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Article ; Online: Employing zero-inflated beta distribution in an exposure-response analysis of TYK2/JAK1 inhibitor brepocitinib in patients with plaque psoriasis.

Tsamandouras, Nikolaos / Qiu, Ruolun / Hughes, Jim H / Sweeney, Kevin / Prybylski, John P / Banfield, Christopher / Nicholas, Timothy

Journal of pharmacokinetics and pharmacodynamics

2024

Abstract: Brepocitinib is an oral selective dual TYK2/JAK1 inhibitor and based on its cytokine inhibition profile is expected to provide therapeutic benefit in the treatment of plaque psoriasis. Efficacy data from a completed Phase 2a study in patients with ... ...

Abstract	Brepocitinib is an oral selective dual TYK2/JAK1 inhibitor and based on its cytokine inhibition profile is expected to provide therapeutic benefit in the treatment of plaque psoriasis. Efficacy data from a completed Phase 2a study in patients with moderate-to-severe plaque psoriasis were utilized to develop a population exposure-response model that can be employed to inform dose selection decisions for further clinical development. A modeling approach that employs the zero-inflated beta distribution was used to account for the bounded nature and distributional characteristics of the Psoriasis Area and Severity Index (PASI) score data. The developed exposure-response model provided an adequate description of the observed PASI scores across all the treatment arms tested and across both the induction and maintenance dosing periods of the study. In addition, the developed model exhibited a good predictive capacity with regard to the derived responder metrics (e.g., 75%/90%/100% improvement in PASI score [PASI75/90/100]). Clinical trial simulations indicated that the induction/maintenance dosing paradigm explored in this study does not offer any advantages from an efficacy perspective and that doses of 10, 30, and 60 mg once-daily may be suitable candidates for clinical evaluation in subsequent Phase 2b studies.
Language	English
Publishing date	2024-03-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	2041601-5
ISSN	1573-8744 ; 1567-567X
ISSN (online)	1573-8744
ISSN	1567-567X
DOI	10.1007/s10928-024-09901-2
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Article ; Online: Population Pharmacokinetics of Oral Brepocitinib in Healthy Volunteers and Patients.

Hughes, Jim H / Qiu, Ruolun / Banfield, Christopher / Dowty, Martin E / Nicholas, Timothy

Clinical pharmacology in drug development

2022 Volume 11, Issue 12, Page(s) 1447–1456

Abstract: ... of distribution were 18.7 L/h (78% coefficient of variation [CV]) and 136 L (60.5% CV), respectively. Absorption ... was rapid with an absorption constant of 3.46 h, with an absorption lag of 0.24 hours observed ...

Abstract	Brepocitinib is a tyrosine kinase 2 and Janus kinase 1 inhibitor in development for treatment of inflammatory autoimmune diseases. This analysis aimed to add to the pharmacokinetic knowledge of the medication, through development of a population pharmacokinetic model and identification of factors that affect drug disposition. Plasma samples from 5 clinical trials were collated, composed of healthy volunteers, patients with psoriasis and patients with alopecia areata taking oral brepocitinib. NONMEM was used to develop a population pharmacokinetic model, and patient demographics were tested as covariates. The final model was a 1-compartment model with first-order absorption. The typical values for apparent clearance and apparent volume of distribution were 18.7 L/h (78% coefficient of variation [CV]) and 136 L (60.5% CV), respectively. Absorption was rapid with an absorption constant of 3.46 h, with an absorption lag of 0.24 hours observed with the oral tablet formulation. The proportional residual error was found to be 52.7% CV in healthy volunteers and 87.5% CV in patients. High-fat meals were associated with a reduction in both the rate (69.9% lower) and extent (28.3% lower) of absorption, while Asian populations had reduced clearance (24.3% lower). Nonlinear pharmacokinetics were observed at doses of 175 mg and above, with a 35.1% higher relative bioavailability at these doses. There were insufficient data to describe this nonlinearity as a continuous relationship. This initial description of the population pharmacokinetics will act as a foundation for the model-informed drug development of brepocitinib and will facilitate future modeling of this medicine. ClinicalTrials.gov numbers NCT02310750 NCT03236493 NCT03656952 NCT02969018 NCT02974868.
MeSH term(s)	Humans ; Biological Availability ; Healthy Volunteers ; Janus Kinase Inhibitors/therapeutic use ; Psoriasis/drug therapy ; Clinical Trials as Topic
Chemical Substances	Janus Kinase Inhibitors
Language	English
Publishing date	2022-08-31
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2649010-9
ISSN	2160-7648 ; 2160-763X
ISSN (online)	2160-7648
ISSN	2160-763X
DOI	10.1002/cpdd.1163
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Article ; Online: Relationship Between Apparent Systemic Clearance of Vemurafenib and Toxicity in Patients With Melanoma.

Kichenadasse, Ganessan / Hughes, Jim Henry / Fahmy, Alia / Rowland, Andrew / Sorich, Michael J / Hopkins, Ashley H

Journal of clinical pharmacology

2021 Volume 61, Issue 9, Page(s) 1243–1248

Abstract: Vemurafenib, a B rapidly accelerated fibrosarcoma inhibitor, is commonly used in combination of cobimetinib for the treatment of melanoma. In the current study, we evaluated the relationship between vemurafenib exposure, as measured by the estimated ... ...

Abstract	Vemurafenib, a B rapidly accelerated fibrosarcoma inhibitor, is commonly used in combination of cobimetinib for the treatment of melanoma. In the current study, we evaluated the relationship between vemurafenib exposure, as measured by the estimated apparent clearance (CL
MeSH term(s)	Aged ; Antineoplastic Agents/adverse effects ; Antineoplastic Agents/pharmacokinetics ; Antineoplastic Agents/therapeutic use ; Azetidines/therapeutic use ; Dose-Response Relationship, Drug ; Female ; Humans ; Male ; Melanoma/drug therapy ; Metabolic Clearance Rate ; Middle Aged ; Patient Acuity ; Piperidines/therapeutic use ; Prospective Studies ; Vemurafenib/adverse effects ; Vemurafenib/pharmacokinetics ; Vemurafenib/therapeutic use
Chemical Substances	Antineoplastic Agents ; Azetidines ; Piperidines ; Vemurafenib (207SMY3FQT) ; cobimetinib (ER29L26N1X)
Language	English
Publishing date	2021-08-07
Publishing country	England
Document type	Clinical Trial, Phase II ; Clinical Trial, Phase III ; Journal Article ; Multicenter Study ; Randomized Controlled Trial
ZDB-ID	188980-1
ISSN	1552-4604 ; 0091-2700 ; 0021-9754
ISSN (online)	1552-4604
ISSN	0091-2700 ; 0021-9754
DOI	10.1002/jcph.1882
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Article ; Online: Predictions of Systemic, Intracellular, and Lung Concentrations of Azithromycin With Different Dosing Regimens Used in COVID-19 Clinical Trials.

Hughes, Jim H / Sweeney, Kevin / Ahadieh, Sima / Ouellet, Daniele

CPT: pharmacometrics & systems pharmacology

2020 Volume 9, Issue 8, Page(s) 435–443

Abstract: Azithromycin (AZ), a broad-spectrum macrolide antibiotic, is being investigated in patients with coronavirus disease 2019 (COVID-19). A population pharmacokinetic model was implemented to predict lung, intracellular poly/mononuclear cell (peripheral ... ...

Abstract	Azithromycin (AZ), a broad-spectrum macrolide antibiotic, is being investigated in patients with coronavirus disease 2019 (COVID-19). A population pharmacokinetic model was implemented to predict lung, intracellular poly/mononuclear cell (peripheral blood monocyte (PBM)/polymorphonuclear leukocyte (PML)), and alveolar macrophage (AM) concentrations using published data and compared against preclinical effective concentration 90% (EC
MeSH term(s)	Anti-Bacterial Agents/administration & dosage ; Anti-Bacterial Agents/pharmacokinetics ; Azithromycin/administration & dosage ; Azithromycin/pharmacokinetics ; COVID-19 ; Coronavirus Infections/drug therapy ; Dose-Response Relationship, Drug ; Humans ; Leukocytes, Mononuclear/metabolism ; Lung/metabolism ; Macrophages, Alveolar/metabolism ; Models, Biological ; Neutrophils/metabolism ; Pandemics ; Pneumonia, Viral/drug therapy ; Tissue Distribution
Chemical Substances	Anti-Bacterial Agents ; Azithromycin (83905-01-5)
Keywords	covid19
Language	English
Publishing date	2020-07-15
Publishing country	United States
Document type	Journal Article ; 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/psp4.12537
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Article ; Online: Photoactive imaging and therapy for colorectal cancer using a CEA-Affimer conjugated Foslip nanoparticle.

Khaled, Yazan S / Khot, M Ibrahim / Aiyappa-Maudsley, Radhika / Maisey, Thomas / Pramanik, Arindam / Tiernan, Jim / Lintern, Nicole / Al-Enezi, Eiman / Shamsuddin, Shazana H / Tomlinson, Darren / Coletta, Louise / Millner, Paul A / Hughes, Thomas A / Jayne, David G

Nanoscale

2024 Volume 16, Issue 14, Page(s) 7185–7199

Abstract: Theranostic nanoparticles hold promise for simultaneous imaging and therapy in colorectal cancer. Carcinoembryonic antigen can be used as a target for these nanoparticles because it is overexpressed in most colorectal cancers. Affimer reagents are ... ...

Abstract	Theranostic nanoparticles hold promise for simultaneous imaging and therapy in colorectal cancer. Carcinoembryonic antigen can be used as a target for these nanoparticles because it is overexpressed in most colorectal cancers. Affimer reagents are synthetic proteins capable of binding specific targets, with additional advantages over antibodies for targeting. We fabricated silica nanoparticles using a water-in-oil microemulsion technique, loaded them with the photosensitiser Foslip, and functionalised the surface with anti-CEA Affimers to facilitate fluorescence imaging and photodynamic therapy of colorectal cancer. CEA-specific fluorescence imaging and phototoxicity were quantified in colorectal cancer cell lines and a LS174T murine xenograft colorectal cancer model. Anti-CEA targeted nanoparticles exhibited CEA-specific fluorescence in the LoVo, LS174T and HCT116 cell lines when compared to control particles (
MeSH term(s)	Humans ; Animals ; Mice ; Carcinoembryonic Antigen ; Colorectal Neoplasms/diagnostic imaging ; Colorectal Neoplasms/drug therapy ; Colorectal Neoplasms/metabolism ; Cell Line, Tumor ; Nanoparticles/therapeutic use ; Mesoporphyrins
Chemical Substances	Carcinoembryonic Antigen ; temoporfin (FU21S769PF) ; Mesoporphyrins
Language	English
Publishing date	2024-04-04
Publishing country	England
Document type	Journal Article
ZDB-ID	2515664-0
ISSN	2040-3372 ; 2040-3364
ISSN (online)	2040-3372
ISSN	2040-3364
DOI	10.1039/d3nr04118b
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Article ; Online: Predictions of Systemic, Intracellular, and Lung Concentrations of Azithromycin With Different Dosing Regimens Used in COVID‐19 Clinical Trials

Jim H. Hughes / Kevin Sweeney / Sima Ahadieh / Daniele Ouellet

CPT: Pharmacometrics & Systems Pharmacology, Vol 9, Iss 8, Pp 435-

2020 Volume 443

Abstract: Azithromycin (AZ), a broad‐spectrum macrolide antibiotic, is being investigated in patients with coronavirus disease 2019 (COVID‐19). A population pharmacokinetic model was implemented to predict lung, intracellular poly/mononuclear cell (peripheral ... ...

Abstract	Azithromycin (AZ), a broad‐spectrum macrolide antibiotic, is being investigated in patients with coronavirus disease 2019 (COVID‐19). A population pharmacokinetic model was implemented to predict lung, intracellular poly/mononuclear cell (peripheral blood monocyte (PBM)/polymorphonuclear leukocyte (PML)), and alveolar macrophage (AM) concentrations using published data and compared against preclinical effective concentration 90% (EC90) for severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2). The final model described the data reported in eight publications adequately. Consistent with its known properties, concentrations were higher in AM and PBM/PML, followed by lung tissue, and lowest systemically. Simulated PBM/PML concentrations exceeded EC90 following the first dose and for ~ 14 days following 500 mg q.d. for 3 days or 500 mg q.d. for 1 day/250 mg q.d. on days 2–5, 10 days following a single 1,000 mg dose, and for > 20 days with 500 mg q.d. for 10 days. AM concentrations exceeded the 90% inhibitory concentration for > 20 days for all regimens. These data will better inform optimization of dosing regimens for AZ clinical trials.
Keywords	Therapeutics. Pharmacology ; RM1-950 ; covid19
Subject code	610
Language	English
Publishing date	2020-08-01T00:00:00Z
Publisher	Wiley
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Predictions of Systemic, Intracellular, and Lung Concentrations of Azithromycin With Different Dosing Regimens Used in COVID‐19 Clinical Trials

Hughes, Jim H. / Sweeney, Kevin / Ahadieh, Sima / Ouellet, Daniele

CPT: Pharmacometrics & Systems Pharmacology

2020 Volume 9, Issue 8, Page(s) 435–443

Keywords	Cardiology and Cardiovascular Medicine ; covid19
Language	English
Publisher	Wiley
Publishing country	us
Document type	Article ; Online
ZDB-ID	2697010-7
ISSN	2163-8306
ISSN	2163-8306
DOI	10.1002/psp4.12537
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Comparison of non-compartmental and mixed effect modelling methods for establishing bioequivalence for the case of two compartment kinetics and censored concentrations.

Hughes, Jim H / Upton, Richard N / Foster, David J R

Journal of pharmacokinetics and pharmacodynamics

2017 Volume 44, Issue 3, Page(s) 233–244

Abstract: Non-compartmental analysis (NCA) is regarded as the standard for establishing bioequivalence, despite its limitations and the existence of alternative methods such as non-linear mixed effects modelling (NLMEM). Comparisons of NCA and NLMEM in ... ...

Abstract	Non-compartmental analysis (NCA) is regarded as the standard for establishing bioequivalence, despite its limitations and the existence of alternative methods such as non-linear mixed effects modelling (NLMEM). Comparisons of NCA and NLMEM in bioequivalence testing have been limited to drugs with one-compartment kinetics and have included a large number of different approaches. A simulation tool was developed with the ability to rapidly compare NCA and NLMEM methods in determining bioequivalence using both R and NONMEM and applied to a drug with two-compartment pharmacokinetics. Concentration-time profiles were simulated where relative bioavailability, random unexplained variability (RUV) at the lower limit of quantification (LLOQ) differed between simulations. NLMEM analyses employed either the M1 or M3 methods for dealing with values below the LLOQ. It was used to elucidate the impact of changes in (i) RUV at the LLOQ, (ii) the extent of censoring data below the LLOQ and (iii) the concentration sampling times. The simulations showed NLMEM having a consistent 20-40% higher accuracy and sensitivity in identifying bioequivalent studies when compared to NCA, while NCA was found to have a 1-10% higher specificity than NLMEM. Increasing data censoring by increasing the LLOQ resulted in decreases of ~10% to the accuracy and sensitivity of NCA, with minimal effects on NLMEM. The tool provides a platform for comparing NCA and NLMEM methods and its use can be extended beyond the scenarios reported here. In the situations examined it is seen that NLMEM is more accurate than NCA and may offer some advantages in the determination of bioequivalence.
Language	English
Publishing date	2017
Publishing country	United States
Document type	Journal Article
ZDB-ID	2041601-5
ISSN	1573-8744 ; 1567-567X
ISSN (online)	1573-8744
ISSN	1567-567X
DOI	10.1007/s10928-017-9511-7
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Zs.A 980: Show issues

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Article ; Online: Imaging biomarkers of lung ventilation in interstitial lung disease from

Tibiletti, Marta / Eaden, James A / Naish, Josephine H / Hughes, Paul J C / Waterton, John C / Heaton, Matthew J / Chaudhuri, Nazia / Skeoch, Sarah / Bruce, Ian N / Bianchi, Stephen / Wild, Jim M / Parker, Geoff J M

Magnetic resonance imaging

2022 Volume 95, Page(s) 39–49

Abstract: Purpose: To compare imaging biomarkers from hyperpolarised : Study type: Prospective longitudinal.: Population: Forty-one ILD (fourteen idiopathic pulmonary fibrosis (IPF), eleven hypersensitivity pneumonitis (HP), eleven drug-induced ILD (DI-ILD), ...

Abstract	Purpose: To compare imaging biomarkers from hyperpolarised Study type: Prospective longitudinal. Population: Forty-one ILD (fourteen idiopathic pulmonary fibrosis (IPF), eleven hypersensitivity pneumonitis (HP), eleven drug-induced ILD (DI-ILD), five connective tissue disease related-ILD (CTD-ILD)) patients and ten healthy volunteers imaged at visit 1. Thirty-four ILD patients completed visit 2 (eleven IPF, eight HP, ten DIILD, five CTD-ILD) after 6 or 26 weeks. Field strength/sequence: MRI was performed at 1.5 T, including inversion recovery T Assessment: Five Statistical test: To evaluate differences at visit 1 among subgroups: ANOVA or Kruskal-Wallis rank tests with correction for multiple comparisons. To assess the relationships between imaging biomarkers, PFT, age and gender, at visit 1 and for the change between visit 1 and 2: Pearson correlations and multilinear regression models. Results: The global PFT tests could not distinguish ILD subtypes. Percentage ventilated volumes were lower in ILD patients than in HVs when measured with Data conclusion: Neither
MeSH term(s)	Humans ; Oxygen ; Prospective Studies ; Lung Diseases, Interstitial/diagnostic imaging ; Idiopathic Pulmonary Fibrosis/diagnosis ; Lung/diagnostic imaging ; Magnetic Resonance Imaging ; Biomarkers
Chemical Substances	Oxygen (S88TT14065) ; Biomarkers
Language	English
Publishing date	2022-10-15
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	604885-7
ISSN	1873-5894 ; 0730-725X
ISSN (online)	1873-5894
ISSN	0730-725X
DOI	10.1016/j.mri.2022.10.005
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Zs.A 1817: Show issues

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Article: Predictions of Systemic, Intracellular, and Lung Concentrations of Azithromycin With Different Dosing Regimens Used in COVID-19 Clinical Trials

Hughes, Jim H / Sweeney, Kevin / Ahadieh, Sima / Ouellet, Daniele

CPT Pharmacometrics Syst Pharmacol

Abstract	Azithromycin (AZ), a broad-spectrum macrolide antibiotic, is being investigated in patients with coronavirus disease 2019 (COVID-19). A population pharmacokinetic model was implemented to predict lung, intracellular poly/mononuclear cell (peripheral blood monocyte (PBM)/polymorphonuclear leukocyte (PML)), and alveolar macrophage (AM) concentrations using published data and compared against preclinical effective concentration 90% (EC90 ) for severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). The final model described the data reported in eight publications adequately. Consistent with its known properties, concentrations were higher in AM and PBM/PML, followed by lung tissue, and lowest systemically. Simulated PBM/PML concentrations exceeded EC90 following the first dose and for ~ 14 days following 500 mg q.d. for 3 days or 500 mg q.d. for 1 day/250 mg q.d. on days 2-5, 10 days following a single 1,000 mg dose, and for > 20 days with 500 mg q.d. for 10 days. AM concentrations exceeded the 90% inhibitory concentration for > 20 days for all regimens. These data will better inform optimization of dosing regimens for AZ clinical trials.
Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #574626
Database	COVID19

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