Best Practices in PBPK: The Case of Efavirenz

Lisa Almond

According to the FDA’s Guidance for Industry on Drug-drug interactions (DDIs), assessment of a new drug’s DDI liability has three major objectives: determining whether any interactions necessitate dosing adjustment, informing the extent of therapeutic monitoring that may be required and identifying any potential contraindications to concomitant use when lesser measures cannot mitigate risk Physiologically-based pharmacokinetic […]

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Topics: Drug Safety, PBPK Modeling and Simulation

Revolutionizing Drug Development— d3 Medicine Joins the Certara Family

Craig Rayner

Thinking Without BordersTM Developing Medicines that MatterTM These guiding principles fueled the creation of d3 Medicine. With a goal of revolutionizing the pharmaceutical paradigm to accelerate developing medicines that benefit society, combining d3 and Certara was a ‘no brainer.’ Delivering on our clients’ mission The d3 Medicine staff join Certara’s Strategic Consulting (CSC) division, which […]

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Topics: Clinical Trial Design, Drug Safety, Model-based Drug Development, PBPK Modeling and Simulation, PK/PD Modeling and Simulation

Modeling and Simulation Guides Dosing for a New Anti-psychotic Drug

Karen Rowland Yeo

Drug development is becoming more complex than ever. Regulatory agencies expect sponsors to consider a wide variety of intrinsic and extrinsic factors that could impact drug safety and efficacy. These factors include intrinsic variability― CYP metabolizer status, age, sex, renal/hepatic impairment― as well as external variables― co-medications, food effects, smoker status, etc. Clinical trials alone […]

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Topics: Drug Safety, Model-based Drug Development, PBPK Modeling and Simulation

Annual Report – Simcyp Consortium Meeting

Ellen Leinfuss

It may be 2016, but we just held the 17th annual Simcyp Consortium meeting in Sheffield, UK. This year’s gathering had >120 attendees with representatives from all but one of the 34 consortium member companies joining. The opening session reviewed the progress made by the Simcyp staff toward the field of regulatory science, physiologically-based pharmacokinetic […]

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Topics: Drug Safety, Model-based Drug Development, PBPK Modeling and Simulation

Quantitative Pharmacology Strategies for Pediatric Drug Development

Patrick Smith

Pediatric patients are not simply small adults. Children differ from adults in both disease pathophysiology and pharmacokinetics/pharmacodynamics (PK/PD). Yet historically, 80 percent of medicines used in children had little to no data guiding prescribers on proper use. In this blog post, I’ll discuss the challenges of developing drugs for children and explain how quantitative pharmacology […]

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Topics: Clinical Trial Design, Drug Safety, Model-based Drug Development, PK/PD Modeling and Simulation

6 Real-Life Lessons about PBPK Modeling

Suzanne Minton

I recently had the pleasure of attending a 1.5 day Certara forum for management on the applications of physiologically-based pharmacokinetic (PBPK) modeling and simulation in Chicago, IL. Our CSO Dr. Amin Rostami and Certara consulting scientist, Dr. Alice Ke aptly led the forum. The highlight of the meeting was discussing the latest challenges and trends […]

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Topics: Clinical Trial Design, Drug Safety, Model-based Drug Development, PBPK Modeling and Simulation

Can QSP Save Lives? Lessons from a Trial Debacle

Neil Benson

The notion that volunteers could be harmed in a clinical trial is every drug developer’s worst nightmare. Earlier this year, the drug company, Bial, investigated inhibitors of the enzyme fatty acid amide hydrolase (FAAH) in clinical trials as a treatment for pain. Tragically, one person in the volunteer group died, and six patients were hospitalized. […]

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Topics: Clinical Trial Design, Drug Safety, Model-based Drug Development

How to Expedite FDA Approvals of Orphan Drugs

Thomas Peyret

350 million patients worldwide suffer from 7,000 rare diseases, yet only 300 of these diseases have approved treatments. This gap, impacting 95% of rare disease patients, represents a huge unmet medical need. Developing drugs for rare diseases poses a range of clinical, regulatory and commercial challenges. The small number of patients are difficult to identify […]

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Topics: Drug Safety, Model-based Drug Development, PBPK Modeling and Simulation, PK/PD Modeling and Simulation

Using PBPK Models to Optimize Antiviral Dosing at the Point of Care

Manoranjenni Chetty

The use of physiologically-based pharmacokinetic (PBPK) modeling for drug development is well-established and is now routinely used by the pharmaceutical industry, regulators, and researchers. In this blog post, I’ll discuss a novel application that combined PBPK and Bayesian modeling to help clinicians optimize dosing at the point of patient care. This application was used to […]

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Topics: Drug Safety, Model-based Drug Development, PBPK Modeling and Simulation

Status of QSP Modeling in the Pharmaceutical Industry

Steve Toon

A primary cause of failures in pharmaceutical research and development (R&D) has been attributed to lack of efficacy1, suggesting inadequate understanding in therapeutic targets’ biology and their relevance to disease progression or modulation. Quantitative systems pharmacology (QSP) has the promise of increasing the probability of success in R&D by bridging scientific gaps between disciplines to […]

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Topics: Drug Safety, Model-based Drug Development, PBPK Modeling and Simulation

Mechanistic Modeling of Antibody Drug Conjugate Pharmacokinetics

Linzhong Li

Antibody Drug Conjugates (ADCs) are constructed by attaching a small molecule drug to an antibody via a linker. The antibody selectively targets tumor cells and releases the cytotoxic drug within the cells to kill cancerous cells while sparing healthy tissue. Although some ADCs have been approved, many unanswered questions remain, such as drug-drug interactions (DDIs) and […]

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Topics: Drug Safety, Model-based Drug Development, PBPK Modeling and Simulation

The Next Horizons in Predicting Drug-Drug Interactions

Matthew Harwood

Physiologically-based pharmacokinetic (PBPK) modeling has arrived in prime time. This quantitative mechanistic framework, combining physiology with drug information and clinical trial design, has become an integral part of drug discovery and development. PBPK has also gained currency within industry and regulatory agencies. Its applications are numerous, including simulation of pre-clinical, healthy volunteer and special population […]

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Topics: Drug Safety, PBPK Modeling and Simulation

Insights on Quantitative Systems Pharmacology with Piet van der Graaf

Suzanne Minton

Quantitative systems pharmacology (QSP) is an emerging biosimulation technology that is going to increase pharmaceutical R&D productivity. This week at the Roundtable, we’re talking with Dr. Piet van der Graaf, PharmD, PhD about QSP and his vision for how it supports meeting the goal of precision medicine. Dr. van der Graaf is a professor of systems pharmacology, chair of pharmacology, and director of the Leiden Academic Centre for Drug Research at Leiden University in the Netherlands. He is also a former director of XenoloqiQ, the UK-based QSP consultancy, which Certara just acquired. Dr. van der Graaf is now the vice president of QSP at Certara.

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Topics: Drug Safety, Model-based Drug Development, PBPK Modeling and Simulation

Can Modeling & Simulation Inform Personalized Medicine?

Kevin Feng

Pharma faces an existential crisis. The cost and time lines of developing new medications have been growing exponentially for decades, with no end in sight. Could modeling and simulation approaches be the Next Great Hope for ending this madness and restoring sustainability to drug development? At the same time, can it deliver on the promise of making the dream of personalized medicine a reality? In this blog post, I’ll discuss how modeling and simulation (M&S) is changing drug development and some of the challenges the pharmacometrics community must overcome to make the greatest improvements in treatments for patients.

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Topics: Drug Safety, Model-based Drug Development

Back to the Future (of Pharmacometrics) with Dr. Lawrence Lesko

Suzanne Minton

Pharmacometrics uses mathematical models of biology, pharmacology, disease, and physiology to describe and quantify interactions between drugs and patients, including beneficial effects and adverse effects. I recently had the pleasure of talking to a thought leader, Dr. Lawrence Lesko, about the history of pharmacometrics and how it will continue to shape drug development in the future.

Dr. Lesko was Director of the Office of Clinical Pharmacology in the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration (FDA) for 16 years until his retirement in July 2011. He currently serves as Clinical Professor and Director of the Center for Pharmacometrics and Systems Pharmacology in the University of Florida, College of Pharmacy at Lake Nona in Orlando, FL.

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Topics: Clinical Trial Design, Drug Safety, Model-based Drug Development, PBPK Modeling and Simulation, PK/PD Modeling and Simulation

Modeling the Influence of Ethnicity on Drug Disposition

Zoe Barter

Ever noticed how people from different ethnic backgrounds respond differently to drugs? For example, you may enjoy having a few drinks with friends on the weekend. When your friends with Eastern Asian heritage drink alcohol, it’s not uncommon for their faces to turn red. This happens because many East Asians possess an enzyme deficiency for aldehyde dehydrogenase 2 (ALDH2). Alcohol is metabolized to acetaldehyde which is further broken down into acetate by ALDH2. When people with the inactive ALDH2 variant drink alcohol, acetaldehyde accumulates in their body causing facial flushing, nausea, and a rapid heartbeat.

Ethnic diversity in drug response and its impact on dosing has been well described for some drugs.1 A recent study of the most widely prescribed proprietary drugs in the US showed that, in around half of all cases, the recommended doses in Japan were considerably lower than both the US and European doses.2 Investigating the potential impact of ethnicity on pharmacokinetics often involves repeating clinical studies in different populations, which may be unnecessary in some cases. Physiologically-based pharmacokinetic (PBPK) modeling and simulation in virtual populations can uncover changes in drug disposition due to ethnic differences, providing supporting information for regulatory review and helping identify and optimize essential bridging studies.

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Topics: Clinical Trial Design, Drug Safety, Model-based Drug Development, PBPK Modeling and Simulation

Assessing the Impact of Liver or Kidney Disease on Pharmacokinetics

Trevor Johnson

Impaired hepatic or renal function can have a major impact on pharmacokinetics. There is a high risk of adverse events in patients with these conditions. Major pharmaceutical companies and drug regulatory agencies use physiologically-based pharmacokinetic (PBPK) modeling in virtual populations to investigate the impact of hepatic or renal impairment on drug exposure as a supplement to clinical investigation. PBPK modeling also helps guide dosage adjustments in these patient groups.

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Topics: Drug Safety, Model-based Drug Development, PBPK Modeling and Simulation

Using Biosimulation to Support Approvals for Orphan Drugs

Suzanne Minton

Rare diseases affect fewer than 1 in 2000 people. Each one affects only a small number of patients. Yet, there are over 7000 rare diseases. And, there are no treatments for 95 percent of them. Thus, many patients suffer from these diseases. The treatments for rare diseases are often referred to as “orphan drugs.” Orphan drug developers face distinct challenges with rare diseases including:

Heterogeneity in disease progress and treatment outcomes
Few patients to run new studies
Uncertain appropriate durations of treatment
Sparse existing data available from limited populations
Biosimulation methods— also known as model based drug development— include both top-down (empirical) and bottom-up (mechanistic) models. These methods use sparse data from small populations to inform dosing and trial designs. For example, population PK/PD models can test the influence of factors such as age, weight, and disease status on drug exposure and response. Likewise, combining drug and disease models can help distinguish between treatment effects on symptoms vs changes in disease processes. Model based approaches can support accelerated approval pathways that get treatments to patients faster.

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Topics: Drug Safety, Model-based Drug Development, PK/PD Modeling and Simulation

How Biosimulation Technology Could Save Us from the Zombie Apocalypse

Martin Beliveau

Skeptical at the idea of ravenous brain-eating undead? You don’t have to take my word for it. The Centers for Disease Control and Prevention (CDC) Office of Public Health Preparedness and Response recognizes this threat. Their Zombie Preparedness website provides information on getting ready for all kinds of disasters.

Biosimulation technology can help fight the Walking Dead. Zombie plague, like other serious infectious diseases, presents unique challenges to drug development. One challenge is that exposing humans to these pathogens in drug efficacy studies is unethical. Biosimulation methods include ‘top down’ approaches such as PK/PD modeling and simulation and ‘bottom up’ approaches such as PBPK modeling and simulation. These approaches can use animal studies and simulate clinical trials to help prove a drug’s safety and efficacy in untestable clinical scenarios.

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Topics: Drug Safety, Model-based Drug Development, PK/PD Modeling and Simulation

The Future is Now: How 3D Printing Could Deliver Personalized Medicine

Adam Calderon

“It will take a few minutes to upload the instructions for your prescription to the 3D printer. We will call you once your medication is ready to be picked up.” While it seems like science fiction, your pharmacist may describe filling your prescription using this emerging technology sooner than you might think. In this blog post, I’ll discuss how 3D printing of drugs in concert with biosimulation technology could accelerate the move towards personalized medicine.

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Topics: Drug Safety, Model-based Drug Development
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