Certara’s Simcyp Division Awarded Modeling and Simulation Grant from the US FDA’s Office of Generic Drugs

PRINCETON, NJ – Oct. 19, 2016 – Certara announces that the Office of Generic Drugs (OGD), US Food and Drug Administration (FDA) has awarded it a multi-year research grant to create and validate a physiologically-based pharmacokinetic (PBPK) modeling and simulation framework that complements existing models within the Simcyp Population-based Simulator.

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Supporting Development of a New Antibacterial Drug

In recent years, proliferation of plasmids encoding extended-spectrum β-lactamases (ESBLs) has fueled the rise of multi-drug resistant Gram-negative bacterial infections. Avibactam inhibits class A and C serine β-lactamases, including KPC carbapenemases. While avibactam itself is not bactericidal, it restores the effectiveness of β-lactam antibiotics, including ceftazidime, against ESBL-producing pathogens. The sponsor sought to combine avibactam […]

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Month 2 culture status and treatment duration as predictors of recurrence in pulmonary tuberculosis: model validation and update.

New regimens capable of shortening tuberculosis treatment without increasing the risk of recurrence are urgently needed. A 2013 meta-regression analysis, using data from trials published from 1973 to 1997 involving 7793 patients, identified 2-month sputum culture status and treatment duration as independent predictors of recurrence. The resulting model predicted that if a new 4-month regimen […]

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Pharmacokinetic profile of defibrotide in patients with renal impairment.

Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is an unpredictable, potentially life-threatening complication of hematopoietic stem cell transplant conditioning. Severe VOD/SOS, generally associated with multiorgan dysfunction (pulmonary or renal dysfunction), may be associated with >80% mortality. Defibrotide, recently approved in the US, has demonstrated efficacy treating hepatic VOD/SOS with multiorgan dysfunction. Because renal […]

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Safety and pharmacokinetics of single and multiple ascending doses of avibactam alone and in combination with ceftazidime in healthy male volunteers: results of two randomized, placebo-controlled studies.

Avibactam is a novel non-β-lactam β-lactamase inhibitor effective against Ambler class A, C and some class D β-lactamases that is currently in clinical development in combination with ceftazidime for the treatment of serious Gram-negative infections. It restores the in vitro activity of a range of β-lactams, including ceftazidime, against extended-spectrum β-lactamase-producing pathogens. Two phase I […]

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Effect of age and sex on the pharmacokinetics and safety of avibactam in healthy volunteers

Avibactam is a novel non-β-lactam β-lactamase inhibitor currently being assessed in combination with ceftazidime, ceftaroline fosamil, and aztreonam. The objectives of this study were to investigate the pharmacokinetics, safety, and tolerability of avibactam in healthy young (aged 18-45 years) and elderly (aged ≥65 years) volunteers of both sexes. This was a Phase I, open-label study […]

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Population pharmacokinetic analysis of axitinib in healthy volunteers.

Axitinib is a potent and selective second generation inhibitor of vascular endothelial growth factor receptors 1, 2 and 3 approved for second line treatment of advanced renal cell carcinoma. The objectives of this analysis were to assess plasma pharmacokinetics and identify covariates that may explain variability in axitinib disposition following single dose administration in healthy […]

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Axitinib in metastatic renal cell carcinoma: results of a pharmacokinetic and pharmacodynamic analysis.

Axitinib is a potent and selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, approved for second-line therapy for advanced renal cell carcinoma (RCC). Axitinib population pharmacokinetic and pharmacokinetic/pharmacodynamic relationships were evaluated. Using nonlinear mixed effects modeling with pooled data from 383 healthy volunteers, 181 patients with metastatic RCC, and 26 patients […]

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Pharmacokinetics of Tramadol and O-Desmethyltramadol Enantiomers Following Administration of Extended-Release Tablets to Elderly and Young Subjects.

Tramadol is frequently used in geriatric patients; however, pharmacokinetic (PK) publications on tramadol and O-desmethyltramadol (ODM) in elderly patients are rare. Our objective was to characterize the PK of tramadol and ODM, including absorption processes and covariates for tramadol, in elderly and young subjects after single-dose administration of 200-mg extended-release tablets. We conducted a PK […]

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Population pharmacokinetic modeling of motesanib and its active metabolite, M4, in cancer patients.

Motesanib is a small molecule and potent multikinase inhibitor with antiangiogenic and antitumor activity. Population pharmacokinetic (POPPK) modeling of motesanib and M4, an active metabolite, was performed to assess sources of variability in cancer patients. The analysis included data collected from 451 patients from 8 clinical trials with oral doses of motesanib ranging from 25 […]

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Population pharmacokinetic/pharmacodynamic modeling of tumor growth kinetics in medullary thyroid cancer patients receiving cabozantinib.

Nonlinear mixed effects models were developed to describe the relationship between cabozantinib exposure and target lesion tumor size in a phase III study of patients with progressive metastatic medullary thyroid cancer. These models used cabozantinib exposure estimates from a previously published population pharmacokinetic model for cabozantinib in cancer patients that was updated with data from […]

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Modeling and Simulation to Support Phase 2 Dose Selection for RG7652, a Fully Human Monoclonal Antibody Against Proprotein Convertase Subtilisin/Kexin Type 9.

RG7652 is a fully humanized monoclonal antibody targeting human PCSK9, a regulator of serum low density lipoprotein cholesterol (LDLc) levels. RG7652 prevents degradation of the hepatic LDLc receptors by blocking PCSK9 binding and thereby resulting in efficient LDLc uptake by hepatocytes. The pharmacokinetics of RG7652 have been evaluated in healthy subjects after single and multiple […]

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Onartuzumab with or without bevacizumab in combination with weekly paclitaxel does not prolong QTc or adversely affect other ECG parameters in patients with locally recurrent or metastatic triple-negative breast cancer.

The purpose of this study was to examine the potential effect of onartuzumab, when administered with or without bevacizumab in combination with weekly paclitaxel, on the corrected QT interval (QTc) and other electrocardiogram (ECG) parameters, was investigated in a randomized, phase 2 study OAM4861g of first- or second-line therapy in patients with locally recurrent or […]

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Systems pharmacology: bridging systems biology and pharmacokinetics-pharmacodynamics (PKPD) in drug discovery and development

Suzanne Minton

Mechanistic PKPD models are now advocated not only by academic and industrial researchers, but also by regulators. A recent development in this area is based on the growing realisation that innovation could be dramatically catalysed by creating synergy at the interface between Systems Biology and PKPD, two disciplines which until now have largely existed in […]

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Phase 1 Study Assessing the Pharmacokinetic Profile and Safety of Avibactam in Patients with Renal Impairment.

Avibactam is a non-β-lactam β-lactamase inhibitor intended for use as a fixed-dose combination with ceftazidime for the treatment of certain serious Gram-negative infections. As avibactam is primarily excreted unchanged in the urine, renal impairment may affect its pharmacokinetics. This Phase 1 study investigated the effect of renal impairment and hemodialysis on avibactam pharmacokinetics and safety. […]

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Model-Based Meta-Analysis of the HbA1c Lowering Effect Of PF-04971729, a Sodium Glucose Co-Transporter-2 Inhibitor (SGLT2i), In Comparison to Other SGLT2i And Anti-Diabetic Agents (ADA)

PF-04971729 is a potent, selective SGLT2i in development for treatment of type 2 diabetes mellitus (T2DM). Since there is growing recognition of the need for comparative effectiveness of various ADA, a model was developed to quantify time course of dose vs HbA1c response of PF-04971729 relative to other ADA including SGLT2i, DPP4 inhibitors (DPP4i), GLP-1 […]

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Model-Based Meta-Analysis of the Effect on Body Weight of PF-04971729, a Sodium Glucose Co-Transporter-2 Inhibitor (SGLT2i), in Comparison to other SGLT2i and Anti-Diabetic Agents (ADA)

PF-04971729 is a potent, selective SGLT2i in development for treatment of type 2 diabetes mellitus (T2DM). Since there is growing recognition of the need for comparative effectiveness of various ADA, a model was developed to quantify the time course of dose vs body weight change for PF-04971729 relative to other ADA including SGLT2i, DPP4 inhibitors […]

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