Debra van Asten1,2, M. Dotinga2, B.J. de Wit-van der Veen2, A.D.R. Huitema1,3,4, H. Huisman-Siebinga1,2
1Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, 2Department of Nuclear Medicine, The Netherlands Cancer Institute, 3Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, 4Department of Pharmacology, Princess Máxima Center for Pediatric Oncology
Objectives: [¹77Lu]Lu-PSMA is an approved radioligand therapy that prolongs progression free survival and overall survival in patients with metastatic castration-resistant prostate cancer (mCRPC). It selectively targets prostate-specific membrane antigen (PSMA) on prostate cancer cells. While [¹77Lu]Lu-PSMA treatment has a favorable overall toxicity profile, dose-limiting hematological toxicities occur in a subset of patients [1]. Furthermore, significant variability in pharmacokinetics (PK), particularly in tumor and bone exposure, has been observed in patients. Therefore, this study aimed to quantify the relationship between [¹77Lu]Lu-PSMA-I&T exposure in bone and bone metastases and its impact on neutrophil levels using a semi-physiological population PK-pharmacodynamic (PD) model. Methods: SPECT/CT scans at 4h, 24h and 6 days after treatment and neutrophil levels were retrospectively collected from patients with mCRPC receiving 1-8 cycles of ~7.4 GBq [¹77Lu]Lu-PSMA-I&T as part of standard clinical care (with a treatment interval of 2 or 6 weeks) at the Antoni van Leeuwenhoek hospital between September 2019 and March 2024. Segmentation of organs (aorta, bones, kidneys and salivary glands) and tumor load from SPECT/CT scans was performed using MIM software (version 7.3.6) to obtain average tissue concentrations (MBq/L) and tissue volumes (L). For tumor segmentation, a minimum volume of 2.5 mL was used together with a semi-automatic segmentation method using a threshold relative to the maximum uptake per region (20% for liver metastases and 15% for primary tumors and other metastases). A previously developed semi-physiological PK model was optimized and expanded (using NONMEM version 7.5) [2]. This resulted in a seven-compartmental model representing blood, salivary glands, kidneys, bones, bone metastases, primary tumors and/or other metastases and a lumped rest compartment. PK data were available for all compartments except for the lumped rest compartment. Structural model parameters consisted of volume of distribution of the blood compartment (V1), renal excretion (k10) and kin and kout values to other compartments. Between subject variability (BSV) was added to uptake rate parameters, V1 and k10. A negative relationship between tumor uptake (k15 and k16) and increasing cycle number was included in the model. Subsequently, an existing PD-model structure of chemotherapy-induced myelosuppression was used to sequentially link the activity in bones (healthy bone and bone metastases compartment) to patient neutrophil data [3]. Both a linear and Emax relationship was explored. Moreover, a delay between bone exposure and its effect on neutrophil cell proliferation was included. Results: Data from 139 patients were included for analysis. The seven-compartment PK model showed adequate goodness of fit, parameter stability and precision (relative standard error (RSE) <20%). Parameter estimates for kin differed between the organ and tumor compartments and were 0.005 h?¹ for k12 (salivary glands), 0.004 h?¹ for k13 (kidney), 0.023 h?¹ for k14 (bones), 0.041 h?¹ for k15 (bone metastases), 0.009 h?¹ for k16 (other tumors). BSV was estimated for k14 (145%), k15 (67%), k16 (79%) and V1 (118%), and fixed for k10 (47%), k13 (60%) and kin rest compartment (k17) (60%). Bone and bone metastases observations were well captured and their BSV values reflect a clinically relevant high variability in exposure observed in our population. A linear relationship between PK and PD best captured neutrophil data. The baseline neutrophil count was estimated at 4.0*10?/L (including 42% BSV) and ? (related to the feedback mechanism of circulating cells on neutrophil proliferation) was fixed to 0.12. The estimated impact of [¹77Lu]Lu-PSMA-I&T (with a slope of 0.00113 MBq?¹) led to a maximum reduction of 15% (median 1.8%) of neutrophil proliferation. Conclusions: Our PK-PD model successfully quantified the exposure-time and exposure-neutrophil relationship of mCRPC patients receiving [¹77Lu]Lu-PSMA-I&T. The high variability in bone and bone metastases suggest that some patients experience higher toxicity at standard doses, whereas others may tolerate dose escalation. These findings highlight the need to integrate personalized approaches when considering higher or prolonged dosing strategies. Future optimization of our model could help establish toxicity thresholds to guide these personalized approaches.
[1] Chi KN, Armstrong AJ, Krause BJ, Herrmann K, Rahbar K, de Bono JS, Adra N, Garje R, Michalski JM, Kempel MM, Fizazi K, Morris MJ, Sartor O, Brackman M, DeSilvio M, Wilke C, Holder G, Tagawa ST. Safety Analyses of the Phase 3 VISION Trial of [177Lu]Lu-PSMA-617 in Patients with Metastatic Castration-resistant Prostate Cancer. Eur Urol. 2024 Apr;85(4):382-391. [2] Siebinga H, de Wit-van der Veen BJ, de Vries-Huizing DMV, Vogel WV, Hendrikx JJMA, Huitema ADR. Quantification of biochemical PSA dynamics after radioligand therapy with [177Lu]Lu-PSMA-I&T using a population pharmacokinetic/pharmacodynamic model. EJNMMI Phys. 2024 Apr 24;11(1):39. [3] Friberg LE, Henningsson A, Maas H, Nguyen L, Karlsson MO. Model of chemotherapy-induced myelosuppression with parameter consistency across drugs. J Clin Oncol. 2002 Dec 15;20(24):4713-21.
Reference: PAGE 33 (2025) Abstr 11719 [www.page-meeting.org/?abstract=11719]
Poster: Drug/Disease Modelling - Oncology