Background: Selumetinib (SLT) is an oral, selective mitogen-activated protein kinase inhibitor administered twice daily to pediatric neurofibromatosis patients. Adverse effects are common, prompting physicians to switch to smaller or alternating doses. Ingestion in the fasted state is recommended, placing a burden on patients. Concentrations show substantial intraindividual fluctuations, exposure is highly variable, and the drug is eliminated almost entirely between intakes. TDM-based therapy guidance may help overcome these issues.

Aims: To construct a nonparametric population pharmacokinetic model based on rich sampling and to perform Monte-Carlo simulations to facilitate a tighter control of exposure to SLT.

Methods: Twenty-two pediatric outpatients [median age (range): 11.5 (5-16) years], receiving doses based on clinical evaluation and follow-ups, were included. Plasma SLT concentrations obtained in 156 samples were used for modeling using PmetricsTM. Monte-Carlo simulation was performed with 40-mg daily doses to evaluate the interindividual variability in exposure and compare concentration fluctuations seen with q6h, q8h, or q12h regimens.

Results: A three-compartment model best fitted the observations. The median half-life was 1.42 (range: 0.36-3.74) hours. Monte-Carlo simulations estimated a 32.7-fold variability in areas under the concentration-time curves with standard q12h dosing and trough/peak concentration ratios of 12.6%, 10.4%, and 6.5% for q6h, q8h, or q12h dosing, respectively.

Conclusions: The substantial interindividual variability of SLT exposure and the intraindividual fluctuations demonstrate the importance of individualizing dosing regimens.

Key Words: Therapeutic drug monitoring, oncology, paediatrics, selumetinib, nonparametric pharmacokinetic modeling

Background
Regorafenib, a multi-targeted tyrosine kinase inhibitor (TKI), has approved for metastatic colorectal cancer (mCRC) and gastrointestinal stromal tumors (GIST). Regorafenib is converted to M2 and further to M5 by CYP3A4. Regorafenib is difficult to be administered in full doses because of toxicity, including hand-foot skin reactions (HFSR). Therapeutic drug monitoring (TDM) of regorafenib may predict the occurrence of toxicity and contribute to treatment continuation.

Methods
TDM study was prospectively recruited from patients who received several TKIs. Blood samples collected at each visit and the concentrations were measured using liquid chromatography-tandem mass spectrometry. Patients treated with regorafenib between September 2022 and November 2024 were analyzed. The association between toxicities in cycle 1 and plasma concentrations of regorafenib and its metabolites at 7days in cycle 1 was assessed.

Results
Twenty-nine patients were recruited, and the median age was 64 years, with mCRC (n=25) and GIST (n=4). Initial dose (mg/day) was 40 (n=1), 80 (n=22), 120 (n=5), and 160 (n=1). Regorafenib, M2, and M5 concentrations throughout the analysis were 356-8617, 31-1755, and 41-1033 ng/mL, respectively, with large individual differences at the same dose. Patients with ≧ grade 2 HFSR of M5 concentrations showed significantly higher than those with < grade 2 HFSR (251ng/ml vs 520ng/ml, p=0.0475).

Conclusions
We found a significant association between M5 concentrations and HFSR in patients treated with regorafenib. TDM of M5 may be applicable to predict HFSR in clinical practice; studies are needed on differences in M5 concentration by CYP3A4 polymorphisms and their association with HFSR.

Background: Genetic factors, inflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor-α (TNF-α), and uremic substances such as 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) have been reported to affect organic anion transporting polypeptide (OATP)1B activity. However, the relationship between OATP1B activity and these factors in patients with cancer cachexia has not been reported.

Aims: This study aimed to identify the factors contributing to individual differences in OATP1B activity in patients with cancer cachexia, using coproporphyrin- I (CP-I) as an endogenous biomarker of OATP1B activity.

Methods: The study included patients with cancer cachexia attending the Oita University Hospital. After obtaining written informed consent, plasma CP-I and CMPF levels were measured by ultra-high performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry, inflammatory cytokines by ELISA, and OATP1B genetic polymorphisms by real-time PCR.

Results: The study recruited 114 patients; 40 with pre-cachexia, 39 with cachexia, and 35 with refractory cachexia. Plasma CP-I levels were higher in patients with pre-cachexia compared with the data in general population reported previously, and tended to be higher in patients with refractory cachexia than in the others. Plasma CP-I correlated positively with IL-6 and TNF-α, but did not correlate with OATP1B polymorphisms or CMPF. Multiple regression analysis identified the refractory cachexia as a significant factor independently affecting plasma CP-I levels.

Conclusions: Reduction in OATP1B activity in patients with cancer cachexia may be attributed to inflammatory cytokines or some other factors that are elevated by cancer cachexia progression, rather than OATP1B polymorphisms and CMPF.

Keywords: cancer cachexia, OATP1B, coproporphyrin-I, biomarker

Backgrounds: Osimertinib is an orally, third-generation epidermal growth factor receptor (EGFR)-TKI that acts by irreversibly binding EGFR activating mutations. Although some patients need dose reduction, efficacy has not been demonstrated. We are conducting a prospective observational study of TDM in patients receiving various TKIs. This is a preliminary assessment of osimertinib.

Methods: Patients treated with osimertinib between March 2022 and May 2024 were analyzed. Blood samples collected at each visit. The plasma concentration was measured using LC-MS/MS.

Results: A total of the 26 was enrolled, of which 25 were evaluable. Of these, 8 (31%) were male, the median age was 74 (range 36-88). the initial dose was 40 mg in 3 patients and 80 mg in 22 patients. In the initial blood sampling of 22 patients who started with 80 mg, the concentrations in patients who required a dose reduction within two months tended to be higher than those in patients who were able to continue treatment without a dose reduction (594ng/mL vs 210 ng/mL, p=0.001). The mean concentrations were comparable between 14 patients who continued 80mg and 8 patients who received 40mg either initially or after dose reduction. (204ng/mL vs 223ng/mL).

Conclusions: The group that started at 80mg, the group that switched to 40mg due to adverse events, and the group that started at 40mg due to concerns about adverse events ultimately showed the same plasma concentration. TDM from the initiation of treatment may help prevent adverse events, and could facilitate the optimization of the dose of osimertinib.

Background: Imatinib is a representative tyrosine kinase inhibitor for the treatment of gastrointestinal stromal tumor (GIST). Elderly patients are more likely to experience imatinib-related adverse events and dose reductions compared with non-elderly patients. The aim of this study was to investigate the relationship between plasma concentrations of imatinib and age in patients with GIST, and to determine the optimal dose in elderly patients.

Methods: This study analyzed the data of the patients receiving imatinib for GIST enrolled between Sep 2022 and Feb 2025 in a prospective observational study. The correlation between age and C/D ratio (plasma concentration normalized by daily dose) at steady-state was evaluated using Pearson linear correlation coefficients. C/D ratio of imatinib were used to determine differences between two groups: the elderly group (aged 75 ≥, E group), and the non-elderly group (aged <75, NE group).　

Results: A total of 34 patients (E: 9, NE: 25) were included. A significant correlation between age and C/D ratio was observed (R²=0.496, p=0.028). The trough C/D ratios for imatinib were 5.86±5.06 for E group and 2.94±2.59 (p=0.17) for NE group, respectively, indicating a wide variation in the E groups. The starting doses required to achieve target concentrations, based on the median trough C/D ratio, were 400 mg for NE group and 100-200 mg for E group .

Conclusions: This study showed that age was associated with a higher imatinib C/D ratio. Almost two-fold higher C/D ratio in the E group suggests that imatinib was initiated at half the standard dose.

Background: TDM for oral molecular targeted anticancer drugs (MTAs) helps individualize dosing regimens and maintain therapeutic target range but is not implemented in routine clinical practice. In addition, age and sex are known to be factors that influence pharmacokinetics for many drugs, but their influence is not clear for MTAs. In this study, we prospectively examined the association of plasma concentrations of various MTAs with age and sex.

Methods: Patients who started treatment with MTAs between March 2022 and January 2025 were included. Plasma concentrations of MTAs were measured by LC-MS/MS at each visit. Patient characteristics were collected on treatment initiation date.

Results: Of the 155 included patients, 37 started imatinib, 25 osimertinib, 23 abemaciclib, and 7 fruquintinib, while the remaining 63 received other MTAs. Of these, 84 patients (54%) were female and the median age was 65 (range: 34-89). The geometric mean ratio (elderly [≥65] to non-elderly) was greater than 1 for imatinib (1.38, 95% CI: 0.95–2.02), abemaciclib (1.85, 0.77–4.44), and fruquintinib (1.39, 0.89–2.19), whereas it was 0.90 (0.55–1.49) for osimertinib. Female receiving osimertinib had significantly higher concentrations than male, regardless of age (p = 0.029). The geometric mean ratio (female to male) for osimertinib was 1.68 (1.15–2.44).

Conclusions: This study suggested certain drug concentrations are associated with age- and sex-related differences in real-world settings. It is expected to validate the impact of TDM by evaluating the relationship between drug concentration and toxicity in the future.

Keywords: Cancer treatment, Oral molecular targeted agents, Therapeutic Drug Monitoring, Plasma concentration

Background: Allogeneic haematopoietic stem-cell transplantation (HSCT) is offered to selected patients with blood cancers at Singapore General Hospital (SGH), a leading transplant center in Asia. A key component of the preparative regimen is Busulfan (BU), a chemotherapy agent. However, weight-based dosing of BU results in significant variability in drug exposure among patients. Achieving therapeutic BU concentrations is essential to prevent graft failure, disease relapse, and reduce toxicities like veno-occlusive disease. Despite this, real-time BU therapeutic drug monitoring (TDM) is unavailable in Singapore.

Aims: This study aims to develop a rapid and accurate assay using liquid chromatography-tandem mass spectrometry (LCMS/MS) to optimize BU dosing in patients receiving BU-based HSCT in Singapore.

Methods: BU concentrations of 0.02–5mg/L was spiked in commercial plasma to create the calibration curve. Four adults with haematological malignancies and three children with underlying non-malignant conditions (2 thalassemia, 1 mucopolysaccharidosis type II) were recruited with consent. Samples underwent protein precipitation with zinc sulphate, followed by hexane extraction. Data was acquired using an LCMS 8060 mass spectrometer. BU area-under-the-concentration-time-curve-at-steady-state(AUCss,24hr) was calculated using Pmetrics software to evaluate efficacy.

Results: Excellent linearity(R² = 0.999) was demonstrated within tested range. 6 subjects were successfully engrafted, 1 paediatric patient with underlying mucopolysaccharidosis type II had graft rejection despite achieving target BU exposure after dose adjustment. All subjects with underlying haematological malignancies remained in remission with no adverse effects related to BU-TDM.

Conclusion: A validated, rapid, and accurate LCMS/MS method was developed for BU-TDM, enabling optimized dosing for BU-based HSCT at SGH and KKH.

Background: Sunitinib at a fixed dose may lead to under- or over-exposure which in Italy is currently adjusted over time based only on trial and error clinical practice. Integrating Therapeutic Drug Monitoring (TDM), pharmacogenetics (PGx), and drug-drug interaction (DDI) assessment could lead to a more rational and faster dose personalization.

Aims: To evaluate sunitinib exposure in patients treated at different drug dosage as an effect of successive toxicity-driven dose adjustments over time.

Methods: Steady-state plasma samples (Cmin) from CRO-2022-14 trial (NCT06822959) patients were analyzed for sunitinib levels using validated LC-MS/MS. Target Cmin ranges were 37.5–60/75 ng/mL (continuous) and 50–80/87.5 ng/mL (intermittent). Genetic polymorphisms affecting sunitinib metabolism and transport were assessed, and DDIs were evaluated via UpToDate Lexi-Drug.

Results: Fourteen patients already on sunitinib therapy (median 28 months) were enrolled. As an effect of toxicity-driven dose reductions eight patients on 50 or 37.5 mg/day had Cmin levels (53–79 ng/mL) within target. Two females on 25 mg/day still exceeded 80 ng/mL with recurrent G2–G3 toxicities, suggesting the need for lower doses. Two others on 25 mg/day had Cmin < 40 ng/mL without severe toxicity, indicating 37.5 mg/day might be optimal. Females (81 ng/mL) had higher exposure than males (65 ng/mL). PGx analysis was limited by sample size, and no significant DDIs were identified.

Conclusions: Toxicity-driven dose adjustments ensured adequate sunitinib exposure over 28 months. Females showed higher plasma levels than males, though sample size limited conclusions. Early TDM could have optimized dosing, improving tolerability, adherence, and exposure.

Keywords: sunitinib, toxicity, plasma exposure