Journal

 
  1. Population exposure-safety analysis of cediranib for Phase I and II studies in patients with cancer
  2. Impact of patient characteristics on the pharmacokinetics of corifollitropin alfa during controlled ovarian stimulation
  3. Montelukast in the treatment of perennial allergic rhinitis in paediatric Japanese patients; an open-label clinical trial
  4. Population pharmacokinetic and exposure simulation analysis for cediranib (AZD2171) in pooled Phase I/II studies in patients with cancer
  5. Exposure-Response and Tumor Growth Inhibition Analyses of the Monovalent Anti-c-MET Antibody Onartuzumab (MetMAb) in the Second- and Third-Line Non-Small Cell Lung Cancer
  6. Model-Based Characterization of the Pharmacokinetics of Pembrolizumab: A Humanized Anti-PD-1 Monoclonal Antibody in Advanced Solid Tumors
  7. Mathematical Modelling of Glucose-Dependent Insulinotropic Polypeptide and Glucagon-like Peptide-1 following Ingestion of Glucose. Basic & Clinical Pharmacology & Toxicology
  8. Model-Based Interspecies Scaling of Glucose Homeostasis
  9. Semimechanistic model describing gastric emptying and glucose absorption in healthy subjects and patients with type 2 diabetes
  10. Mechanism-Based Modeling of Gastric Emptying Rate and Gallbladder Emptying in Response to Caloric Intake
  11. Safety, Pharmacokinetics, and Pharmacodynamics in Healthy Volunteers Treated With GDC-0853, a Selective Reversible Bruton’s Tyrosine Kinase Inhibitor
  12. HATT: a phase IV, single-arm, open-label study of sorafenib in Taiwanese patients with advanced hepatocellular carcinoma
  13. Safety,Pharmacokinetics and Pharmacologic Effects of the Selective Androgen Receptor Modulator, GSK2881078, in Healthy Men and Postmenopausal Women
  14. Application of an NLME–Stochastic Deconvolution Approach to Level A IVIVC Modeling
  15. The Effects of Vehicle Mixtures on Transdermal Absorption: Thermodynamics, Mechanisms, Assessment, and Prediction. In: Dragicevic N., I. Maibach H. (eds) Percutaneous Penetration Enhancers Drug Penetration Into/Through the Skin
  16. Pharmacokinetics of 14 C-ortho-phenylphenol following intravenous administration in pigs: Pharmacokinetics of 14 C-ortho-phenylphenol in pigs
  17. Assessment of penetrant and vehicle mixture properties on transdermal permeability using a mixed effect pharmacokinetic model of ex vivo porcine skin: Model of Vehicle Mixture Effects on Ex Vivo Transdermal Permeability
  18. Stochastic nonlinear mixed effects: a metformin case study
  19. Using Kalman Filtering to Predict Time-Varying Parameters in a Model Predicting Baroreflex Regulation During Head-Up Tilt
  20. SAGE-547 Injection for the treatment of super-refractory status epilepticus: primary endpoints and response rates in relationship to underlying patient characteristics and comorbidities
  21. A Model-Based Meta-analysis to Compare Efficacy and Tolerability of Tramadol and Tapentadol for the Treatment of Chronic Non-Malignant Pain.
  22. Sex differences in hepatic one-carbon metabolism
  23. Systems biology of phenotypic robustness and plasticity
  24. Design and Testing of an EHR-Integrated, Busulfan Pharmacokinetic Decision Support Tool for the Point-of-Care Clinician
  25. Population pharmacokinetic and exposure simulation analysis for cediranib (AZD2171) in pooled Phase I/II studies in patients with cancer
  26. Exposure-Response and Tumor Growth Inhibition Analyses of the Monovalent Anti-c-MET Antibody Onartuzumab (MetMAb) in the Second- and Third-Line Non-Small Cell Lung Cancer
  27. Model-Based Characterization of the Pharmacokinetics of Pembrolizumab: A Humanized Anti-PD-1 Monoclonal Antibody in Advanced Solid Tumors
  28. Mathematical Modelling of Glucose-Dependent Insulinotropic Polypeptide and Glucagon-like Peptide-1 following Ingestion of Glucose. Basic & Clinical Pharmacology & Toxicology
  29. Model-Based Interspecies Scaling of Glucose Homeostasis
  30. Semimechanistic model describing gastric emptying and glucose absorption in healthy subjects and patients with type 2 diabetes
  31. Montelukast in the treatment of perennial allergic rhinitis in paediatric Japanese patients; an open-label clinical trial
  32. Exposure–Response Modeling and Simulation of Progression-Free Survival and Adverse Events of Sorafenib Treatment in Advanced Thyroid Cancer Patients
  • CS to FTIH
  • FTIH to PoC
  • PoC to Registration
  • Registration
  • Lifecycle Management

Objectives

Tools/Deliverables

Impact on Drug Development

Predict exposure-response relationship in humans.

  • Utilize PK/PD data from preclinical models to inform candidate selection and developability to FIH.
  • Estimated therapeutic dose range for humans.

Propose relevant dose range and design for FIH.

  • Model-predicted human PK.
  • Estimation of Minimum Anticipated Biological Effect Level (MABEL) and toxicological coverage for humans.
  • Estimate safe starting dose for humans.
  • Ensure that the proper dose range is studied.

Assess clinical drug-drug interaction (DDI) potential.

  • Preclinical drug metabolism data.
  • A qualitative prediction of clinical DDIs.
  • A quantitative prediction of clinical DDI magnitude.
  • Provide development strategy for clinical DDI studies and inclusion/exclusion of key con-meds in clinical trials.

Benchmark competitor compounds for precedented MOA (through development)

  • Meta- or a descriptive-analysis of relative potencies, therapeutic indices, DDI
  • Differentiate compound against key competitors.

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Objectives

Tools/Deliverables

Impact on Drug Development

Inform dose escalation and repeat dose decisions in human subjects.

  • NCA PK analyses.
  • Evaluation of systemic exposure and variability.
  • Determine steady-state and dose proportionality of systemic exposure.

 

  • Exposure in humans relative to pharmacologic target and toxicological risk informs appropriate dose escalation.
  • Estimate variability in systemic exposure.

Characterize the clinical PK in healthy subjects and/or patients

  • NCA PK analyses.
  • Population-PK-model of exposure and variability.
  • Early evaluation of potential inter-ethnic differences.
  • Sampling strategies for population PK-PK/PD analyses.
  • Determine early sources of variability in exposure.
  • Evaluate potential differences between healthy subjects and patients.

Provide rationale for dose regimen(s) for PoC studies.

  • Identify relationship between exposure and response to select appropriate dose regimens.
  • Estimate key parameters of pharmacological response.
  • Conduct model-based analysis of exposure-response, PK and drivers of variability.
  • Predictions of therapeutic index.
  • Enhanced understanding of benefit and risk and increase chances of a successful PoC.

Advocate for innovative trial designs

  • Model-based trial simulations including key drivers of outcome.
  • Adaptive trial design simulations.
  • Exposure-response power estimates
  • Non-traditional endpoint evaluations.

 

  • Improved drug development decisions using model-based simulations of the drug- and disease-time course

Initial evaluation of the risk of potential DDIs and Food Effect (FE)

  • Rationale (PK or PD), design, dose rationale, and interpretation of appropriate DDI studies
  • Recommend appropriate doses for future studies.

Initial assessment of QTc risk

  • Meta-analysis of concentration-QTc data from Phase 1/2a
  • Estimate QTc-risk potential to inform development strategy

Inform Pediatric Investigation Plan (PIP)/strategy

  • Pediatric development strategy. Exposure-response modeling to justify pediatric dose(s), study design(s) and PK sampling
  • Dose regimen(s) that provide optimal response for a range of ages and development groups  

Support EOP2a regulatory submission

  • Exposure-Response and Clinical Pharmacology sections of FDA End of Phase 2a briefing document and other global regulatory briefing documents
  • Regulatory review of rationale for dose regimen(s) based on exposure-response relationships,  Clinical Pharmacology strategy, Phase 2b study design

Inform and support formulation strategy

  • Apply modeling techniques (e.g. IVIVC) to predict in vivo performance of selected formulations.
  • Guide development of formulations to maximize the probability of success to deliver desired concentration-time profile in humans.

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Objectives

Tools/Deliverables

Impact on Drug Development

Characterize the clinical PK in larger patient populations

  • Population PK analyses of Phase 2b and Phase 3 studies with identification of covariates
  • Determine sources (intrinsic and extrinsic) of variability in exposure in patient populations.

Innovative dose-ranging trial design proposal

  • Clinical trial simulation of predicted dose response and power to estimate EC50/ED50 and other key parameters
  • Predict outcome for various trial designs, patient populations, endpoints to inform optimal designs

Execute dose- and model-based meta-analysis of exposure- response for key efficacy/safety endpoints

  • Simulation strategy to support selection of optimal Phase 2b/3 dose(s)
  • Apply population modeling methods to characterize exposure-response for labelling

 

  • Enhanced understanding of benefit and risk.
  • Dose regimen(s) and trial designs that deliver safety and efficacy for a differentiated product for patients that maximizes benefit and reduces risk.
  • Avoid replicate trials

Support/design Phase 1 studies:

  • Definitive Food Effect
  • Drug-drug interaction studies.
  • Bioequivalence study (if necessary).

               

  • Identification of appropriate studies. 
  • Rationale, design, analysis and interpretation of  PK
  • Identify appropriate dose and dose regimen for the appropriate patient population. 

Conduct definitive assessment of QTc risk

  • Concentration-QTc analysis of thorough QTc study
  • Clinical QTc-risk defined

Support EOP2 regulatory submission

  • Clinical Pharmacology sections of the FDA and EMA briefing documents
  • Regulatory review of rationale for dose regimen(s), Clinical Pharmacology strategy, Phase 3 study design

Evaluation of special populations (e.g., renal/hepatic impairment)

  • Clinical PK evaluation of exposure in special populations
  • Model-based extrapolation of alternative dosing regimens

 

  • Recommend appropriate doses in special populations (e.g., renal/ hepatic impairment)

Assessment of demographic
and responder/non-responder differences in exposure- response

  • Population PK/PD analyses with identification of significant covariates that impact PK and/or response
  • Identify groups that demonstrate different efficacy or safety based on exposure-response relationships

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Objectives

Tools/Deliverables

Impact on Drug Development

Deliver Clinical Pharmacology sections of global regulatory submissions (adults and pediatrics).

Enable registration in global markets
Enable use of non-EU/US data in EU/US

  • CTD Modules 2.7.1 and 2.7.2
  • Contribute to CTD Module 2.7.3 (dose justification) and Module 2.5
  • Labeling sections (i.e. PLR, PIL, GDS): Dosage and Administration, Drug Interactions, Use in Specific Populations, Clinical Pharmacology;  Clinical Studies/Contraindications/ Warnings/Precautions (as applicable)
  • Provide responses to regulatory questions pertaining to Clinical Pharmacology and dose
  • Clinical Pharmacology science (understanding of drug) and labelling optimal for appropriate use of medication in patients and for registration
  • Reduces / eliminates need for local studies, shortens approval times.

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Objective(s)

Deliverable(s)

Impact

  • Post-approval regulatory support 
  • Provide responses to regulatory questions pertaining to Clinical Pharmacology, labeling [PLR, GDS], registration in additional countries, post-approval studies
  • Clinical Pharmacology science (understanding of drug) and labelling optimal for appropriate use of medication in patients
  • Alternative indications and routes of administration
  • Dose regimen(s) rationale based on exposure-response and model extrapolation
  • Sections of regulatory submissions (as above)
  • Efficient Clinical Pharmacology strategy for appropriate use of medication in patients
  • Guide new formulation strategy
  • Apply modeling techniques (e.g IVIVC) to guide new formulation clinical development strategy
  • Formulation delivers desired concentration-time profile in humans

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