a first-order elimination process best describes cebranopadol data in healthy subjects and patients after single- and multiple-dose administration. Cebranopadol formulated as an IR product can be used as a once-daily formulation; it reaches C max after only 4–6 h, and has a long HVD and a low PTF. Therefore, from a PK perspective, cebranopadol is an attractive treatment option for patients with chronic pain.
- Published
- 2017
- Full Text
- View/download PDF
7. Correction to: Clinical Pharmacokinetic Characteristics of Cebranopadol, a Novel First-in-Class Analgesic
- Author
-
Robert Nemeth, Chiara Piana, Shaonan Wang, Elke Kleideiter, and Michael Gautrois
- Subjects
Pharmacology ,03 medical and health sciences ,0302 clinical medicine ,030202 anesthesiology ,Computer science ,Cebranopadol ,Analgesic ,Pharmacology toxicology ,Pharmacology (medical) ,Computational biology ,Original Research Article ,Clinical pharmacokinetic ,Class (biology) - Abstract
Background and Objectives Cebranopadol is a novel first-in-class analgesic acting as a nociceptin/orphanin FQ peptide and opioid peptide receptor agonist with central analgesic activity. It is currently in clinical development for the treatment of chronic pain conditions. This trial focuses on the clinical pharmacokinetic (PK) properties of cebranopadol after oral single- and multiple-dose administration. Methods The basic PK properties of cebranopadol were assessed by means of noncompartmental methods in six phase I clinical trials in healthy subjects and patients. A population PK analysis included two further phase I and six phase II clinical trials. Results After oral administration of the immediate-release (IR) formulation, cebranopadol is characterized by a late time to reach maximum plasma concentration [C max] (4–6 h), a long half-value duration [HVD] (14–15 h), and a terminal phase half-life in the range of 62–96 h. After multiple once-daily dosing in patients, an operational half-life (the dosing interval resulting in an accumulation factor [AF] of 2) of 24 h was found to be the relevant factor to describe the multiple-dose PKs of cebranopadol. The time to reach steady state was approximately 2 weeks, the AF was approximately 2, and peak-trough fluctuation (PTF) was low (70–80%). Dose proportionality at steady state was shown for a broad dose range of cebranopadol 200–1600 µg. A two-compartment disposition model with two lagged transition compartments and a first-order elimination process best describes cebranopadol data in healthy subjects and patients after single- and multiple-dose administration. Conclusions Cebranopadol formulated as an IR product can be used as a once-daily formulation; it reaches C max after only 4–6 h, and has a long HVD and a low PTF. Therefore, from a PK perspective, cebranopadol is an attractive treatment option for patients with chronic pain.
- Published
- 2018
8. Cebranopadol: A Novel Potent Analgesic Nociceptin/Orphanin FQ Peptide and Opioid Receptor Agonist
- Author
-
Thomas M. Tzschentke, Michael Gautrois, Wolfgang P. Schröder, Stefan Schunk, Werner Englberger, Horst Beier, Thomas Christoph, Klaus Schiene, Jean De Vry, Thomas Koch, Babette Kögel, Ulrich Jahnel, Klaus Linz, and Stefanie Frosch
- Subjects
Male ,Indoles ,medicine.drug_class ,NOP ,Analgesic ,Pain ,Bone Neoplasms ,CHO Cells ,(+)-Naloxone ,Pharmacology ,Rats, Sprague-Dawley ,Polyneuropathies ,Radioligand Assay ,Cricetulus ,Opioid receptor ,Cricetinae ,medicine ,Animals ,Spiro Compounds ,Rats, Wistar ,Behavior, Animal ,Chemistry ,Cebranopadol ,Cell Membrane ,Receptor antagonist ,Arthritis, Experimental ,Rats ,Analgesics, Opioid ,Nociceptin receptor ,Opioid Peptides ,Opioid ,Rotarod Performance Test ,Receptors, Opioid ,Molecular Medicine ,Female ,Protein Binding ,medicine.drug - Abstract
Cebranopadol (trans-6'-fluoro-4',9'-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine) is a novel analgesic nociceptin/orphanin FQ peptide (NOP) and opioid receptor agonist [Ki (nM)/EC50 (nM)/relative efficacy (%): human NOP receptor 0.9/13.0/89; human mu-opioid peptide (MOP) receptor 0.7/1.2/104; human kappa-opioid peptide receptor 2.6/17/67; human delta-opioid peptide receptor 18/110/105]. Cebranopadol exhibits highly potent and efficacious antinociceptive and antihypersensitive effects in several rat models of acute and chronic pain (tail-flick, rheumatoid arthritis, bone cancer, spinal nerve ligation, diabetic neuropathy) with ED50 values of 0.5-5.6 µg/kg after intravenous and 25.1 µg/kg after oral administration. In comparison with selective MOP receptor agonists, cebranopadol was more potent in models of chronic neuropathic than acute nociceptive pain. Cebranopadol's duration of action is long (up to 7 hours after intravenous 12 µg/kg; >9 hours after oral 55 µg/kg in the rat tail-flick test). The antihypersensitive activity of cebranopadol in the spinal nerve ligation model was partially reversed by pretreatment with the selective NOP receptor antagonist J-113397[1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one] or the opioid receptor antagonist naloxone, indicating that both NOP and opioid receptor agonism are involved in this activity. Development of analgesic tolerance in the chronic constriction injury model was clearly delayed compared with that from an equianalgesic dose of morphine (complete tolerance on day 26 versus day 11, respectively). Unlike morphine, cebranopadol did not disrupt motor coordination and respiration at doses within and exceeding the analgesic dose range. Cebranopadol, by its combination of agonism at NOP and opioid receptors, affords highly potent and efficacious analgesia in various pain models with a favorable side effect profile.
- Published
- 2014
- Full Text
- View/download PDF
9. Removal of SO2from the marine boundary layer over the Atlantic Ocean: A case study on the kinetics of the heterogeneous S(IV) oxidation on marine aerosols
- Author
-
Michael Gautrois, Wolfgang Jaeschke, Jan Burkert, Dirk Stöbener, Theo Brauers, Regina Staubes, and Udo Krischke
- Subjects
Atmospheric Science ,Planetary boundary layer ,Soil Science ,Aquatic Science ,Oceanography ,Atmospheric sciences ,Atmosphere ,chemistry.chemical_compound ,Reaction rate constant ,Geochemistry and Petrology ,Earth and Planetary Sciences (miscellaneous) ,Sulfate ,Southern Hemisphere ,Earth-Surface Processes ,Water Science and Technology ,Ecology ,Northern Hemisphere ,Paleontology ,Forestry ,Aerosol ,Plume ,Geophysics ,chemistry ,Space and Planetary Science ,Environmental science - Abstract
Measurements of SO2 and NSS-SO42− were made over the Atlantic Ocean on board the RV Polarstern from October 9 to November 2, 1996, as part of the ALBATROSS campaign. The measurements were performed between 66.7°N and 37.8°S with a mean longitude of approximately 30°W. The most frequent background values for SO2 were found to be 13 parts per trillion by volume (pptv) (0.54 nmol m−3 at standard ambient temperature and pressure (SATP)) in the Southern Hemisphere, and 15 pptv (0.62 nmol m−3 SATP) in the Northern Hemisphere. The mean values for total NSS-SO42− in particles with a d>0.2 μm were (5.99±2.93) nmol m−3 (SATP) in the Southern Hemisphere, and (8.93±5.29) nmol m−3 (SATP) in the Northern Hemisphere. An analysis of the size-fractionated aerosol samples (d >1 μm and 0.2 μm 1 μm. The main fraction of this NSS-SO42− is most likely produced by the oxidation of dissolved SO2 via heterogeneous reactions occurring in the aqueous phase of coarse mode marine aerosols. A case study on the kinetics of this oxidation pathway was conducted during ALBATROSS. October 12, 1996, the ship sailed in the plume of a volcano on Iceland during its eruption from September 30 to October 13, 1996, as indicated by trajectory analysis and by the measurements of NSS-SO42−, SO2, CO, and Hg. An empirical physicochemical approach considering the atmosphere as a natural flow reactor is used for the presented case study. The determined pseudo-first-order reaction rate constant for the oxidation of SO2 on marine aerosols is 3.31×10−4 s−1 at 25°C. Assuming that the occurrence of coarse mode marine aerosols is the rate-limiting variable of the reaction, the second-order reaction rate constant is found to be 1.32×10−6 cm3 s−1 particle−1 at 25°C. These values are in good agreement with results of previous field experiments as well as with the results of model studies.
- Published
- 2000
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.