A MODEL INFORMED DRUG DEVELOPMENT (MIDD)-BASED QUANTITATIVE DECISION FRAMEWORK (QDF) FOR IMPROVING R&D PRODUCTIVITY: PROOF OF CONCEPT FOR ATOPIC DERMATITIS (AD)

E. Anderson¹, BW. Corrigan¹, M. Cala Pane¹, A. Tredennick¹, T. Dunlap¹, L. Lomeli¹, B. Davis¹, MR.Gastonguay¹1Metrum Research Group, Boston, MA

Project Rationale

QDF Components QDF Components
Competitive Landscape
MIDD Enhanced Valuations

Rising costs, uncertain reimbursement, competition, and declining success rates have
reduced drug R&D productivity and investment over the last decade.
Proposed strategies to improve R&D productivity include four key factors: 1) leveraging all
data sources; 2) utilizing quantitative models; 3) elimination of information silos across R&D
and commercial organizations; and 4) application of decision frameworks to reduce
cognitive bias and improve decision making.1

A QDF for a drug development program in atopic dermatitis (AD) was developed to: 1) link
MIDD models aligned with a target product profile (TPP) to risk-adjusted net present value
(rNPV); and 2) integrate context-sensitive large language models (LLMs) to incorporate
non-structured data from novel sources into the decision-making framework in a responsible
manner.

This study presents a validated whole-body PBPK model characterizing drug-drug interactions (DDIs) involving posaconazole, a broad-spectrum antifungal, in individuals with normal weight and obesity. Findings highlight a prolonged half-life and irreversible CYP3A4 inhibition in patients with BMI ≥35 kg/m², underscoring the increased risk of DDIs even after discontinuation. The model supports optimized dosing and risk assessment for co-administered CYP3A4-sensitive drugs.

Presented at the ENAR 2025 Spring Meeting. Monitoring vaccine effectiveness (VE) against emerging variants is critical, but traditional methods can take substantial time to implement. This presentations includes an approach that leverages dynamic case-control sampling to provide timely VE estimates–helping public health officials make more informed decisions.

DZIF-10c (BI 767551) is a SARS-CoV-2-neutralizing recombinant monoclonal antibody designed for both systemic and respiratory tract exposure via intravenous infusion and inhalation. A semi-mechanistic population pharmacokinetic model integrated preclinical and clinical data using allometric scaling to characterize lung and systemic exposure profiles. Simulations showed that inhalation offers effective lung exposure at lower doses, while combining inhalation with intravenous therapy achieves sustained levels in both lungs and systemic circulation, optimizing treatment outcomes.

Presented at ACoP 2024. Efavirenz is metabolized primarily by CYP2B6, to form 8-OH EFV, and also by CYP2A6, to form 7-OH EFV. Upon chronic administration, efavirenz induces both CYP2B6 and CYP2A6, leading to autoinduction of its metabolism. A population pharmacokinetic model was constructed to quantify the impact of CYP2B6 phenotype on efavirenz autoinduction and subsequent exposure.

Presented at ACoP 2024. The poster introduces a framework for developing physiologically based pharmacokinetic (PBPK) models that incorporate partial differential equations (PDEs) to account for spatial drug distribution, using open-source Julia tools. This approach simplifies the integration of spatial components into PBPK models, demonstrated through a case study on naphthalene diffusion, and is applicable to various pharmacometric models requiring spatial considerations, such as topical, inhaled, and antitumor therapies.

Neutralizing monoclonal antibodies (mAb) have emerged as promising therapeutics for COVID-19, with research efforts accelerated through open-access in silico models. Innovative approaches, including a physiologically-based pharmacokinetic (PBPK) model and a longitudinal SARS-CoV-2 viral dynamic model, facilitated the selection of optimal mAb candidate and therapeutic dose. By utilizing these models, the first-in-human trial of bamlanivimab (NCT04411628) initiated with a conservative dose of 700 mg, aiming to achieve maximum therapeutic effect while ensuring safety and tolerability.

Katherine Kay, Justin Goodwin, Hanna Ehrlich, Joyce Ou, Tracey Freeman, Kaicheng Wang, Fangyong Li, Martina Wade, Jonathan French, Liusheng Huang, Francesca Aweeka, Norah Mwebaza, Richard Kajubi, Matthew Riggs, Ana Ruiz-Garcia, Sunil Parikh. Clin Pharmacol Ther. Published online October 19, 2022. doi:10.1002/cpt.2768

Katherine Kay, Justin Goodwin, Hanna Ehrlich, Joyce Ou, Tracy Freeman, Kaicheng Wang, Fangyong Li, Martina Wade, Jonathan French, Liusheng Huang, Francesca T. Aweeka, Norah Mwebaza, Richard Kajubi, Matthew Riggs, Ana Ruiz-Garcia, Sunil Parikh. Poster presented at American Society of Tropical Medicine and Hygiene (ASTMH). October 30 – November 3, 2022. Poster #1434.

Tim Knab, Ahmed Elmokadem, Emmanuel Chigutsa, Eric Jordie, Matthew Riggs, Patricia Brown-Augsburger, Christopher Wiethoff, Ajay Nirula, Jenny Y Chien, Lisa O’Brien.  Poster presented at Population Approach Group Europe Annual Meeting; 2-3 and 6-7 September 2021.  Poster I-64.

Hastings, IM, Hardy, D, Kay, K, Sharma, R. Evol Appl. 2020; 13: 2723– 2739.

Kay K, Goodwin J, Mwebaza N, Ruiz A, Ehrlich H, Ou J, Freeman T, Wade M, Huang L, Wang K, Li F, Aweeka FT, Riggs M, Kajubi R, Parikh S.  Presented at the annual meeting of the American Society of Tropical Medicine and Hygiene, October 16-18, 2020.

Presentation by Katherine Kay Ph.D at R/Medicine. Boston, MA. 14 September 2019.

Riccobene TA, Khariton T, Knebel W, Das S, Li J, Jandourek A, Carrothers TJ, Bradley JS.  The Journal of Clinical Pharmacology, March 2017; 57: 345–355. doi: 10.1002/jcph.809

Nagy CF, Mondick J, Serbina N, Casey LS, Carpenter SE, French J, Guttendorf R.  Clinical And Translational Science, 2016 Dec; 10: 12–19.

Yamamoto BJ, Shadiack AM, Carpenter S, Sanford D, Henning LN, O’Connor E, Gonzales N, Mondick J, French J, Stark GV, Fisher AC, Casey LS, Serbina NV. Antimicrob Agents Chemother 60:5787–5795. doi:10.1128/AAC.00972-16

Riccobene TA, Pushkin R, Jandourek A, Knebel W, Khariton T.  Antimicrob Agents Chemother. 2016 Sep 23;60(10):5849-57.

Wilbur JD, Ohuma E, Xiao L, Mouksassi S, Hafen R.  Presented at the Annual Meeting of the Population Approach Group in Europe (PAGE), Lisboa, June 2016.

Olson S, Baron K, Riggs M, Bocher WO, Mensa FJ.  Journal of Hepatology, 58:S492–S493.

Riggs MM, Bergsma TT, Rogers JA, Gastonguay MR, Subramanian GM, Chen C, Devalaraja M, Corey AE, Sun H, Yu J, and Stein DS. The Journal of Clinical Pharmacology, 52: 475–486, April 2012. doi:10.1177/0091270011399576

Johnston CK, Tsuji BT.  Presented at the American College of Clinical Pharmacy (ACCP) Annual Meeting; October 2011; Pittsburgh, PA.

Baron KT, Ravva P, Purohit V, Riggs MM, Gastonguay MR. 6th International Workshop on Clinical Pharmacology of Hepatitis Therapy, June 2011.