Using IVIVC to Optimize Your Drug Formulation After a Failed BA/BE Study

Speaker(s): JM Cardot
Date: July 18, 2018
Time: 11 am EDT
Duration: 1 hour

Bioequivalence (BE) trials are used to show that a new treatment is identical (within an acceptable range) to a current treatment. Comparative bioavailability (BA) studies are used, in the case of pilot studies, to select the best candidate for the pivotal BE study. BE studies are used in the registration and approval of generic drugs that are shown to be bioequivalent to their branded reference drugs. BE studies can also be required for pharmaceutical variations made to drugs. These pharmaceutical variations might include changes in manufacturing site, raw material suppliers, or minor changes in formulation.

To show bioequivalence, you must demonstrate similarity of the systemic drug levels expressed as extent (AUC) and rate (Cmax). The 90% confidence intervals of the ratio of AUC and Cmax of the generic drug to name-brand drug must lie between 80-125%.

But, what if your BE or BA study was a failure? Now what?

This webinar will introduce how in vitro-in vivo correlation (IVIVC) can be used to get your drug program back on track! An IVIVC is a predictive mathematical model describing the relationship between the in vitro properties of a dosage form and the in vivo responses. By attending this webinar, you will gain an appreciation of the following:

  • How to analyze the failed BE study
  • How to use IVIVC to:
    • Explore better dissolution tests
    • Predict your target dissolution to meet the reference
    • Optimize your drug’s formulation

About Our Speaker

Jean-Michel Cardot is a professor and head of the Department of Biopharmaceutics and Pharmaceutical Technology at the Auvergne University in France. Prior to coming to Auvergne University, he worked in the pharmaceutical industry for 15 years. Prof. Cardot earned degrees in pharmacy (PharmD), a Masters in Bio-pharmaceutical, Statistical sciences and Pharmacokinetics, and a doctorate in pharmaceutical sciences from Auvergne University. His research interests include biopharmaceutical development of drugs, in vitro dissolution, and in vivo bioequivalence and in vitro-in vivo correlation.

Application of Tracer Kinetics in Drug Development: A Valuable but Underused Tool in Clinical Pharmacology

Speaker(s): Pau Aceves
Date: August 7, 2018
Time: 11 am EDT
Duration: 1 hour

Clinical pharmacology has generally involved the study of pharmacokinetics/pharmacodynamics (PK/PD) under reasonably controlled experimental conditions including:

  • Known dose/concentration/volume of study drug (extent of input)
  • Known infusion duration into a given bodily compartment (rate of input)
  • Accessible compartments for sampling: Blood, Urine, CSF, etc.
  • The drug and its metabolites are distinguishable from endogenous compounds
  • Rapidly changing biomarkers following drug administration
  • Ability to determine routes of elimination using “hot” drug (ADME study)
  • Use of healthy volunteers to ease the feasibility of PK/PD assessments

Quantitative PK/PD analyses tools using drug/metabolite/biomarker static concentration data have become a cornerstone in drug R&D.

But what other quantitative tools are available when we face less controlled conditions?

Tracers can be substances such as dyes or drugs labelled with radioactive or stable isotopes. Tracer kinetics analysis allows the study of more than one form of a compound simultaneously thereby opening new opportunities such as tracing two isoforms of the same drug given by two routes or obtaining rates of production, pool size, and half-life of endogenous substances.

Tracers have been mostly relegated to nutrition and sport sciences, but there are instances where this technique could prove powerful in drug development. In this webinar, Pau Aceves, Associate Director of Consulting Services at Certara, will present case studies on how tracer kinetics were used to inform development of new drugs for lung, CNS, and liver diseases. By attending this webinar, you will learn how tracer kinetics can be leveraged for PK, PD, and in silico modeling applications.

Who should attend?

  • Clinical pharmacologists
  • Bioanalysts
  • Pharmacokineticists

About Our Speaker

Pau Aceves joined Certara Strategic Consulting in February 2017. Pharmacist by training, and with previous work experience in diverse aspects of the Pharmacy practice—including Community, Clinical and Production Pharmacy—Pau focused his professional career path in the field of Quantitative Clinical Pharmacology (QCP) and PK/PD Modeling & Simulation, since 2006.

Pau Aceves holds a Master’s Degree in PK/PD Modeling & Simulation from the University of Manchester in the UK. His MSc project was on an Exploratory Quantitaitve Systems Pharmacology Model (QSP) of the Squalene Synthase Inhibitor Lapaquistat Acetate.

In addition to having worked on QCP-type studies (ie, food effect, bioavailability, DDIs), Pau also has a wide range of experience on other modalities, including: First-in-human (SAD/MAD), Proof-of-mechanism (PoM), Proof-of-concept (PoC), Positron Emission Tomography (PET), and highly complex combination (or umbrella-type) protocols; as well as experience interacting with regulatory agencies (FDA, EMEA) at various stages of drug development.

He brings to Certara a total of 11 years of QCP experience in the design, analysis and reporting of studies in a wide range of therapeutic areas across all phases of drug development. Pau always enjoys devising innovative strategies to streamline and maximize the value of clinical development programmes by combining efficient clinical strategies with fit-for-purpose PK/PD analysis methods, eg, Population PK/PD, Physiologically-based Pharmacokinetic modeling, and Quantitative Systems Pharmacology approaches.

Leveraging In Vitro Data to Improve Prediction of Drug Clearance in Renally-impaired Populations

Speaker(s): Kristin Follman
Date: September 5, 2018
Time: 11 am EDT
Duration: 1 hour

Renal Impairment (RI) is a major and growing health concern in the US and globally. It can occur alone or can accompany a number of disease states. RI affects the pharmacokinetics (PK) of many compounds due to a decrease in the glomerular filtration rate (GFR) with the decline of kidney function. In addition to these changes to GFR, changes in protein binding, drug transporter expression, and activity have been identified in RI. Many of these changes are mediated by elevated concentrations of uremic toxins in RI, which can cause toxin-drug interactions (TDIs).

These additional changes on the PK of compounds that are actively transported in the kidney carry both clinical and regulatory relevance. Patients with RI often require dose-adjustments for renally-cleared drugs. Also, the FDA currently recommends that drug developers conduct clinical trials in RI populations for investigational drugs where 30% or more of the drug is eliminated renally.

Physiologically-based pharmacokinetic (PBPK) modeling has been increasingly used to predict PK in specialized populations. The Simcyp Simulator PBPK modeling platform contains specialized virtual populations, including those for RI. The advantage of using a PBPK approach is that it can incorporate physiologically-relevant information about specialized populations such as organ size and function as well as information from in vitro studies.

This webinar will focus on the impact of RI on substrates of organic cation transporter 2 (OCT2), one of the major renal transporters which has been shown to be affected—both in activity and expression—in RI in pre-clinical species and in vitro systems.

The objectives of this webinar are to demonstrate the following:

  • The impact of alterations in GFR, protein binding, and TDIs on PK predictions for the OCT2 model substrate, metformin
  • The utility of available in vitro data to improve predictions of renal clearance for OCT2 substrates in clinical RI populations.

About Our Speaker

Kristin Follman is a PhD candidate the University at Buffalo in the Pharmaceutical Sciences department. She is in her 5th year in the program and is a member of Dr. Marilyn E. Morris’s lab where she studies the impact of transporters on special populations and in drug overdose. Prior to joining UB, Kristin obtained her bachelors of biochemistry at Canisius College.




How to Use a Reference-scaled Average Bioequivalence Approach for Narrow Therapeutic Index Drugs

Speaker(s): Chris Mehl, Ana Henry, Linda Hughes
Date: September 25, 2018
Time: 11 am EDT
Duration: 1 hour

The standard approach for approval of generic drugs is to run a bioequivalence study to demonstrate that a generic product is comparable to an approved (i.e., reference) drug in their rate and extent of absorption. The rate and extent of drug absorption are determined from the pharmacokinetic parameters: peak concentration (Cmax) and the area under the concentration-time curve (AUC) respectively. The approach is referred to as average bioequivalence (ABE) where the 90% confidence interval for the ratio of the average geometric means (test/reference) for AUC and Cmax must fall between preset regulatory bioequivalence limits from 80% to 125%.

Drugs with a narrow therapeutic index (NTIDs) have a narrow range between therapeutic and toxic dose levels. Traditional ABE methodology may be unacceptable for NTIDs because small differences in drug exposure may lead to serious therapeutic failures and/or adverse drug reactions. The usual average ABE limits are not considered sufficient for NTIDs, and several regulatory agencies have narrowed the limits for bioequivalence. For NTIDs, a fully replicated clinical trial design must be used, and the test formulation must pass the following three criteria:

  1. RSABE, scaled to the reference variability, eg, 90% CI within limits of 90.00-111.11% for reference formulations with CVWR = 10%,
  2. Unscaled ABE, within 90% CI limits of 80.00-125.00%,
  3. The upper bound of the 90% CI of the ratio σWT/σWR must be ≤ 2.5.

The US FDA guidance for warfarin sodium (2012) proposed a new bioequivalence methodology for NTIDs as an extension of reference-scaled average bioequivalence (RSABE) to scale bioequivalence limits to the within-subject variability of the reference product and to compare within-subject variabilities of test and reference products.

A Phoenix template workflow was created to analyze narrow NTIDs per the FDA’s Warfarin Guidance criteria. Attend this webinar to learn how RSABE for NTIDs can be performed in Phoenix WinNonlin using this reusable template. Because the template projects require minimal user input to be used with any input dataset from a replicated 4-period crossover design, they can provide significant time savings and increased efficiency to users!

Who should attend?

  • Pharmacokineticists
  • Generic drug developers
  • Formulation scientists

About Our Speakers

Christopher Mehl is the Customer Support Manager, and is a software trainer at Certara since 2003. His educational background is a BS in Molecular Biology from the Ohio State University, and an MS in Pharmacology from the University of Wisconsin. He has conducted over 200 training courses with desktop products such as Phoenix WinNonlin, IVIVC, NLME, PKS, and Trial Simulator. These include workshops at the US Food and Drug Administration, universities, customer sites, and courses open to the public.

Ana Henry has extensive experience in a variety of roles in the pharmaceutical industry. Most recently she acted as product manager for the complete suite of Certara desktop products, personally leading the development of Phoenix, the industry’s premier PK/PD software platform. Currently, she is with Certara University’s Scientific Training and Education Department, tasked with training and content development of E-learning courses. Ana has extensive experience in software demonstration and training, and is adept at offering technical expertise and evaluation of software products. She has trained and provided support for Phoenix WinNonlin, Phoenix Connect, Phoenix NLME, Phoenix Knowledgebase Suite, AutoPilot, PKS Reporter, Trial Simulator, and PK/PD methodology courses. Prior to Certara, Ana worked in the pharmaceutical industry as a biostatistician and a pharmacokineticist, designing, analyzing, and reporting on clinical studies. Ana is also a regular guest speaker in the graduate PK/PD course at the University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences.

Linda Hughes is a Principal Software Engineer with Certara. She has worked in software development for the pharmaceutical industry for 18 years. At Certara, she has worked on development of the tools for non-compartmental analysis, bioequivalence, non-linear mixed effects modeling, descriptive statistics, IVIVC, convolution, and deconvolution. She holds an MS degree in Electrical Engineering and BA degree in Mathematics, both from the University of Maryland.

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