While COVID19 pandemic rattled and forever changed the world in 2020 and continue to present challenges in different ways, crises on the other hand are commonplace in professional and personal lives. These crises present us with different challenges that require an effective leadership to maneuver through times of difficulty or adversity. During his presentation, Dr Mahajan will share his perspective and few principles on leading through crisis and how COVID19 transformed him as a leader and how he battled distractions and stress to be equally or even more productive during those challenging times. These simple principles, when applied, can help anyone to effectively lead during times of uncertainty for themselves as well as for those around them. Participants will further learn how to adopt successful thinking habits to think their way through any crisis by implementing small and practical steps which leads to greater peace and empowerment for leaders as they lead through crisis.
As change is inevitable during any crisis, one must be flexible and ready to adapt. No matter who we are or what we do or the stage of leadership or professional journey, there is always room for growth. Dr Mahajan will talk about Leadershift and the importance of Leadershift in keeping the organizations and careers alive in the ever-changing world especially during crisis. He will cover the what, why and how of Leadershift and the essential requirements for transformational leadership. Dr Mahajan will share various actions that leaders must take while covering one of his favorite Leadershift – the impact shift, a shift from trained leader to the transformational leader. He will also share opportunity to further learn various leadership principles for those who would want to take their leadership to the next level!

Dr. Mukesh Mahajan is currently the Director and US Head of Discovery DMPK Project Specialist Team at GSK. In this role, he leads an experienced and talented team of DMPK project specialists and is responsible for setting strategic direction for the team to support GSK discovery portfolio for small molecules and other modalities. He started in GSK in 2006 and since then he has taken different roles in DMPK with increased responsibilities that span in vitro, in vivo and bioanalytical sciences. As team leader of discovery in vitro group, Dr Mahajan led the set-up of high throughput in vitro DMPK screening and state-of-the-art automated DMPK data visualizations platforms for GSK. Over the years, Dr Mahajan has also led DMPK department in various multidisciplinary global project teams as DMPK project specialist and successfully supported nomination of multiple new chemical entities to candidate selection milestone. He is known for his positive attitude, enthusiasm, people centric and servant leadership style which he believes is the cornerstone of his successful career over the years at GSK. Dr Mahajan feels that there is a ‘science to leadership’ that can be learnt just like any other science. He has been a good student of personal, professional and leadership development over the past 2-3 decades. He is also the certified and licensed coach, trainer and inspirational speaker at Maxwell Leadership Team, the largest leadership development organization in the world. After he himself experienced the transformation and impact of certain growth and leadership principles (aka laws), he made a commitment to further equip others in the scientific community as he believes there are 3 phases in life – Learn it, Live it and Lead it. As a growth visionary, Dr Mahajan founded RSJ Coaching and Leadership Academy, LLC to deliver on his vision to equip, inspire, and communicate life-altering success principles to other professionals in the ‘Lead it’ phase of his life aligned with his passion and calling. He enjoys working with growth hungry and like-minded professionals who are committed to continuous learning as he believes that professional and leadership development is more of a process than a one-time event.

PAXLOVID™ (nirmatrelvir[PF-07321332]/ritonavir – 300/100 mg) is the first oral SARS-CoV-2 main protease inhibitor to receive emergency use authorization (EUA) for the treatment of COVID-19 in patients with high risk of progression to severe disease. Because of the urgent need for new medicines to address the COVID pandemic, innovative approaches had to be employed to accelerate the development of PAXLOVID™. An overall understanding of the disposition of a compound in humans is a requirement for registration of any new medicine and is almost always done through an absorption, distribution, metabolism and excretion (ADME) study. Historically, ADME data has been obtained via the incorporation of a radiolabel (typically 14C) into the parent compound. The radiolabel is used because of the low inherent background and its universal analytical response factor. The synthesis of 14C analogs can often be costly and more importantly time-consuming. Following the administration of 14C labeled drug, excreta and plasma samples are then analyzed for total drug content by liquid scintillation counting (LSC) to establish mass balance. To support the accelerated development of Paxlovid™, synthesis of [14C]nirmatrelvir for a conventional human ADME study was not feasible. Hence, alternative detection methods for the ADME study were evaluated. Because 19F qNMR affords the same type of universal response, independent of chemotype, as radioactivity and that nirmatrelvir contains a trifluoroacetamide, 19F qNMR was used as a detection technique for the human ADME study. Using 19F qNMR we were able to assess the metabolism and excretion of nirmatrelvir within the first-in-human study following the administration of a single dose of unlabeled drug. Mass balance was achieved with approximately 84.9 ± 8.9% of the total administered dose recovered (urine 47.0% and feces 33.9%). Nirmatrelvir was the only drug-related entity observed in plasma. These data were accepted by the FDA for the EUA of PAXLOVID™. To the best of our knowledge, this is the first time a regulatory agency agreed to the use of 19F-qNMR data in lieu of a 14C study for ADME characterization.

Gregory S. Walker is an Associate Research Fellow at Pfizer Inc. with 35 years of experience in both pharmaceutical science and drug metabolism. Currently, he manages the drug metabolism NMR facility at Pfizer’s research headquarters in Groton, CT. For the past 30 years he has worked in NMR groups at The Upjohn Company, Pharmacia and Pfizer. Greg has specialized in the structural characterization of low level unknown organic molecules originating from complex matrices using a variety of chromatographic and spectroscopic techniques. His career highlights include establishing NMR as a global analytical resource for the Pfizer drug metabolism division, developing a generalized quantitative NMR assay for qualification of bio-generated analytical standards and 80+ external publications and presentations. Greg is a member of the APA organizing committee and was chair of the SMASH 2018 NMR meeting. Greg is a recognized expert in structural elucidation of metabolites and has taught numerous short courses for such organizations as the American Chemical Society, Applied Pharmaceutical Analysis (APA) and International Society for the Study of Xenobiotics (ISSX). Greg is a two-time recipient of the Pfizer Achievement Award, most recently for his work in quantitative NMR as it pertains to drug metabolism.

Abstract: The COVID-19 pandemic has highlighted the need for the rapid implementation of global immunization strategies informed by well-designed clinical trials, considering vaccine formulation, dosing regimens, Drug metabolism, drug-drug interactions, patient-specific effects and protection against emerging variants. In this talk, speaker provides clinical pharmacology/DMPK considerations across stages of COVID therapeutics discovery and development. Furthermore, the differences in DMPK/ clinical pharmacology aspects of small molecules and large molecules will be discussed. In addition, a few recent case examples from literature to illustrate such approaches will be explained, along with existing challenges in such analysis followed by future focus areas to fill the identified gaps.

Dr. Venkatesh Pilla Reddy, PhD is Director, Clinical Pharmacology and Quantitative Pharmacology function of AstraZeneca, Cambridge UK. He is currently supporting COVID-19 Projects (AZ Vaccine and EVUSHELD) as a Global Clinical Pharmacology Lead. He obtained his PhD in Pharmacometrics through a unique industry collaboration program between Pfizer, Janssen Pharmaceuticals and Merck via TI Pharma in the Netherlands. His PhD work was focused on PKPD M&S of antipsychotic drugs. He subsequently worked at Quantitative Pharmacology and Pharmacometrics group in Merck & Co before joining AstraZeneca Early Oncology function. Venkatesh provided Model-Informed Drug Development support to various oncology projects. He has been influential in gaining acceptance and addressing questions from regulatory agencies for EVUSHELD (Tixagevimab and Cilgavimab), Olaparib and Osimertinib programs. He has participated on MIDD related panel discussion with the European Medicines Agency and the US Food and Drug Administration (FDA). Venkatesh currently holds the Deputy Topic Leader position at the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) Management Committee to work on the ICH M12 DDI guidelines, and co-leads various cross-industry working groups such as IQ TALG, ISOP and ISSX M&S. Over 20 years of his industry experience, he has published > 60 peer-reviewed research articles, 2 book chapters.

Molnupiravir (MOV) is a 5’-isobutyrate prodrug of the broadly active, antiviral ribonucleoside analog N-hydroxycytidine (NHC). NHC and its triphosphate anabolite NHC-TP adopt two tautomeric forms – an oxime and hydroxylamine – which behave either like UTP or CTP, respectively. NHC-TP is a substrate for the SARS-CoV-2 RNA polymerase and exerts its antiviral effect by introducing transition errors in viral RNA which impair SARS-CoV-2 viral replication and viral infectivity.
NHC differs from native cytidine by only one additional oxygen, and this structural similarity is the main driver of its overall ADME properties. For example, uptake into tissues, metabolism to the active NHC-TP, as well as its elimination are governed primarily by transporters and enzymes typically involved in pyrimidine nucleoside regulation, not xenobiotic drug metabolism. Elucidation of the ADME profile of MOV and NHC, along with some of the challenges nucleosides pose in development, will be presented in detail.

Randy Miller: After receiving a B.S. in Biochemistry at the Pennsylvania State University in 1987, Randy joined the Department of Drug Metabolism at Merck & Co., Inc. in Rahway, NJ, where he is currently a Senior Principal Scientist. Over the past 30+ years he’s been an active contributor or co-lead on numerous drug discovery and development teams spanning a wide range of pharmacological targets, and has coauthored over 45 peer-reviewed journal articles. Randy’s focus for many years has been on strategies for optimizing small molecule pharmacokinetics during drug discovery, resulting in numerous internal and external lectures on this topic throughout his career.