Background:
The impact of genetic polymorphisms (SNP) and plasma levels of tamoxifen (TAM) and endoxifen (ENDO) on adverse events (AE) remains controversial.

Aims:
This prospective, multicenter, 3-year follow-up study (PHACS, NCT01127295) of adjuvant TAM (20 mg/day) in patients with breast cancer (n=880) aimed to evaluate the relationships between pharmacogenetics, pharmacokinetics of TAM and ENDO and AE.

Methods: Patients were genotyped for 92 SNPs selected from literature in 23 genes including CYP2D6. Each 6-month post-inclusion, residual concentrations for TAM and metabolites were measured and patients were assessed for 28 types of AE (NCI-CTC grade), over 3 years. For each AE, visit and patient a binary (increase in severity since inclusion) and a continuous toxicity variable (increase in severity since inclusion multiplied by grade) were created. Mixed effects generalised linear models were used to explore the relationship between the toxicity variables and TAM and ENDO concentrations, adjusting for genetic polymorphisms, weight and hormonal status.

Results: For the 8 most frequent AE, no statistically significant association was found between ENDO (or TAM) concentrations or CYP2D6 metabolizer status and an increase of severity. SNPs in CYP19A1, UGT2B17 were significantly associated with the risk of having an increase in the severity of sweating or depression since inclusion respectively. CYP2C19*2 allele had a significant protective effect on the occurrence of thrombo-embolic events.

Conclusions: No clear relationship was observed between pharmacokinetics and toxicity. Some genetic polymorphisms may be involved in the occurrence of AE but this requires confrmation in future studies.

Keywords:
Tamoxifen, adverse events, pharmacokinetics, pharmacogenetics

Background: Therapeutic drug monitoring (TDM)-guided busulfan (BU) dosing improves outcomes in hematopoietic stem cell transplantation (HSCT), but optimal BU exposure (AUC) in Chinese pediatric patients remains unclear.

Aims: This multicenter study aimed to develop a population pharmacokinetic (Pop-PK) model for BU and identify optimal AUC for clinical outcomes in Chinese pediatric HSCT recipients.

Methods: Pediatric patients (n=455) from five Chinese centers receiving BU-based conditioning (2018–2023) were analyzed. A Pop-PK model was constructed to estimated cumulative AUC. Outcomes included event-free survival (EFS), overall survival (OS), and toxicities (hemorrhagic cystitis, acute GVHD, oral mucositis). Exposure-outcome relationships were assessed using restricted cubic spline, Cox proportional hazards, and logistic regression models.

Results: For 3-day regimens, cumulative AUC (AUCs)≥54 mg·h/L was associated with superior 2.7-year EFS vs. AUCs <54 mg·h/L [86.4% (80.1–90.9) vs. 77.7% (70.4–83.5); HR=0.58 (0.34–0.99), P=0.045]. For 4-day regimens, AUCs 70–90 mg·h/L yielded higher 2.7-year EFS (88.9% [75.3–95.2]) vs. AUCs <70 mg·h/L (68.3% [54.2–78.9]; HR=2.94 [1.09–7.92], P=0.033) and AUC >90 mg·h/L (66.1% [43.4–81.4]; HR=3.22 [1.05–9.85], P=0.040). Multivariate analysis identified BU AUC, age, and anti-thymocyte globulin use as predictors of grade ≥2 hemorrhagic cystitis in 3-day regimens.

Conclusion: Targeting BU AUC ≥54 mg·h/L for 3-day regimens and 70–90 mg·h/L for 4-day regimens may improve EFS in Chinese pediatric HSCT patients, supporting TDM-based BU optimization.

Keywords: hematopoietic stem cell transplantation; pediatric pharmacotherapy; population pharmacokinetics; busulfan therapeutic drug monitoring; clinical outcomes

Background: Venetoclax, a potent and expensive oral therapy for hematological malignancies, follows a fixed dosing approach, often leading to suboptimal exposure and both clinical and financial toxicity. Its variable pharmacokinetics (PK) highlight the need for exposure-guided dosing. Capillary microsampling enables easier, more intensive PK assessment beyond trough levels, offering a practical, less invasive alternative to venipuncture.

Aims: To clinically validate the interchangeability of microsampling with venous plasma sampling and evaluate the feasibility of home-based self-microsampling for venetoclax PK-monitoring.

Methods: A bioanalytical assay was validated for venetoclax using the HemaXis DB10 device to collect a fixed blood volume (~10 μL). Clinical validation included 65 paired microsamples and venous plasma samples from 25 venetoclax-treated patients. Method agreement was assessed via Passing–Bablok regression and Bland–Altman analysis. Home-based feasibility was evaluated using both the HemaXis DB10 and Mitra Clamshell devices, based on sample acceptability and usability (System Usability Scale, SUS).

Results : After hematocrit correction, Passing–Bablok analysis showed strong agreement between methods with a regression slope of 0.96 (95% CI: 0.92–1.01) and an intercept of 13.13 (95% CI: −22.02 to 45.64). Bland–Altman analysis showed no significant bias (mean difference: 0.68% [95% CI: −2.46% to 3.81%]), with 95% of concentrations within ±20% of the mean. A total of 76% of home-based self-microsamples were successfully sampled, with median SUS scores of 75 and 78.

Conclusions: Capillary microsampling is a feasible, patient-friendly alternative to venous sampling for venetoclax PK monitoring. Strong agreement with venous sampling and successful home-based implementation support its use for decentralized PK self-monitoring.

Background: Taking 1000 mg Abiraterone (Abi) on an empty stomach is an effective treatment for metastatic castration-resistant prostate cancer (mCRPC), improving survival by 4 to 15 months. Abi trough concentrations (Cmin) ≥ 8.4 µg/L are associated with prolonged progression-free survival (12 vs. 7 months). Standard Abi administration resulted in Cmin < 8.4 µg/L in 63% of patients in a tertiary academic hospital, while pharmacologically (TDM) guided Abi with a light meal (food intervention) improved Cmin ≥ 8.4 µg/L in 87.5% [1].

Aims: This prospective study evaluates the feasibility of this Abi TDM food intervention in a secondary hospital setting.

Methods: mCRPC patients from two non-academic hospitals underwent three-monthly Abi Cmin monitoring. Those with Cmin < 8.4 µg/L received a food intervention.

Results: Among 47 included patients (median 2 Cmin samples per patient), 14 (30%) had Cmin < 8.4 µg/L: median 6.1 µg/L (range 2.0–8.3). In 9 patients with follow-up post-intervention, Cmin improved from 6.3 (2.0–8.3) to 9.8 µg/L (3.9–688 µg/L); p = 0.021, achieving Cmin ≥ 8.4 µg/L in 7 (78%) patients (p = 0.016), without added toxicity. Among patients with Cmin ≥ 8.4 µg/L throughout the study, 11 had Cmin > 100 µg/L.

Conclusions: Although the group with subtherapeutic Abi exposure was smaller, presumably due to more non-trough sampling, the food intervention demonstrated comparable efficacy in our community hospital setting. These findings support integrating the TDM-guided Abi food intervention into routine clinical practice for mCRPC management.

[1]Eur J Cancer 2020;130:32

Keywords: Abiraterone, TDM, Pharmacokinetics, Clinical Practice, Prostate Cancer, Real-World

Background
The dosing of pembrolizumab has been established in phase I-III clinical studies. Based on these studies, flat dose treatment regimens have been developed with the aim of achieving 95% target engagement in at least 90% of patients. A minimum plasma concentration of 10-15 μg/ml has been suggested for adequate target engagement.

Aim
The main objective of this study was to determine the variation in trough levels in cancer patients treated with pembrolizumab during 4 consecutive cycles.

Methods:
Patients were treated with pembrolizumab according to the standard schedule for their disease. In one group trough samples were collected at the end of treatment cycle 1-4, just before the next dose. In a second group trough samples were obtained during 3 consecutive cycles after at least 2 earlier treatment cycles.

Results
Patients were treated for lungcancer n=20 (100-200mg/3weeks or 400mg/6 weeks), melanoma n=19 (200-400mg/6weeks) or other cancers n=7 (100-200mg/3weeks or 200-300mg/6weeks).
Trough levels increased from 11±6 μg/ml (n=27) during cycle 1 to respectively 16±8 μg/ml (n=31), 18±8 μg/ml (n=22) and 20±9 μg/ml (n=17) during cycles 2-4. In >2 cycles pretreated patients trough levels were 28±11 μg/ml (n=41), 27±12 μg/ml (37) and 27±10 μg/ml (n=28) during three consecutive cycles.
In at least 87% of all treated patients the trough level was above 15 μg/ml after at least three treatment cycles.

Conclusion
In a high proportion of all pembrolizumab treated patients trough plasma levels were a above 15 μg/ml. This suggests that stretching of dosing intervals might be possible without losing treatment efficacy.

Background: The NCCN recently endorsed low-dose abiraterone as a cost-effective alternative to the standard dose, potentially improving access and reducing costs globally.

Aim: To evaluate the exposure-response relationship of low-dose (250 mg/day with food) versus standard-dose abiraterone (1000 mg/day fasting) in metastatic castration-resistant prostate cancer (mCRPC) patients and assess the feasibility of achieving the target abiraterone concentration (8.4 ng/mL).

Methods: A prospective observational pilot study (2023–2025) included 20 patients in each dosing cohort. Plasma abiraterone trough concentrations were analyzed using LC-MS. The primary objective was to compare therapeutic drug levels and clinical efficacy.

Results: Among twenty patients receiving low dose, 15 (75%) achieved >50% PSA decline at 3 months. Similarly, in the standard dose group (n=18), 15 (83%) demonstrated >50% PSA reduction (p=0.397). PFS was 24.8 vs. 19.54 months in the low dose vs standard dose group and OS was 27.1 vs. 24.78 months respectively. The abiraterone plasma trough level was 4.1 ± 1.71ng/mL and 21.6 ± 7.96 ng/mL in the low dose and standard dose respectively. This analysis showed a weak positive relationship (r = 0.26, p = 0.575) between concentration and PSA levels at low dose, while at standard dose, a moderate negative correlation (r = -0.57, p = 0.433) was observed.

Conclusion: Low-dose abiraterone demonstrated a comparable PSA response to standard dosing, suggesting potential non-inferiority, with slightly better survival outcomes. Further studies, including RCTs are needed to confirm these findings and optimize dosing strategies.

Keywords: Abiraterone Acetate, mCRPC, Exposure-Response Relationship

Background: 5-Fluorouracil (5-FU) is the cornerstone of first-line chemotherapy for various gastrointestinal cancers. 5-FU has due to myelosuppression and other toxicities, a narrow therapeutic window, for which recently an area under the curve (AUC0-inf) target 20–30 mg·h/L was proposed.
Aims: Primary aim was to develop a 5-FU population pharmacokinetic (POPPK) model and identify covariates. Secondary aims were to develop a limited sampling strategy (LSS) to estimate individual AUC0-inf and to develop an MIPD application to facilitate both initial dose and subsequent dose individualization.
Methods: Retrospective data from multiple centers was collected to establish the 5-FU POPPK model with non-linear mixed effect modelling. A workflow to identify LSS was developed using simulated data from 1000 virtual patients of the final model. The final POPPK model was integrated into a user-friendly shiny application to provide individualized dosing recommendations.
Results: 140 individuals with 435 PK samples were best described using a two-compartment model with Michaelis-Menten elimination. Body surface area (BSA) significantly influenced the maximum rate of reaction (Vmax) and was implemented using allometric scaling with an exponent of 1.14 (RSE24%). For bolus and 46h continuous infusion, the LSS was T=0.1(end-of-bolus),1,3 hours after treatment initiation, while for 46h continuous infusion, the LSS was T=2,3,5 hours. MIPD algorithms were developed and implemented in a shiny application(https://tanzy1995.shinyapps.io/5FU-shiny-app/).
Conclusions: The developed POPPK model effectively described 5-FU pharmacokinetics with BSA as covariate. In addition, the LSS and the shiny MIPD application demonstrated the potential for dose individualization of 5-FU.
Key Words: 5-Fluorouracil, population pharmacokinetics, MIPD, optimal sampling