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 […]Read More
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 […]Read More
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 […]Read More
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 […]Read More
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. […]Read More
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 […]Read More
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 […]Read More
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 […]Read More
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 […]Read More
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 […]Read More
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.Read More
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.Read More
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.Read More
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.Read More
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.Read More
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.
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.Read More
“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.Read More
In therapeutic areas with tough competition, it is challenging to establish a complete, confident understanding of a drug’s safety and efficacy profile. Any misunderstanding of a drug’s characteristics can derail the entire development program. Biosimulation, also known as model based drug development, uses a number of techniques, such as population PK modeling, model based meta analysis, and PBPK modeling, to help gain a better understanding of a drug’s risk-benefit profile to increase the likelihood of regulatory success. In this blog post, I’ll discuss how I worked with my colleagues to help develop a novel combination therapy for obesity.Read More
Last month, I was fortunate to be able to represent Certara® at the BIO International Conference in Philadelphia, PA. One of the most exciting sessions that I attended was the Personalized Medicine Plenary with Dr. Francis Collins, the director of the NIH. He discussed how the Precision Medicine Initiative (PMI) will revolutionize the approach to improving health and treating disease. In this blog post, I’ll discuss the goals of PMI and how this initiative aligns with our mission to use biosimulation and strategic regulatory writing to bring safer and more effective medications to patients.Read More