Projections Research Inc.

Phoenixville, PA, United States

Projections Research Inc.

Phoenixville, PA, United States
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Mould D.R.,Projections Research Inc.
Clinical Pharmacology and Therapeutics | Year: 2012

Modeling during drug development is routinely used to integrate subject-level information, evaluate response, and inform clinical trials. Model-based meta-analysis (MBMA) combines aggregate safety and efficacy results from many trials. Because MBMA is based on results from large numbers of subjects, it increases the power to precisely detect small but clinically significant effects, providing a basis for quantitative drug development decisions and reducing time and cost. This Commentary describes an overview of MBMA and its application during drug development. © 2012 American Society for Clinical Pharmacology and Therapeutics.


Mould D.R.,Projections Research Inc. | Green B.,Projections Research Inc. | Green B.,Model Answers Pty Ltd
BioDrugs | Year: 2010

Monoclonal antibodies (mAbs) have complex pharmacology; pharmacokinetics and pharmacodynamics depend on mAb structure and target antigen. mAbs targeting soluble antigens often exhibit linear pharmacokinetic behavior, whereas mAbs targeting cell surface antigens frequently exhibit nonlinear behavior due to receptor-mediated clearance. Where nonlinear kinetics exist, clearance can change due to receptor loss following repeated dosing andor disease severity. mAb pharmacodynamics are often indirect, with delayed clinically relevant outcomes. This behavior provides challenges during clinical development; studies must be carefully planned to account for complexities specific to each agent.Selection of a starting dose for human studies can be difficult. Species differences in pharmacology need to be considered. Various metrics are available for scaling from animals to humans. Optimal dose selection should ensure uniform mAb exposure across all individuals. Traditional approaches such as flat dosing and variable dosing based upon body surface area or weight should be supported by pharmacokinetic and pharmacodynamic behavior, including target antigen and concurrent disease states. The use of loading doses or dose adjustments to improve clinical response is also a consideration.The evaluation of drug interactions requires innovative designs. Due to the pharmacokinetic properties of mAbs, interacting drugs may need to be administered for protracted periods. Consequently, population pharmacokinetic and pharmacodynamic model-based approaches are often implemented to evaluate mAb drug interactions. © 2010 Adis Data Information BV.


Mould D.R.,Projections Research Inc. | Upton R.N.,Projections Research Inc. | Upton R.N.,University of South Australia
CPT: Pharmacometrics and Systems Pharmacology | Year: 2013

Population pharmacokinetic models are used to describe the time course of drug exposure in patients and to investigate sources of variability in patient exposure. They can be used to simulate alternative dose regimens, allowing for informed assessment of dose regimens before study conduct. This paper is the second in a three-part series, providing an introduction into methods for developing and evaluating population pharmacokinetic models. Example model files are available in the Supplementary Data online. © 2013 ASCPT All rights reserved 2163-8306/12.


Mould D.R.,Projections Research Inc. | Dubinsky M.C.,Cedars Sinai Medical Center
Journal of Clinical Pharmacology | Year: 2015

Many marketed drugs exhibit high variability in exposure and response. While these drugs are efficacious in their approved indications, finding appropriate dose regimens for individual patients is not straightforward. Similar dose adjustment problems are also seen with drugs that have a complex relationship between exposure and response and/or a narrow therapeutic window. This is particularly true for monoclonal antibodies, where prolonged dosing at a sub-therapeutic dose can also elicit anti-drug antibodies which will further compromise safety and efficacy. Thus, finding appropriate doses quickly would represent a substantial improvement in healthcare. Dashboard systems, which are decision-support tools, offer an improved, convenient means of tailoring treatment for individual patients. This article reviews the clinical need for this approach, particularly with monoclonal antibodies, the design, development, and testing of such systems, and the likely benefits of dashboard systems in clinical practice. We focus on infliximab for reference. © 2015, The American College of Clinical Pharmacology.


Mould D.R.,Projections Research Inc.
Digestive Diseases | Year: 2015

Monoclonal antibodies (MAbs) exhibit complex pharmacokinetics (PK) and pharmacodynamics (PD, response) against tumor necrosis factor (TNF). Many factors impact anti-TNF MAb PK, altering MAb clearance and therefore the half-life: albumin, weight (particularly, obesity), disease (severity, stage and co-morbidities) and concomitant administration of immunosuppressants (e.g. methotrexate). These factors can alter MAb exposure, impacting on the likelihood of clinical response. Formation of anti-drug antibodies (ADAs) is another potential factor that can affect MAb PK. Factors impacting the likelihood of developing ADA are classified as patient-related (concomitant immunosuppressants, prior ADA against other anti-TNF MAb) or product-related (structure, manufacturing process, aggregate formation, route of administration and dosing regimen). Repeated episodic exposure can induce ADAs, shortening the effective treatment interval. Avoiding intervals where anti-TNF MAbs are non-measurable is important for efficacy and may delay onset of ADAs. Thus, patients whose factors predispose them to having faster clearance (or short half-life) such as severe disease, low albumin or high body weight may need shorter dose intervals to reduce the likelihood of intermittent exposure. ADAs can have no effect or can impact efficacy through MAb binding, thus inhibiting its function or potentially causing hypersensitivity reactions (PD). ADA can also increase MAb clearance (PK). Because of their impact on MAb clearance, ADAs have been linked to lower serum drug concentrations, potentially negatively impacting clinical response. ADAs have been reported for biologics in most therapeutic areas. ADAs are well documented in clinical studies due to the Food and Drug Administration and the European Medicines Agency recommendations regarding testing and impact of immunogenicity. Lastly, the dose metrics (e.g. mg vs. mg/kg) can cause issues as well. MAbs such as infliximab are dosed on a mg/kg basis, which commonly results in low concentrations in patients with low body weight. Conversely MAbs such as adalimumab are administered as a flat (mg) dose, which can result in low concentrations in high weight patients. © 2015 S. Karger AG, Basel.


Liu P.,Pfizer | Mould D.R.,Projections Research Inc.
Antimicrobial Agents and Chemotherapy | Year: 2014

To evaluate the exposure-response relationships for efficacy and safety of voriconazole and anidulafungin in adult patients with invasive aspergillosis (IA), a population pharmacokinetic-pharmacodynamic (PK-PD) analysis was performed with data from a phase 3, prospective, double-blind, comparative study evaluating voriconazole and anidulafungin combination therapy versus voriconazole (and placebo) monotherapy. Anidulafungin/placebo treatment duration was 2 to 4 weeks, and voriconazole treatment duration was 6 weeks. Efficacy (6-week all-causality mortality and 6-week global response [n=176]) and safety (hepatic [n=238], visual [n=199], and psychiatric [n=183] adverse events [AEs]) endpoints were analyzed separately using a binary logistic regression model. In IA patients receiving voriconazole monotherapy, no positive associations between voriconazole exposure and efficacy or safety were identified. In IA patients receiving combination therapy, no positive associations between voriconazole or anidulafungin exposures and efficacy were identified. The 6-week survival rate tended to increase as anidulafungin treatment duration increased; this finding should be considered with caution. Additionally, in IA patients receiving combination therapy, a positive association between voriconazole and anidulafungin exposures (area under the curve [AUC] and trough concentration [Cmin]) and hepatic AEs was established; a weak positive association between voriconazole exposure (AUC and Cmin) and psychiatric AEs was also established, but no association between voriconazole exposure and visual AEs was identified. Besides the drug exposures, no other covariates (i.e., CYP2C19 genotype status, age, weight, body mass index, sex, race, or neutropenia status) were identified as significant predictors of the efficacy and safety endpoints in IA patients. This study was registered on ClinicalTrials.gov (NCT00531479). Copyright © 2014, American Society for Microbiology. All Rights Reserved.


Mould D.R.,Projections Research Inc.
Clinical Pharmacology and Therapeutics | Year: 2016

Monoclonal antibodies (mAbs) have improved clinical outcomes for many therapeutic indications. However, extensive between-subject variability (BSV) contributes to therapeutic failures through suboptimal exposure. Therapeutic drug monitoring (TDM) is routinely implemented for inflammatory diseases; improving outcomes and reducing treatment costs. BSV can be more extensive with anticancer mAbs. Clearance BSV is associated with patient factors and disease burden, suggesting that TDM could benefit anticancer mAbs, as was seen with inflammatory disease, however, there are many hurdles. © 2015 ASCPT.


Mould D.R.,Projections Research Inc.
Clinical Pharmacology and Therapeutics | Year: 2012

Disease-progression models are useful tools in drug development. They increase the information obtained from clinical trials, improve study designs, and allow in silico evaluations of new treatment combinations and dose regimens. Disease-progression modeling can save time and strengthen "go/no-go" criteria. The use of meta-based modeling and the linking of disease progression to discrete clinical end points have improved the utility of this valuable approach. This article provides an overview of disease-progression evaluations using these new approaches.


Liu P.,Pfizer | Mould D.R.,Projections Research Inc.
Antimicrobial Agents and Chemotherapy | Year: 2014

To assess the pharmacokinetics (PK) of voriconazole and anidulafungin in patients with invasive aspergillosis (IA) in comparison with other populations, sparse PK data were obtained for 305 adults from a prospective phase 3 study comparing voriconazole and anidulafungin in combination versus voriconazole monotherapy (voriconazole, 6 mg/kg intravenously [IV] every 12 h [q12h] for 24 h followed by 4 mg/kg IV q12h, switched to 300 mg orally q12h as appropriate; with placebo or anidulafungin IV, a 200-mg loading dose followed by 100 mg q24h). Voriconazole PK was described by a two-compartment model with first-order absorption and mixed linear and time-dependent nonlinear (Michaelis-Menten) elimination; anidulafungin PK was described by a two-compartment model with first-order elimination. For voriconazole, the normal inverse Wishart prior approach was implemented to stabilize the model. Compared to previous models, no new covariates were identified for voriconazole or anidulafungin. PK parameter estimates of voriconazole and anidulafungin are in agreement with those reported previously except for voriconazole clearance (the nonlinear clearance component became minimal). At a 4-mg/kg IV dose, voriconazole exposure tended to increase slightly as age, weight, or body mass index increased, but the difference was not considered clinically relevant. Estimated voriconazole exposures in IA patients at 4 mg/kg IV were higher than those reported for healthy adults (e.g., the average area under the curve over a 12-hour dosing interval [AUC 0-12] at steady state was 46% higher); while it is not definitive, age and concomitant medications may impact this difference. Estimated anidulafungin exposures in IA patients were comparable to those reported for the general patient population. This study was approved by the appropriate institutional review boards or ethics committees and registered on ClinicalTrials.gov (NCT00531479). Copyright © 2014, American Society for Microbiology. All Rights Reserved.


Upton R.N.,University of South Australia | Mould D.R.,Projections Research Inc.
CPT: Pharmacometrics and Systems Pharmacology | Year: 2014

Population pharmacodynamic (PD) models describe the time course of drug effects, relating exposure to response, and providing a more robust understanding of drug action than single assessments. PD models can test alternative dose regimens through simulation, allowing for informed assessment of potential dose regimens and study designs. This is the third paper in a three-part series, providing an introduction into methods for developing and evaluating population PD models. Example files are available in the Supplementary Data.

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