Clinical Pharmacology Podcast with Nathan Teuscher

Toxicokinetics (Ep. 39) Dec 09, 2024

In this episode I discuss toxicokinetic analysis. This is the analysis of exposure data to support animal toxicology studies. I review the purpose of toxicology studies and how exposure metrics are used. Then I discuss different blood sampling schemes, and how to calculate exposure parameters for both full profiles and mean profiles.

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Steady State (Ep. 38) Nov 25, 2024

This episode is a discussion of steady state pharmacokinetics. Steady state occurs when the amount of drug input is equivalent to the amount of drug elimination in a dosing interval. I discuss some key PK parameters at steady state and how to use them. I also discuss different methods of confirming that you have reached steady state.

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Dose Proportionality (Ep. 37) Nov 11, 2024

In this episode I talk about dose proportionality, which is a surrogate for determining if we have linear clearance across a range of dose levels. I discuss 3 different methods that people use to determine dose proportionality along with a recommendation to use the power model method.

Links discussed in the show:

Power model method
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Covariate Search Methods (Ep. 36) Oct 28, 2024

This episode is a discussion of covariate search methods. I give definitions of covariates and predictors, and then I describe 3 different covariate search methods. For each method I describe the pros and cons associated with each one, including bias and time limitations.

Links discussed in the show:

Evaluation of the Boruta method for covariate selection
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Stimulatory Indirect Response PK-PD Models (Ep. 35) Oct 14, 2024

In this episode I describe stimulatory indirect response PK-PD models. I describe how they work, how to set up the dataset for NONMEM, and how to code the model in NONMEM. This is the last of 4 episodes on different PK-PD models.

Links discussed in the show:

Indirect response PK-PD model equations
Example NONMEM code for stimulatory indirect response PK-PD model
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Inhibitory Indirect Response PK-PD Models (Ep. 34) Sep 23, 2024

In this episode I describe inhibitory indirect response PK-PD models. I describe how they work, how to set up the dataset for NONMEM, and how to code the model in NONMEM. This is the third of 4 episodes on different PK-PD models.

Links discussed in the show:

Indirect response PK-PD model equations
Example NONMEM code for inhibitory indirect response PK-PD model
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Effect compartment PK-PD models (Ep. 33) Sep 09, 2024

In this episode I describe effect compartment PK-PD models. I describe how they work, a method of creating exploratory plots, how to set up the dataset for NONMEM, and how to code the model in NONMEM. This is the 2nd of 4 episodes on different PK-PD models.

Links discussed in the show:

Example NONMEM code for effect compartment model
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Direct effect PKPD models (Ep. 32) Aug 26, 2024

In this episode I describe direct effect PK-PD models. I describe how they work, a method of creating exploratory plots to identify direct effect models, how to set up the dataset for NONMEM, and how to code the model in NONMEM. This is the first of 4 episodes on different PK-PD models.

Links discussed in the show:

Example NONMEM code for direct effect model
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What should you use to present PK results? (Ep. 31) Aug 12, 2024

In this episode I discuss different methods of presenting pharmacokinetic and pharmacometrics results. I spoke about using PowerPoint and R Markdown derived HTML files. While I prefer HTML files in nearly all cases, I appreciate that sometimes PowerPoint format is required by some companies. I included multiple suggestions for both PowerPoint and HTML files that can help make the information presentation more effective.

Links discussed in the show:

Floating table of contents in R Markdown HTML output
How to include CSS in your R Markdown
Creating tabs in R Markdown
Code folding in R Markdown
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How important is terminal rate constant? (Ep. 30) Jul 22, 2024

This episode covers the terminal elimination rate constant calculated using non-compartmental analysis techniques. I reviewed how the rate constant is used to estimate half-life and extrapolate AUC to infinity, reviewed the methods for calculating the terminal rate constant value, and some important points about sample selection. Finally, I gave my reasons that we should ultimately stop talking about this and fretting over the method of calculation. Instead, let’s design better PK experiments with more optimal sampling to capture decline of the drugs we are studying.

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Parellelization in modeling (Ep. 29) Jul 08, 2024

This episode covered parallelization in modeling analyses. I spoke about across model parallelization and within model parallelization. I recommended some approaches for choosing how many cores to use in parallelization and also discussed different modeling computer systems you can use.

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Residual errors and submission packages (Ep. 28) Jun 24, 2024

Today I covered 2 different topics. First, I spoke about residual error models when modeling. I discussed additive, proportional, and power models. I also reviewed combined models and when they can be helpful. Then I spoke about modeling report submission packages. I explained what I put in those packages, how they are used, and some potential changes coming in the future.

Links discussed in the show:

Publication on model master file
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Simulations (Ep. 27) Jun 10, 2024

This episode discusses simulations. I group simulations into 4 categories: (1) average response, (2) population, (3) individual, and (4) clinical trial simulations. I discuss details of each of these types of simulations and the different variability terms included in each one. I strongly recommend that we implement more clinical trial simulations in our work. This will help us design and execute more successful clinical trials that take advantage of our existing knowledge about a drug. Enjoy the show and connect with me using the links below if you have any questions.

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Different work environments (Ep. 26) May 27, 2024

Today’s show is about different work environments and not scientific topics. Throughout my career I have worked in many different types of companies, and I would like to share some observations with you from those experiences. I have held positions at startup companies or small biotechnology companies, large pharmaceutical companies, contract research laboratories, consulting firms, and working for myself as a consultant, and now as a software developer. Although my work has been focused on clinical pharmacology and pharmacometrics, the jobs and work environments are very different.

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Biosimilar products (Ep. 25) May 13, 2024

Today’s show discussed biosimilar development from a clinical pharmacology perspective. I describe what biosimilar products are and the necessary comparisons to the reference product. I review requirements for PK similarity, PD similarity, immunogenicity, and safety. I also touch on the idea of interchangeability between the biosimilar and reference products.

Links discussed in the show:

FDA Guidance on Clinical Pharmacology Data to support Biosimilarity (May 2016)
FDA Guidance on Demonstrating Interchangeability (May 2019)
FDA Q&A on Biosimilarity and Interchangeability (Sep 2023)
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Choosing an absorption model (Ep. 24) Apr 22, 2024

Today’s show discussed approaches for modeling absorption profiles. I discussed the rationale behind modeling absorption and then described some common models. These included first-order absorption, zero-order absorption, transit compartments, distributed delay, Weibull, and zero/first order absorption. I also provided my recommendations on how to model absorption.

Links discussed in the show:

Distributed delay modeling in PK and PD
Modeling biphasic formulation of methylphenidate
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What is Aplos NCA? (Ep. 23) Apr 08, 2024

Today’s show was an overview of Aplos Analytics and the development story for Aplos NCA. Please consider participating in the Early Access Program. Use the link below to learn more about Aplos NCA.

Links discussed in the show:

Aplos Analytics website
Aplos Analytics Contact Us Page
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Big announcement and Hepatic impairment studies (Ep. 22) Mar 25, 2024

Today’s show is about hepatic impairment clinical studies. I cover the rationale behind evaluating hepatic impairment, common study designs, and key factors in the analysis and interpretation of the study results. I also share a huge announcement about Aplos NCA, a cloud-based solution for calculating NCA PK parameters. Use the link below to learn more about Aplos NCA.

Links discussed in the show:

FDA guidance
EMA guideline
Aplos Analytics website
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Project Optimus (Ep. 21) Mar 11, 2024

Today’s episode was about Project Optimus, the FDA initiative to improve dose selection and optimization for oncology products. Julie Bullock was a guest on this episode and shared her expertise as a former oncology clinical pharmacology reviewer at the FDA and as a current consultant in the pharmaceutical industry.

Links discussed in the show:

Project Optimus FDA
List of FDA guidances and publications for Project Optimus
May 2022 FDA-ASCO workshop: Getting the Dose Right: Optimizing Dose Selection Strategies in Oncology
Sept 2023 Second Annual FDA ASCO WORKSHOP on Getting the Dosage Right (this one focused on combinations)
Feb 2024 FDA/AACR Public Workshop: Optimizing Dosages for Oncology Drugs
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Tackling TMDD Models (Ep. 20) Feb 26, 2024

Today’s show is about TMDD or target-mediated drug disposition models. I review the scientific and physiologic basis for TMDD models, how to review data and determine if a TMDD model is needed. I review the various modeling approaches along with my recommendations for specific TMDD models. I hope this information helps you understand how to recognize TMDD behaviors and the options for modeling that data.

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Communication for scientists (Ep. 19) Feb 12, 2024

Today’s episode is about communication for scientists. I believe that improvements in communication skills can have a greater impact on your career and work than technical skills. Michael Piperno, an expert in communication and leadership skills joins me to discuss communication challenges and solutions for clinical pharmacologists and pharmacometricians.

Links discussed in the show:

You can connect with Michael

On his website
On LinkedIn
On his blog
On his podcast
Subscribe to Michael’s newsletter
View upcoming leadership and communication workshops

You can connect with me

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Cell Therapy and Clinical Pharmacology (Ep. 18) Jan 22, 2024

Today’s episode is about cell therapies, including CAR T-cell theraphy for cancer. I give an overview of cell therapy and the challenges of clinical pharmacology in this new area of research.

Links discussed in the show:

CAR T-cell Therapy Image

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Allometry in Pediatrics and First in Human Studies (Ep. 17) Jan 08, 2024

Happy New Year! Today’s episode is all about allometric scaling in pharmacokinetic and pharmacodynamics. In particular, I’ll discuss how to use it for scaling from adults to pediatrics and for selection of first in human doses.

Links discussed in the show:

Boxenbaum manuscript
FDA guidance on First in Human doses
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Computer System Validation for Pharmacometrics (Ep. 16) Dec 25, 2023

This is the last podcast for 2023. Thank you for listening throughout the year! In today’s episode I talk about computer system validation for pharmacometrics. I review my experience with validation in multiple companies over 20 years and discuss what auditors and FDA inspectors want to see.

Links discussed in the show:

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QSP, PBPK, PKPD, PopPK … analysis abbreviation soup! (Ep. 15) Dec 11, 2023

In today’s episode I cover 4 different modeling approaches: QSP, PBPK, PopPK, and PKPD. All of these are methods for analyzing data to predict either drug concentrations, or a response variable. But each method is developed in a different way and has different assumptions and limitations.

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Handling BLQ samples (Ep. 13) Nov 27, 2023

In today’s episode I discuss BLQ handing for both non-compartmental and modeling analysis approaches. I discuss how BLQ samples are defined, methods for analyzing them, and situations when you should use different analysis approaches.

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Clinical Drug Interaction Studies (Ep. 14) Nov 27, 2023

In today’s episode I covered the different types of drug interactions, followed by features of clinical drug evaluation studies recommended in the guidance. Then I will review recommendations for both stand-alone clinical drug interaction studies, as well as nested drug interaction studies. I’ll finish with recommended approaches for interpreting drug interaction study results and expressing that information in drug labeling.

Links discussed in the show:

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PK in patients with impaired renal function (Ep. 12) Oct 23, 2023

In today’s episode I discuss the evaluation of pharmacokinetics in patients with impaired renal function. I include information from both the US FDA and EMA guidance documents linked below. I discuss the determination of when a dedicated renal impairment study is needed, characteristics of the study design and how to analyze and interpret the results.

Links discussed in the show:

• FDA guidance on PK in patients with impaired renal function

• EMA guidance on Evaluation of PK in patients with decreased renal function

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Model diagnostics and selection (Ep. 11) Oct 09, 2023

This episode is a discussion on model evaluation and selection. I discussed diagnostic plots using predictions and residuals. I covered approaches for model selection and factors to consider. The focus of this episode is on models that predict continuous endpoints like drug concentration, biomarkers, or other continuous endpoints. Several figures are mentioned in the podcast and links to those images can be found below.

Links discussed in the show:

Figure 1: Observed vs Predicted for single-subject model (example of a good model fit). Figure generated using ggplot in R.
Figure 2: Observed vs Predicted for single-subject model (example of a poor model fit) using logarithmic scales. Figure generated using ggplot in R.
Figure 3: Observed vs Population and Individual Predicted for population model. Figures generated using ggCertara package in R.
Figure 4: Weighted residuals versus time, time after dose, and population prediction for population model. Figures generated using ggCertara package in R.
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Exposure-Response FDA Guidance (Ep. 10) Sep 25, 2023

This episode is a discussion of the FDA guidance “Exposure-Response Relationships”. The relationship between drug exposure and response is critical to any determination of the safety and effectiveness of a drug product. In this episode I discuss the regulatory applications of exposure-response, the exposure-response relationships over time, the design of studies to collection exposure-response information, and modeling exposure-response relationships. Links discussed in the show: • FDA guidance “Exposure-Response Relationships” • ICH E4 guideline “Dose-Response Information” • You can connect with me on LinkedIn and send me a message • Send me a message • Sign up for my newsletter Copyright Teuscher Solutions LLC All Rights Reserved

Finding a job in Clinical Pharmacology (Ep. 9) Sep 11, 2023

This episode I talk about finding a job in Clinical Pharmacology or Pharmacometrics. I share a few thoughts from my experience followed by an interview with TJ Elder, the president of STEM Sourcing Recruiting and Staffing. TJ shares his insights and best practices on securing a new job in Clinical Pharmacology or Pharmacometrics.

Links discussed in the show:

• Connect with TJ Elder on LinkedIn

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QT Prolongation Guidance ICH E14 (Ep. 8) Aug 28, 2023

This episode is a discussion of the FDA and ICH guidance E14 titled “Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs”. I start with background on the reason for these evaluations, then move to an overview of the key evaluations needed. I then discuss in some detail the thorough QT study and the concentration QT analysis. Then I provide some parting thoughts from my experiences with these analyses.

Links discussed in the show:

• ICH E14 Guidance (FDA website)

• Scientific white paper on concentration – QTc modeling by Garnett et. al

• Correction to publication

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Pediatric Extrapolation (Ep. 7) Aug 14, 2023

Thank you to everyone who sent me feedback on this podcast. This episode is based on a suggestion from Kushal and Parmesh. In this episode, I discuss a general clinical pharmacology pediatric extrapolation plan. I describe the basics of the plan that is commonly proposed to regulatory bodies. I discuss specific technical approaches for extrapolation of adult pharmacokinetic data to pediatric patients and the extrapolation of adult exposure-response or pharmacodynamic data to pediatrics. And I conclude with a discussion of how to use physiologic-based pharmacokinetic models for pediatric extrapolation.

Links discussed in the show:

• Baby arms over head video

• PBPK Models in Pediatric Development

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Bioequivalence Guidances from FDA and EMA (Ep. 6) Jul 24, 2023

Thank you to everyone who sent me feedback on this podcast. This episode is based on a suggestion from Drew. In this episode, I discuss bioequivalence studies and generic drug development. I will refer to guidance documents from both the European Medicines Agency or EMA and the US Food and Drug Administration or FDA. First, I will start with a discussion of the definition of bioequivalence or BE. Then I will discuss the statistical basis for bioequivalence and how you can leverage that for study design. And I will end with some unique challenges related to bioequivalence. Throughout, I will give practical suggestions based on my experiences in the past with BE studies.

Links discussed in the show:

• EMA guidance on bioequivalence

• FDA guidance on statistical approaches to bioequivalence (December 2022)

• FDA statistical approaches to BE (January 2001)

• FDA guidance on BE studies (2022)

• FDA product-specific guidances on BE

• Lecture from Helmut Schütz on finding intra-subject variability (or CV%) for power calculations

• PowerTOST R Package

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Nuances of NCA (Ep. 5) Jul 10, 2023

In this episode, I discuss some nuances of non-compartmental analysis or NCA. I am going to focus on three separate parameters: Cmax, AUC, and the terminal elimination rate constant. These three are the most commonly used parameters to describe drug exposure. I’ll discuss the basic methodology for each and then discuss challenges that may arise when you are performing an analysis. Links discussed in the show: Images mentioned in the podcast Derivation of logarithmic AUC Calculating the elimination rate constant You can connect with me on LinkedIn and send me a message Send me a message Sign up for my newsletter Copyright Teuscher Solutions LLC All Rights Reserved

Population PK FDA guidance (Ep. 4) Jul 03, 2023

In this episode, I discuss the 2022 FDA Guidance on Population PK analysis. This includes a discussion of the applications, methods, and submission requirements for population PK models.

Links discussed in the show:

• FDA Population PK Guidance

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Comparing NCA and PK models (Ep. 3) Jul 03, 2023

In this episode, I discuss two data analysis techniques: (1) non-compartmental analysis or NCA, and (2) PK modeling. I discuss the basic premise of each method and similarities and differences between them.

Links discussed in the show:

Publication about NCA by Johan Gabrielsson and Dan Weiner
Publication about PK modeling by Hartmut Derendorf et. al.
Play Angry Birds as a fun diversion today
Here’s a link to the Dexcom glucose sensor and the Tandem T-slim insulin pump
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Food Effect FDA Guidance (Ep 2) Jul 03, 2023

In this episode, I discuss the 2022 FDA guidance on food effect studies. I discuss the timing of these studies in your development programs, various aspects of study design, and some unique exceptions to the standard food effect study.

Links discussed in the show:

• Here’s the current FDA guidance for food effect studies

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Podcast about clinical pharmacology (Ep 1) Jul 03, 2023

In my inaugural episode, I introduce myself, describe the type of clinical pharmacology and pharmacometrics content I will share, let you know how to get in touch with me, and give the reason why I started this podcast.

Links discussed in the show: