Case Study

Evaluating Absorption and Exposure
Under Altered Gastric pH Conditions: How One Client Used GastroPlus®
 to Avoid a DDI Clinical Study 

Overview

A new drug candidate showed therapeutic potential but carried a development risk: its pH-dependent solubility could alter pharmacokinetics (PK) when co-administered with acid-reducing agents (ARAs). The sponsor sought an efficient way to address this potential interaction without committing to a costly and time-consuming clinical trial. 

1.3X
Return on investment
200K
Estimated saved study costs
5 Months
in reduced time-to-market
Challenge

The main concern was whether co-administration with ARAs would reduce drug absorption and systemic exposure, ultimately impacting efficacy and patient safety.  

Regulatory agencies could have required a dedicated drug-drug interaction (DDI) clinical study, but this would be costly, involve challenges related to patient recruitment and trial logistics, and delay approval. 

The sponsor needed a scientifically rigorous and efficient path forward. 

Solution

The sponsor decided to work with Simulations Plus scientists and use physiologically based pharmacokinetic (PBPK) modeling to evaluate the drug’s absorption and exposure under altered gastric pH conditions. This approach allowed them to predict absorption changes at elevated gastric pH and generate evidence strong enough to inform regulatory labeling recommendations. 

By relying on a mechanistic, modeling-based strategy, the team could address regulatory concerns without conducting a dedicated DDI study. 

Results

The PBPK modeling analysis was accepted by regulators, eliminating the need for an additional clinical trial and saving an estimated five months to market and $200,000 in study costs, for an estimated 1.3x return on investment (ROI).*  

*The ROI values presented in this case study are based on direct, quantifiable savings such as study waivers, reduced experimental requirements, and other avoided costs. These figures are intended to represent a conservative estimate of the total potential return. They do not capture the broader—and often more significant—economic impact of accelerated regulatory approval and earlier market entry, including competitive positioning, increased patient access, and additional revenues that may result from an expedited development timeline. 

Learn More

Examples of using GastroPlus PBPK modeling to evaluate the effects of ARAs to support regulatory submissions

Note: ROI shown reflects only direct cost savings (e.g., study waivers). The significant additional benefits from accelerated approval/market entry are not included. 

Drug   GastroPlus Version  Predicted AUCR  Observed AUCR  Predicted Effect  Observed Effect  Predictive performance   Comments   References  
Alectinib  V8.6  No effect  1.22  No effect  No effect  Same category  Model was submitted to FDA  (1, 2) 
Axitinib   V9.5  0.82  0.85  No effect  No effect   Same category  Model submitted to FDA  (3, 4) 
Panobinostat  Not reported  No effect  NA  No effect   NA  NA  Model was submitted to FDA, DDI study with an ARA was waived  (5) 
Ribociclib  V9.0  No effect  NA  No effect  NA  NA  Model was submitted to FDA, DDI study with an ARA was waived  (6, 7) 
Sebetralstat  V9.8.3  Decrease by up to 30%  NA  No to Weak effect  NA  NA  submitted to FDA, DDI study with an ARA was waived  (8, 9) 

 

The interaction effect magnitude  (no, weak, moderate, or strong) is defined based on the definition for induction effect: no effect if AUCR >= 0.8, weak effect if 0.5<= AUCR < 0.8, moderate effect if 0.2<= AUCR < 0.5, strong effect if AUCR < 0.2 where AUCR is the ratio of AUC in the presence and absence of an acid reducing agent (ARA). NA: not available; the default prandial status is fasting condition if not specified 

  1. FDA. NDA 208434 Alectinib Clinical Pharmacology Biopharmaceutics Review(s). Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208434Orig1s000ClinPharmR.pdf. 
  1. Parrott NJ, Yu LJ, Takano R, Nakamura M, Morcos PN. Physiologically Based Absorption Modeling to Explore the Impact of Food and Gastric pH Changes on the Pharmacokinetics of Alectinib. AAPS J. 2016;18(6):1464-1474.
  2. FDA. NDA 202324 Aaxitinib Tablets Clinical Pharmacology Biopharmaceutics Review(s) 2025 Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202324Orig1s000ClinPharmR.pdf.
  3. Dodd S, Kollipara S, Sanchez-Felix M, Kim H, Meng Q, Beato S, Heimbach T. Prediction of ARA/PPI Drug-Drug Interactions at the Drug Discovery and Development Interface. J Pharm Sci. 2019;108(1):87-101.
  4. FDA. NDA 205353 Panobinostat Capsules Clinical Pharmacology Biopharmaceutics Review(s) 2025 Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/205353Orig1s000ClinPharmR.pdf.
  5. FDA. NDA 209092 Ribociclib MULTI-DISCIPLINE REVIEW. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209092Orig1s000MultidisciplineR.pdf.
  6. Samant TS, Dhuria S, Lu Y, Laisney M, Yang S, Grandeury A, Mueller-Zsigmondy M, Umehara K, Huth F, Miller M, Germa C, Elmeliegy M. Ribociclib Bioavailability Is Not Affected by Gastric pH Changes or Food Intake: In Silico and Clinical Evaluations. Clin Pharmacol Ther. 2018;104(2):374-383. 
  7. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/219301s000lbl.pdf 
  8. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2025/219301Orig1s000IntegratedR.pdf