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1.
CPT Pharmacometrics Syst Pharmacol ; 6(7): 439-448, 2017 07.
Article in English | MEDLINE | ID: mdl-28556506

ABSTRACT

Fosdagrocorat (PF-04171327), a dissociated agonist of the glucocorticoid receptor, has potent anti-inflammatory activity in patients with rheumatoid arthritis with reduced adverse effects on bone health. To identify fosdagrocorat doses with bone formation marker changes similar to prednisone 5 mg, we characterized treatment-related changes in amino-terminal propeptide of type I collagen (P1NP) and osteocalcin (OC) with fosdagrocorat (1, 5, 10, or 15 mg) and prednisone (5 or 10 mg) in a phase II randomized trial (N = 323). The time course of markers utilized a mixed-effects longitudinal kinetic-pharmacodynamic model. Median predicted changes from baseline at week 8 with fosdagrocorat 5, 10, and 15 mg were -18, -22, and -22% (P1NP), and -7, -13, and -17% (OC), respectively. Changes with prednisone 5 and 10 mg were -15% and -18% (P1NP) and -10% and -17% (OC). The probability of fosdagrocorat doses up to 15 mg being noninferior to prednisone 5 mg for P1NP and OC changes was >90%.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Arthritis, Rheumatoid/blood , Organophosphates/pharmacology , Osteocalcin/blood , Peptide Fragments/blood , Phenanthrenes/pharmacology , Prednisone/pharmacology , Procollagen/blood , Receptors, Glucocorticoid/agonists , Adolescent , Adult , Aged , Aged, 80 and over , Anti-Inflammatory Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Biomarkers/blood , Double-Blind Method , Female , Humans , Male , Middle Aged , Models, Biological , Organophosphates/therapeutic use , Phenanthrenes/therapeutic use , Prednisone/therapeutic use , Young Adult
2.
CPT Pharmacometrics Syst Pharmacol ; 5(6): 324-35, 2016 06.
Article in English | MEDLINE | ID: mdl-27318037

ABSTRACT

Exposure-response analysis of QT interval in clinical studies has been proposed as a thorough QT study alternative. Many exposure-response model structures have been proposed for cardiovascular (CV) safety markers, but few studies have compared models across multiple drugs. To recommend preferred drug-effect exposure-response models on vital signs and electrocardiogram (ECG) intervals, an individual-level model-based meta-analysis (39 studies and 1,291 subjects) compared 90 model structures. Models were selected to describe the data and cross-validate studies on the same drug. The most commonly selected baseline model was an unstructured model (estimation of a value at each study nominal time) for all measures but blood pressure. The unstructured model estimated a better cross-validated drug-effect when considering all markers. A linear model was the most commonly selected to characterize drug-effect on all markers. We propose these models as a starting point assisting with CV safety exposure-response assessment in nondedicated small studies with healthy subjects.


Subject(s)
Cardiovascular Diseases/chemically induced , Drug-Related Side Effects and Adverse Reactions/diagnosis , Models, Theoretical , Biomarkers/metabolism , Cardiovascular Diseases/physiopathology , Clinical Trials as Topic/methods , Electrocardiography , Humans , Linear Models , Long QT Syndrome/chemically induced
3.
J Pharm Biomed Anal ; 44(4): 985-90, 2007 Aug 15.
Article in English | MEDLINE | ID: mdl-17544609

ABSTRACT

A rapid, simple and sensitive LC-MS/MS analytical method was developed and validated for the determination of voriconazole (VRC) in rat plasma, using ketoconazole as internal standard (IS). Analysis was performed on a Shimadzu HPLC system using a Shimadzu C18 column and isocratic elution with acetonitrile-water-formic acid (60:40:0.05, v/v/v), at a flow of 1.0 mL/min (split ratio 1:5), and a mass spectrometer Micromass, equipped with a double quadrupole and an electrospray ionization interface, operated in a positive mode. Plasma samples were deproteinized with methanol (1:2) and 30 microL of the supernatant was injected into the system. The retention times of VRC and IS were approximately 3.3 and 2.7 min, respectively. Calibration curves in spiked plasma were linear over the concentration range of 50-2500 ng/mL with determination coefficient >0.98. The lower limit of quantification was 50 ng/mL. The accuracy of the method was within 5%. Intra- and inter-day relative standard deviations were less or equal to 12.5 and 7.7%, respectively. The applicability of the LC-MS-MS method for pharmacokinetic studies was tested using plasma samples obtained after intravenous administration of VRC to male Wistar rats. The reported method provided the necessary sensitivity, linearity, precision, accuracy, and specificity to allow the determination of VRC in pre-clinical pharmacokinetic studies.


Subject(s)
Antifungal Agents/blood , Pyrimidines/blood , Triazoles/blood , Animals , Antifungal Agents/pharmacokinetics , Chromatography, Liquid , Injections, Intravenous , Male , Mass Spectrometry , Pyrimidines/pharmacokinetics , Quality Control , Rats , Rats, Wistar , Reference Standards , Reproducibility of Results , Solvents , Triazoles/pharmacokinetics , Voriconazole
4.
J Pharm Biomed Anal ; 43(2): 677-82, 2007 Jan 17.
Article in English | MEDLINE | ID: mdl-16979864

ABSTRACT

A simple and sensitive LC-MS/MS analytical method was developed and validated for the determination of LASSBio-579 in plasma rat, using fluconazole as internal standard. Analyses were performed on a Shimadzu HPLC system using a Shimadzu C18 column and isocratic elution with acetonitrile-water (80:20, v/v), containing 0.4mM ammonium hydroxide and 0.2 mM acetic acid at a flow rate of 1.0 ml/min (split ratio 1:5). A Micromass triple quadrupole mass spectrometer, equipped with an electrospray ionization interface, operated in the positive mode. Plasma samples were deproteinized with acetonitrile (1:2) and 50 microl of the supernatant were injected into the system. The retention times of LASSBio-579 and IS were approximately 4.7 and 2.4 min, respectively. Calibration curves in spiked plasma were linear over the concentration range of 30-2000 ng/ml with determination coefficient >0.98. The lower limit of quantification was 30 ng/ml. The accuracy of method was within 15%. Intra- and inter-day relative standard deviations were less or equal to 13.5% and 6.4%, respectively. The applicability of the LC-MS/MS method for pharmacokinetic studies was tested using plasma samples obtained after intraperitoneal administration of LASSBio-579 to male Wistar rats. No interference from endogenous substances was observed, showing the specificity of the method developed. The reported method can provide the necessary sensitivity, linearity, precision, accuracy, and specificity to allow the determination of LASSBio-579 in pre-clinical pharmacokinetic studies.


Subject(s)
Antipsychotic Agents/blood , Chromatography, High Pressure Liquid/methods , Piperazines/blood , Spectrometry, Mass, Electrospray Ionization/methods , Tandem Mass Spectrometry/methods , Animals , Antipsychotic Agents/administration & dosage , Antipsychotic Agents/pharmacokinetics , Chromatography, High Pressure Liquid/standards , Drug Evaluation, Preclinical/methods , Fluconazole/blood , Injections, Intraperitoneal , Linear Models , Male , Molecular Structure , Rats , Rats, Wistar , Reference Standards , Reproducibility of Results , Sensitivity and Specificity , Spectrometry, Mass, Electrospray Ionization/standards , Tandem Mass Spectrometry/standards , Time Factors
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