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Article ; Online: Postprandial triglyceride reduction following acute treatment of a selective 5-hydroxytryptamine-2c agonist and characterization using a semi-physiological model.

Leohr, Jennifer / Heathman, Michael / Kjellsson, Maria C

2021 Volume 23, Issue 4, Page(s) 1001–1010

Abstract: Aim: To investigate the tolerability, pharmacokinetics (PK) and postprandial triglyceride (TG) response of single, escalating oral doses of a selective 5-hydroxytryptamine-2c (5-HT: Materials and methods: This phase 1, single-centre, double-blind, ... ...

Abstract	Aim: To investigate the tolerability, pharmacokinetics (PK) and postprandial triglyceride (TG) response of single, escalating oral doses of a selective 5-hydroxytryptamine-2c (5-HT Materials and methods: This phase 1, single-centre, double-blind, randomized, placebo-controlled, four-period, two-alternating cohorts study evaluated single escalating oral doses ranging from 5 to 130 mg of LY2140112 (LY) in subjects with overweight/obesity (body mass index: 27-39 kg/m Results: Seventeen subjects entered the study and 16 subjects received at least one dose of LY. LY2140112 was generally well tolerated up to 75 mg. The PK of LY were described by a two-compartment model with first-order elimination. The 100 and 130 mg dose levels of LY significantly reduced the postprandial TG of VLDL-V6 by approximately 50%, while total TG and chylomicrons were not significantly different from placebo. The application of a published lipokinetic model successfully described the postprandial TG response in this study and indicated that LY reduced the conversion of TGs from chylomicron to VLDL-V6. Conclusions: LY significantly reduced the postprandial TG of VLDL-V6 following a single dose, when food consumption was controlled. The data indicate that a selective 5-HT
MeSH term(s)	Chylomicrons ; Humans ; Lipoproteins, VLDL ; Postprandial Period ; Serotonin ; Triglycerides
Chemical Substances	Chylomicrons ; Lipoproteins, VLDL ; Triglycerides ; Serotonin (333DO1RDJY)
Language	English
Publishing date	2021-01-20
Publishing country	England
Document type	Clinical Trial, Phase I ; Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	1454944-x
ISSN	1463-1326 ; 1462-8902
ISSN (online)	1463-1326
ISSN	1462-8902
DOI	10.1111/dom.14306
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Article ; Online: Incorporating Placebo Response in Quantitative Systems Pharmacology Models.

Wang, Evan B / Shen, Lei / Heathman, Michael / Chan, Jason R

CPT: pharmacometrics & systems pharmacology

2019 Volume 8, Issue 6, Page(s) 344–346

MeSH term(s)	Empirical Research ; Humans ; Models, Biological ; Pharmacology, Clinical/methods ; Placebo Effect ; Systems Biology/methods
Language	English
Publishing date	2019-06-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	2697010-7
ISSN	2163-8306 ; 2163-8306
ISSN (online)	2163-8306
ISSN	2163-8306
DOI	10.1002/psp4.12412
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Article ; Online: Semi-physiological model of postprandial triglyceride response in lean, obese and very obese individuals after a high-fat meal.

Leohr, Jennifer / Heathman, Michael / Kjellsson, Maria C

Diabetes, obesity & metabolism

2017 Volume 20, Issue 3, Page(s) 660–666

Abstract: Aims: To quantify the postprandial triglyceride (TG) response of chylomicrons and very-low-density lipoprotein-V6 (VLDL-V6) after a high-fat meal in lean, obese and very obese healthy individuals, using a mechanistic population lipokinetic modelling ... ...

Abstract	Aims: To quantify the postprandial triglyceride (TG) response of chylomicrons and very-low-density lipoprotein-V6 (VLDL-V6) after a high-fat meal in lean, obese and very obese healthy individuals, using a mechanistic population lipokinetic modelling approach. Methods: Healthy individuals from three body mass index population categories: lean (18.5-24.9 kg/m Results: The TGs in chylomicrons and VLDL-V6 particles had a prominent postprandial peak and represented the majority of the postprandial response; only the VLDL-V6 showed a difference across the populations. A turn-over model successfully described the TG concentration-time profiles of both chylomicrons and large VLDL-V6 particles after the high-fat meal. This model consisted of four compartments: two transit compartments for the lag between meal consumption and appearance of TGs in the blood, and one compartment each for the chylomicrons and large VLDL-V6 particles. The rate constants for the production of chylomicrons and elimination of large VLDL-V6 particles, along with the conversion rate of chylomicrons to large VLDL-V6 particles were well defined. Conclusions: This is the first lipokinetic model to describe the absorption of TGs from dietary fats into the blood stream and compares the dynamics of TGs in chylomicrons and large VLDL-V6 particles among lean, obese and very obese people. Such a model can be used to identify where pharmacological therapies act, thereby improving the determination of efficacy, and identifying complementary mechanisms for combinational drug therapies.
MeSH term(s)	Adult ; Chylomicrons/metabolism ; Diet, High-Fat ; Dietary Fats/pharmacology ; Healthy Volunteers ; Humans ; Lipoproteins, VLDL/metabolism ; Meals ; Obesity/metabolism ; Obesity, Morbid/metabolism ; Postprandial Period/physiology ; Thinness/metabolism ; Triglycerides/metabolism
Chemical Substances	Chylomicrons ; Dietary Fats ; Lipoproteins, VLDL ; Triglycerides
Language	English
Publishing date	2017-12-04
Publishing country	England
Document type	Clinical Trial ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1454944-x
ISSN	1463-1326 ; 1462-8902
ISSN (online)	1463-1326
ISSN	1462-8902
DOI	10.1111/dom.13138
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Article ; Online: Population pharmacokinetic meta-analysis of ramucirumab in cancer patients.

O'Brien, Lisa / Westwood, Paul / Gao, Ling / Heathman, Michael

British journal of clinical pharmacology

2017 Volume 83, Issue 12, Page(s) 2741–2751

Abstract: Aims: Ramucirumab is a human IgG1 monoclonal antibody that specifically binds vascular endothelial growth factor receptor-2 (VEGFR-2) and blocks binding of VEGF-A, VEGF-C and VEGF-D. The objective of the analysis was to characterize the clinical ... ...

Abstract	Aims: Ramucirumab is a human IgG1 monoclonal antibody that specifically binds vascular endothelial growth factor receptor-2 (VEGFR-2) and blocks binding of VEGF-A, VEGF-C and VEGF-D. The objective of the analysis was to characterize the clinical pharmacology profile of ramucirumab using a population pharmacokinetic approach. Methods: A total of 1639 patients with 6427 serum concentrations from 11 Phase 1b, 2 and 3 clinical trials in patients with various cancer indications were included in the analysis. Ramucirumab was administered as an intravenous infusion over 1 h at 8 mg kg Results: The pharmacokinetics of ramucirumab were well characterized by a two-compartment model. Mean population estimates of clearance, volume of distribution and half-life for a typical 68-kg patient were 0.0148 l h Conclusions: The final model adequately described the concentration-time profile of ramucirumab in patients with a range of cancer indications. The model confirmed that a weight-normalized dosing regimen is appropriate for ramucirumab therapy. Dose adjustment was not required for patients with mild to moderate renal impairment or mild hepatic impairment.
MeSH term(s)	Antibodies, Monoclonal/administration & dosage ; Antibodies, Monoclonal/adverse effects ; Antibodies, Monoclonal/blood ; Antibodies, Monoclonal/pharmacokinetics ; Antibodies, Monoclonal, Humanized ; Antineoplastic Agents, Immunological/administration & dosage ; Antineoplastic Agents, Immunological/adverse effects ; Antineoplastic Agents, Immunological/blood ; Antineoplastic Agents, Immunological/pharmacokinetics ; Area Under Curve ; Clinical Trials as Topic ; Half-Life ; Humans ; Infusions, Intravenous ; Metabolic Clearance Rate ; Models, Biological ; Neoplasms/blood ; Neoplasms/drug therapy ; Treatment Outcome ; Ramucirumab
Chemical Substances	Antibodies, Monoclonal ; Antibodies, Monoclonal, Humanized ; Antineoplastic Agents, Immunological
Language	English
Publishing date	2017-09-27
Publishing country	England
Document type	Journal Article ; Meta-Analysis
ZDB-ID	188974-6
ISSN	1365-2125 ; 0306-5251 ; 0264-3774
ISSN (online)	1365-2125
ISSN	0306-5251 ; 0264-3774
DOI	10.1111/bcp.13403
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Article ; Online: Pharmacokinetics of vaginal versus buccal misoprostol for labor induction at term.

Vorontsova, Yana / Haas, David M / Flannery, Kathleen / Masters, Andrea R / Silva, Larissa L / Pierson, Rebecca C / Yeley, Brittany / Hogg, Graham / Guise, David / Heathman, Michael / Quinney, Sara K

Clinical and translational science

2022 Volume 15, Issue 8, Page(s) 1937–1945

Abstract: The IMPROVE study (NCT02408315) compared the efficacy and safety of vaginal and buccal administration of misoprostol for full-term, uncomplicated labor induction. This report compares the pharmacokinetics of misoprostol between vaginal and buccal routes. ...

Abstract	The IMPROVE study (NCT02408315) compared the efficacy and safety of vaginal and buccal administration of misoprostol for full-term, uncomplicated labor induction. This report compares the pharmacokinetics of misoprostol between vaginal and buccal routes. Women greater than or equal to 14 years of age undergoing induction of labor greater than or equal to 37 weeks gestation without significant complications were randomized to vaginal or buccal misoprostol 25 μg followed by 50 μg doses every 4 h. Misoprostol acid concentrations were determined using liquid chromatography-tandem mass spectrometry for the first 8 h in a subgroup of participants. A population pharmacokinetic model was developed using NONMEM. Plasma concentrations (n = 469) from 47 women were fit to a one-compartment nonlinear clearance model. The absorption rate constant (k
MeSH term(s)	Administration, Buccal ; Administration, Intravaginal ; Biological Availability ; Female ; Humans ; Infant ; Labor, Induced/methods ; Misoprostol/adverse effects ; Misoprostol/pharmacokinetics ; Pregnancy
Chemical Substances	Misoprostol (0E43V0BB57)
Language	English
Publishing date	2022-06-12
Publishing country	United States
Document type	Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2433157-0
ISSN	1752-8062 ; 1752-8054
ISSN (online)	1752-8062
ISSN	1752-8054
DOI	10.1111/cts.13306
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Article ; Online: Pharmacokinetic modeling of R and S-Methadone and their metabolites to study the effects of various covariates in post-operative children.

Aruldhas, Blessed W / Quinney, Sara K / Overholser, Brian R / Heathman, Michael A / Masters, Andrea R / Ly, Reynold C / Gao, Hongyu / Packiasabapathy, Senthil / Sadhasivam, Senthilkumar

CPT: pharmacometrics & systems pharmacology

2021 Volume 10, Issue 10, Page(s) 1183–1194

Abstract: Methadone is a synthetic opioid used as an analgesic and for the treatment of opioid abuse disorder. The analgesic dose in the pediatric population is not well-defined. The pharmacokinetics (PKs) of methadone is highly variable due to the variability in ... ...

Abstract	Methadone is a synthetic opioid used as an analgesic and for the treatment of opioid abuse disorder. The analgesic dose in the pediatric population is not well-defined. The pharmacokinetics (PKs) of methadone is highly variable due to the variability in alpha-1 acid glycoprotein (AAG) and genotypic differences in drug-metabolizing enzymes. Additionally, the R and S enantiomers of methadone have unique PK and pharmacodynamic properties. This study aims to describe the PKs of R and S methadone and its metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) in pediatric surgical patients and to identify sources of inter- and intra-individual variability. Children aged 8-17.9 years undergoing orthopedic surgeries received intravenous methadone 0.1 mg/kg intra-operatively followed by oral methadone 0.1 mg/kg postoperatively every 12 h. Pharmacokinetics of R and S methadone and EDDP were determined using liquid chromatography tandem mass spectrometry assays and the data were modeled using nonlinear mixed-effects modeling in NONMEM. R and S methadone PKs were well-described by two-compartment disposition models with first-order absorption and elimination. EDDP metabolites were described by one compartment disposition models with first order elimination. Clearance of both R and S methadone were allometrically scaled by bodyweight. CYP2B6 phenotype was a determinant of the clearance of both the enantiomers in an additive gene model. The intronic CYP3A4 single-nucleotide polymorphism (SNP) rs2246709 was associated with decreased clearance of R and S methadone. Concentrations of AAG and the SNP of AAG rs17650 independently increased the volume of distribution of both the enantiomers. The knowledge of these important covariates will aid in the optimal dosing of methadone in children.
MeSH term(s)	Adolescent ; Analgesics, Opioid/pharmacokinetics ; Analgesics, Opioid/therapeutic use ; Biological Variation, Individual ; Biological Variation, Population ; Child ; Female ; Humans ; Intraoperative Care ; Male ; Methadone/pharmacokinetics ; Methadone/therapeutic use ; Orthopedic Procedures ; Pain Management ; Pain, Postoperative/drug therapy ; Pharmacogenomic Variants ; Postoperative Care ; Pyrrolidines/pharmacokinetics ; Stereoisomerism
Chemical Substances	Analgesics, Opioid ; Pyrrolidines ; Methadone (UC6VBE7V1Z) ; 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (Z3LC48U94I)
Language	English
Publishing date	2021-08-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2697010-7
ISSN	2163-8306 ; 2163-8306
ISSN (online)	2163-8306
ISSN	2163-8306
DOI	10.1002/psp4.12687
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Article ; Online: Exposure-Response Modeling to Characterize the Relationship Between Ixekizumab Serum Drug Concentrations and Efficacy Responses at Week 12 in Patients With Moderate to Severe Plaque Psoriasis.

Chigutsa, Emmanuel / Velez de Mendizabal, Nieves / Chua, Laiyi / Heathman, Michael / Friedrich, Stuart / Jackson, Kimberley / Reich, Kristian

Journal of clinical pharmacology

2018 Volume 58, Issue 11, Page(s) 1489–1500

Abstract: Ixekizumab, a high-affinity monoclonal antibody, selectively targets interleukin-17A and has been shown to be efficacious in the treatment of moderate to severe psoriasis. The objective was to describe the relationship between ixekizumab concentrations ... ...

Abstract	Ixekizumab, a high-affinity monoclonal antibody, selectively targets interleukin-17A and has been shown to be efficacious in the treatment of moderate to severe psoriasis. The objective was to describe the relationship between ixekizumab concentrations and efficacy response (static Physician Global Assessment [sPGA] and the Psoriasis Activity and Severity Index [PASI) scores] after 12 weeks of ixekizumab treatment in psoriasis patients from 3 phase 3 studies. Data from 2888 psoriasis patients randomized to receive placebo or 80 mg ixekizumab every 2 weeks or every 4 weeks were analyzed. Separate logistic regression models describing the relationship between ixekizumab concentrations and sPGA or PASI scores at week 12 were used to determine the probability of patients achieving a response and to investigate the impact of various patient factors other than drug concentrations on response rates. Both dosing regimens were efficacious, with higher rates of response achieved with the higher range of observed ixekizumab concentrations after every-2-week dosing. Although higher bodyweight, palmoplantar involvement, lower baseline disease state, or high baseline C-reactive protein were associated with slightly lower response rates, the magnitude of effect of these factors on sPGA(0,1) response was small, with all subgroups able to achieve high levels of response. Other factors tested had no effect including age, sex, and antidrug antibody status. Logistic regression modeling of ixekizumab concentration and efficacy data accurately identified the proportion of responders using sPGA or PASI end points. The higher concentration ranges achieved with 80 mg every 2 weeks versus every 4 weeks were associated with higher response levels.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Antibodies, Monoclonal, Humanized/administration & dosage ; Antibodies, Monoclonal, Humanized/blood ; Antibodies, Monoclonal, Humanized/pharmacokinetics ; Antibodies, Monoclonal, Humanized/pharmacology ; Dermatologic Agents/administration & dosage ; Dermatologic Agents/blood ; Dermatologic Agents/pharmacokinetics ; Dermatologic Agents/pharmacology ; Female ; Humans ; Interleukin-17/antagonists & inhibitors ; Male ; Middle Aged ; Models, Biological ; Psoriasis/drug therapy ; Severity of Illness Index ; Treatment Outcome ; Young Adult
Chemical Substances	Antibodies, Monoclonal, Humanized ; Dermatologic Agents ; IL17A protein, human ; Interleukin-17 ; ixekizumab (BTY153760O)
Language	English
Publishing date	2018-06-07
Publishing country	England
Document type	Clinical Trial, Phase III ; Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	188980-1
ISSN	1552-4604 ; 0091-2700 ; 0021-9754
ISSN (online)	1552-4604
ISSN	0091-2700 ; 0021-9754
DOI	10.1002/jcph.1268
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Article ; Online: Population Pharmacokinetic Modeling of Olaratumab, an Anti-PDGFRα Human Monoclonal Antibody, in Patients with Advanced and/or Metastatic Cancer.

Mo, Gary / Baldwin, John R / Luffer-Atlas, Debra / Ilaria, Robert L / Conti, Ilaria / Heathman, Michael / Cronier, Damien M

Clinical pharmacokinetics

2017 Volume 57, Issue 3, Page(s) 355–365

Abstract: Background and objectives: Olaratumab is a recombinant human monoclonal antibody that binds to platelet-derived growth factor receptor-α (PDGFRα). In a randomized phase II study, olaratumab plus doxorubicin met its predefined primary endpoint for ... ...

Abstract	Background and objectives: Olaratumab is a recombinant human monoclonal antibody that binds to platelet-derived growth factor receptor-α (PDGFRα). In a randomized phase II study, olaratumab plus doxorubicin met its predefined primary endpoint for progression-free survival and achieved a highly significant improvement in overall survival versus doxorubicin alone in patients with advanced or metastatic soft tissue sarcoma (STS). In this study, we characterize the pharmacokinetics (PKs) of olaratumab in a cancer patient population. Methods: Olaratumab was tested at 15 or 20 mg/kg in four phase II studies (in patients with nonsmall cell lung cancer, glioblastoma multiforme, STS, and gastrointestinal stromal tumors) as a single agent or in combination with chemotherapy. PK sampling was performed to measure olaratumab serum levels. PK data were analyzed by nonlinear mixed-effect modeling techniques using NONMEM Results: The PKs of olaratumab were best described by a two-compartment PK model with linear clearance (CL). Patient body weight was found to have a significant effect on both CL and central volume of distribution (V Conclusion: The PKs of olaratumab were best described by a model with linear disposition. Patient body weight and tumor size were found to be significant covariates. The PKs of olaratumab were not affected by immunogenicity or chemotherapeutic agents.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Antibodies, Monoclonal/administration & dosage ; Antibodies, Monoclonal/pharmacokinetics ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/pharmacokinetics ; Antineoplastic Combined Chemotherapy Protocols/administration & dosage ; Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics ; Body Weight ; Disease-Free Survival ; Dose-Response Relationship, Drug ; Doxorubicin/administration & dosage ; Female ; Humans ; Male ; Middle Aged ; Models, Biological ; Neoplasm Metastasis ; Neoplasms/drug therapy ; Neoplasms/pathology ; Nonlinear Dynamics ; Receptor, Platelet-Derived Growth Factor alpha/antagonists & inhibitors ; Survival Rate ; Time Factors ; Young Adult
Chemical Substances	Antibodies, Monoclonal ; Antineoplastic Agents ; Doxorubicin (80168379AG) ; Receptor, Platelet-Derived Growth Factor alpha (EC 2.7.10.1) ; olaratumab (TT6HN20MVF)
Language	English
Publishing date	2017-08-07
Publishing country	Switzerland
Document type	Clinical Trial, Phase II ; Comparative Study ; Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	197627-8
ISSN	1179-1926 ; 0312-5963
ISSN (online)	1179-1926
ISSN	0312-5963
DOI	10.1007/s40262-017-0562-0
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Article: Prediction of prasugrel active metabolite concentrations from 2 downstream inactive metabolite concentrations using multilinear regression analysis.

Ernest, C Steven / Heathman, Michael A / Wrishko, Rebecca E

Journal of clinical pharmacology

2009 Volume 49, Issue 8, Page(s) 973–983

Abstract: Prasugrel is a thienopyridine prodrug that is metabolized to an active metabolite (Pras-AM), which inhibits adenosine diphosphate (ADP)-induced platelet aggregation. The study objective was to describe a multilinear regression correlation model that was ... ...

Abstract	Prasugrel is a thienopyridine prodrug that is metabolized to an active metabolite (Pras-AM), which inhibits adenosine diphosphate (ADP)-induced platelet aggregation. The study objective was to describe a multilinear regression correlation model that was used to quantitatively predict concentrations of Pras-AM from downstream inactive metabolites, R-119251 and R-106583, for the purpose of estimating Pras-AM exposure in patients in the TRITON-TIMI 38 substudies. The model development included 1462 Pras-AM, 1345 R-119251, and 1456 R-106583 concentration data points from 103 healthy participants with a prasugrel dose range of 15 to 80 mg. The model was shown to provide good correlation between predicted and observed concentrations with only a minor deviation of approximately 6% from the unity line and described the variability within approximately 4.5%. Examination of the data indicated that regardless of ethnicity, age, weight, moderate hepatic impairment, or renal impairment, predictions were reliable. Predicted Pras-AM concentrations in TRITON-TIMI 38 were comparable with historical data.
MeSH term(s)	Adolescent ; Adult ; Aged ; Clinical Trials, Phase III as Topic ; Dose-Response Relationship, Drug ; Female ; Humans ; Linear Models ; Male ; Middle Aged ; Models, Biological ; Piperazines/administration & dosage ; Piperazines/pharmacokinetics ; Platelet Aggregation Inhibitors/administration & dosage ; Platelet Aggregation Inhibitors/pharmacokinetics ; Prasugrel Hydrochloride ; Prodrugs ; Thiophenes/administration & dosage ; Thiophenes/pharmacokinetics ; Young Adult
Chemical Substances	Piperazines ; Platelet Aggregation Inhibitors ; Prodrugs ; R-138727 ; Thiophenes ; Prasugrel Hydrochloride (G89JQ59I13)
Language	English
Publishing date	2009-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	188980-1
ISSN	1552-4604 ; 0091-2700 ; 0021-9754
ISSN (online)	1552-4604
ISSN	0091-2700 ; 0021-9754
DOI	10.1177/0091270009340416
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Article ; Online: Clinical Pharmacokinetics of Dulaglutide in Patients with Type 2 Diabetes: Analyses of Data from Clinical Trials.

Geiser, Jeanne S / Heathman, Michael A / Cui, Xuewei / Martin, Jennifer / Loghin, Corina / Chien, Jenny Y / de la Peña, Amparo

Clinical pharmacokinetics

2016 Volume 55, Issue 5, Page(s) 625–634

Abstract: Background and objective: Dulaglutide is a long-acting glucagon-like peptide-1 receptor agonist administered as once-weekly subcutaneous injections for the treatment of type 2 diabetes (T2D). The clinical pharmacokinetics of dulaglutide were ... ...

Abstract	Background and objective: Dulaglutide is a long-acting glucagon-like peptide-1 receptor agonist administered as once-weekly subcutaneous injections for the treatment of type 2 diabetes (T2D). The clinical pharmacokinetics of dulaglutide were characterized in patients with T2D and healthy subjects. Methods: The pharmacokinetics of dulaglutide were assessed throughout clinical development, including conventional pharmacokinetic analysis in clinical pharmacology studies and population pharmacokinetic analyses of data from combined phase 2 and phase 3 studies in patients with T2D. The effects of potential covariates on dulaglutide population pharmacokinetics were evaluated using nonlinear mixed-effects models. Results: Dulaglutide gradually reached the maximum concentration in 48 h and had a terminal elimination half-life of 5 days. Steady state was achieved between the second and fourth doses. The accumulation ratio was 1.56 for the 1.5 mg dose. Intra-individual variability estimates for the area under the plasma concentration-time curve and the maximum concentration were both <17% [coefficient of variation (CV)]. There was no difference in pharmacokinetics between injection sites (arm, thigh or abdomen). Dulaglutide pharmacokinetics were well described by a two-compartment model with first-order absorption and elimination. The population clearance was estimated at 0.126 L/h [inter-individual variability (CV) 33.8%]. Age, body weight, sex, race and ethnicity did not influence dulaglutide pharmacokinetics to any clinically relevant degree. Conclusion: The pharmacokinetics of dulaglutide support once-weekly administration in patients with T2D. The pharmacokinetic findings suggest that dose adjustment is not necessary on the basis of body weight, sex, age, race or ethnicity or site of injection.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Diabetes Mellitus, Type 2/metabolism ; Drug Administration Routes ; Female ; Glucagon-Like Peptides/administration & dosage ; Glucagon-Like Peptides/analogs & derivatives ; Glucagon-Like Peptides/blood ; Glucagon-Like Peptides/pharmacokinetics ; Humans ; Hypoglycemic Agents/administration & dosage ; Hypoglycemic Agents/blood ; Hypoglycemic Agents/pharmacokinetics ; Immunoglobulin Fc Fragments/administration & dosage ; Immunoglobulin Fc Fragments/blood ; Male ; Middle Aged ; Recombinant Fusion Proteins/administration & dosage ; Recombinant Fusion Proteins/blood ; Recombinant Fusion Proteins/pharmacokinetics ; Young Adult
Chemical Substances	Hypoglycemic Agents ; Immunoglobulin Fc Fragments ; Recombinant Fusion Proteins ; Glucagon-Like Peptides (62340-29-8) ; dulaglutide (WTT295HSY5)
Language	English
Publishing date	2016-05
Publishing country	Switzerland
Document type	Clinical Trial, Phase I ; Clinical Trial, Phase II ; Clinical Trial, Phase III ; Journal Article
ZDB-ID	197627-8
ISSN	1179-1926 ; 0312-5963
ISSN (online)	1179-1926
ISSN	0312-5963
DOI	10.1007/s40262-015-0338-3
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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

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Full text online

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito