Abstract: TH-PO1223
Population Pharmacokinetic and Exposure-Response Modeling Supports BI 764198 20 mg as the Therapeutic Dose for Phase 3, with No Dose Adjustment Required
Session Information
- Late-Breaking Research Posters
November 06, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
- 2000 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
Authors
- Retlich, Silke, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
- Lagraauw, Hendrik Maxime, qPharmetra LLC, Uppsala, Sweden
- Petersson, Klas Jf, qPharmetra LLC, Uppsala, Sweden
- Falkenhagen, Undine, qPharmetra LLC, Uppsala, Sweden
- Voelkner, Alexander, qPharmetra LLC, Uppsala, Sweden
- Soleymanlou, Nima, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut, United States
- Lobmeyer, Maximilian T, Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany
- Prasad, Srinivasa, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut, United States
- Trachtman, Howard, Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, United States
- Bungert, Lisa, Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany
Background
BI 764198, a transient receptor potential cation channel, subfamily-C, member-6 (TRPC6) inhibitor, is being developed for the treatment of focal segmental glomerulosclerosis (FSGS). A comprehensive population pharmacokinetic (popPK) and exposure-response (E-R) analysis was conducted to inform dose selection and assess the impact of covariates.
Methods
A popPK model was developed using data from four Phase I studies and updated based on a Phase II study in FSGS. Covariate analysis included body weight, race, and baseline estimated glomerular filtration rate (eGFR [CKD-EPI]). An E-R model was developed to characterize the effects of BI 764198 on 24-hour urinary protein excretion (UPE) and urinary protein-creatinine ratio (UPCR). Serum and urinary creatinine were included to account for the known, reversible off-target inhibition of MATE1, MATE2-K and OCT2 that increases serum creatinine without affecting renal function.
Results
A two-compartment model with first-order absorption and elimination adequately described the PK of BI 764198 in healthy volunteers and patients. Body weight, Asian race and baseline eGFR had small, statistically significant effects on BI 764198 PK but none warranted dose adjustment. The E-R model incorporated a concentration-dependent Imax model to describe the inhibition of creatinine secretion by BI 764198 with a maximum inhibition of 34.7% (95% CI: 29.7–40.1). UPE was modeled using a zero-order elimination process and a gradual, proportional treatment effect across the tested doses (20, 40 and 80 mg). Despite a clear treatment effect, a distinct E-R relationship could not be identified between BI 764198 exposure and either UPE or UPCR. Consistent with this, the median unbound BI 764198 Cav,ss for the 20 mg dose (117 nmol/L; assuming 36.4% unbound fraction) corresponded to a >IC90 of in vitro human TRPC6 inhibition, supporting the hypothesis that BI 764198 20 mg achieves a near-maximal pharmacodynamic effect.
Conclusion
The final popPK and E-R models support BI 764198 20 mg as the therapeutic dose for Phase III, with no dose adjustment required based on the covariates investigated.
Funding
- Commercial Support – The study was supported and funded by Boehringer Ingelheim. Medical writing support for the preparation of this abstract was provided by Laura George, PhD, CMPP of OPEN Health Communications, and funded by Boehringer Ingelheim, in accordance with Good Publication Practice (GPP) guidelines (www.ismpp.org/gpp-2022).