Background: TDM of 5-flurouracil (5FU) is standard practice at many centres globally, although, not commonly practiced in India. Lack of infrastructure and evidence supporting TDM from within the country is vastly responsible for this.

Aim: A feasibility study to assess the utility of 5FU TDM in a tertiary care cancer hospital in western India.

Methods: Patients diagnosed with gastrointestinal malignancies wherein 5FU was administered as a 48 hour infusion were enrolled. All patients were treated with one of the two generic brands of 5FU available in our pharmacy. A single blood sample was collected between 44-48 hour of infusion to measure 5FU concentration. Plasma 5FU was measured by HPLC. AUC of 5FU was calculated for each patient using non compartmental analysis. Toxicity was assessed using CTCAE v5.0.

Results: Between November 2023 to January 2024, 29 patients (4F/25M) were enrolled. Median age was 48(18-67) years. Carcinoma of the stomach and rectum were the most common diagnosis (11 each). The average AUC was 16.7±21.7 mg*35;h/L. Only 6 patients achieved AUC in the therapeutic range of 20-30 mg*35;h/L. 20 patients and 3 patients achieved AUC below and above the therapeutic range respectively. Four patients suffered grade ≥3 toxicity, however, no correlation was observed between 5FU AUC and toxicity.

Conclusions: Frequent sub-therapeutic exposure and low incidence of grade ≥3 toxicity was noted, raising concerns about the quality of drugs. A potential application of TDM in our setting could be to identify patients with very low exposures and make a brand switch early-on in treatment.

Background:
Cytarabine is a key drug in acute myeloid leukemia (AML) treatment, where its pharmacokinetics (PK) influence therapeutic efficacy.
Aims:
This study evaluates the PK of cytarabine and explores the impact of clinical covariates using multiple linear regression and principal component analysis (PCA).
Methods:
Thirty AML patients (13 women, 17 men) received intravenous cytarabine over 2 hours in two dosing regimens: high dose (HD, 3000 mg/m², n=21) and intermediate dose (ID, 1500 mg/m², n=9). Plasma concentrations were measured using LC-MS/MS, with 4–5 samples collected up to 2 hours post-infusion. PK parameters, including dose-normalized area under the curve (AUC/D), maximum plasma concentration (Cmax), and half-life (t½), were estimated using Pkanalix 2024R1. Covariate effects were assessed via multiple linear regression, and PCA was conducted to explore global variability.
Results:
Cmax was 19.14 mg/L (CV% = 37.9%) in the HD group and 8.23 mg/L (CV% = 30%) in the ID group, confirming dose-proportionality. AUC/D was similar in both groups (HD: 0.3316, ID: 0.308), suggesting linear PK. Hematocrit significantly influenced AUC/D (p = 0.0067), while higher blast counts correlated with prolonged half-life. PCA showed that the first principal component explained 23% of total variance, with seven components required to capture 80%.
Conclusions:
This study confirms the linear PK of cytarabine and highlights the role of hematocrit and blast counts in drug exposure and elimination. PCA underscores the complexity of PK variability, advocating for personalized dosing in AML treatment.
Keywords: Cytarabine, AML, PK

Background: The IATDMCT guideline have emphasized the necessity of TDM for gastrointestinal stromal tumors (GIST) patients and recommend 1100 μg/L as the concentration thresholds for advanced or metastatic patients. Notably, the concentration threshold for adjuvant population still remain unreported.
Aims: To investigate the efficacy of IM dose adjustment guided by TDM in GIST patients with adjuvant therapy after complete resection.
Methods: Patient who received IM for adjuvant therapy, TDM-guided dose adjustment and had complete follow-up data were enrolled. Dose adjustment was determined through comprehensive consideration of the presence of grade 3 or higher intolerable adverse reactions, current concentration levels, and the threshold range of 760–1100 μg/L. The impact of TDM-guided dosage on relapse-free survival (RFS), adverse reaction, and health-related quality of life were evaluated
Results: A total of 70 patients were included and received an initial IM dose of 400 mg/d, with a mean C0 of 1900±568 μg/L and a median treatment duration of 8.3 months. After adjustment, 60 patients received 300 mg/day (C0: 1216±350 μg/L), and 10 patients received 200 mg/day (C0: 1023±269 μg/L). TDM-guided dosage showed significant reductions in the incidence of bone marrow suppression, edema, cutaneous reactions, and gastrointestinal symptoms. Total physical and mental health scores were improved. The 3-year overall survival was 100%, 3-year RFS was 92.8%, and high-risk patients achieved 89.8% 3-year RFS.
Conclusions: TDM-guided dose reduction effectively mitigates toxicity, improves quality of life, and enhances long-term prognosis in GIST patients with severe adverse reactions during adjuvant therapy.
Keywords: GIST, Imatinib, Dose adjustment, TDM

Background: Anti-Thymocyte Globulin (ATG) is a polyclonal antibody used as an immunosuppressant to prevent graft-versus-host-disease in haematopoietic stem cell transplantation. While recent studies have worked toward understanding the pharmacokinetic-pharmacodynamic relationship via population pharmacokinetic modelling, dosing remains weight-based and largely empirical in clinical practice.

Aims: To evaluate current ATG dosing regimens and improve pharmacokinetic target attainment by utilising therapeutic drug monitoring.

Methods: Conventional and novel ATG regimens were examined using Monte Carlo simulation with an existing population pharmacokinetic model and an in-silico population of 10,000 representative patients. Individualised ATG dosing regimens were simulated with sparse sampling, empirical Bayesian estimation of pharmacokinetic parameters, and a dose optimisation function. Post-transplant AUC and probability of target attainment was determined for each regimen.

Results: No conventional ATG dosing regimen was able to dose >25% of individuals within the defined target range of 60-95AU.day/mL. Model-based dose optimisation was only able to improve target attainment by up to 9%. In all cases, pharmacokinetic parameter estimation was poor, with ETA shrinkage of >30% noted on three of the five variable pharmacokinetic parameters influencing ATG elimination.

Conclusions: Wide inter-individual variability of ATG leads to universally poor target attainment with current weight-based dosing regimens. Improving attainment by means of Bayesian estimation and dose optimisation leads to minor improvements only and is unlikely to be of clinical benefit in stem cell transplant recipients. Further research into factors influencing the pharmacokinetic parameters of ATG is required to allow for dose individualisation and optimisation.

Keywords: anti-thymocyte globulin, haematological malignancy, dose optimisation, population pharmacokinetics

Background: Most non-specific anticancer treatment options can cause serious toxicities. Currently, the response rate to clinical treatment for lung adenocarcinoma (LUAD) is not ideal, and the poor prognosis severely affects patients' quality of life. Therefore, there is an urgent need to explore models that can be used as personalized therapy for LUAD patients to improve the efficiency of drug application, reduce irrational drug use, and improve clinical prognostic outcomes.

Aims: To develop predictive models for personalized therapy in lung adenocarcinoma (LUAD) patients, aiming to enhance the efficiency of drug application, minimize irrational drug use, and improve clinical prognostic outcomes.

Methods: Using bioinformatics/statistics, we analyzed cancer markers to build genetic profiles predicting LUAD therapy responses; developed a nomogram incorporating genetic and clinicopathological factors for risk stratification and quantified assessment. Finally, in vivo and in vitro experimental validation of analyses was performed.

Results: Our study demonstrated that high and low-risk levels of glycolysis were important indicators for differentiating the prognosis of LUAD patients and could be used as an independent risk factor for survival, effectively differentiating high-risk patients. The nomogram prediction model showed high predictive accuracy and was a good predictor of patient sensitivity to three commonly used targeted chemotherapeutics.

Conclusions: This research helps to optimize the survival risk stratification of LUAD patients and predict the sensitivity of commonly used chemotherapeutic agents for precision treatment.

Keywords: lung adenocarcinoma, glycolysis, prognosis, precise treatment, therapeutic resistance

Background: Integrating pharmacogenetics (PGx), therapeutic drug monitoring (TDM), and drug-drug interaction (DDI) assessments (MedReview) into routine clinical practice of oral anticancer drugs (OADs) may enhance their appropriate use.

Aims: A prospective observational clinical trial (NCT06822959) is underway at our center to implement an active pharmacovigilance approach for optimizing OADs treatment (palbociclib, ribociclib, abemaciclib, olaparib, niraparib, imatinib, sunitinib).

Methods: Consenting adult OAD-treated patients, underwent PGx analysis and periodic TDM. Co-medications, co-morbidities, adherence, and ADRs were recorded through interviews. DDI assessment used Lexicomp, and oncologists received integrated pharmacological counseling reports.

Results: 160 patients were enrolled, covering 69% of those on treatment, with higher rates for drugs with available TDM guidelines. TDM found 56% of measurements outside the therapeutic range, while PGx analysis identified 27% of cases with variant genotypes. DDIs were detected in 24% of cases, including grade D (therapy modification recommended). These findings led to 227 pharmacological consultations. ADR review (completed for 29% of cases) showed 58% of patients that experienced clinically relevant toxicity, resulting in dose reduction (84%), therapy discontinuation (9%), or treatment change (7%). An association between comorbidities (e.g. COVID-19) and increased exposure and toxicity was observed. Eleven ADRs were reported to Italian Drug Agency (AIFA)

Conclusions: The interim analysis supports this approach in identifying cases of under- or over-exposure and detecting potentially harmful drug-drug, drug-comorbidity, and drug-gene interactions. It also improved ADR reporting. Completion of data collection will provide further insights. The study was funded by AIFA and Italian Ministry of Health (RF-2021-12374355).

Keywords: pharmacogenetics, TDM, DDI, pharmacovigilance

Background: Ideally, therapeutic drug monitoring (TDM) would be performed using minimally invasive, real-time, wearable sensors (analogous to glucose sensing). Achieving this vision requires improved understanding of how drugs are transported between blood into the interstitial fluid (ISF) of these solid tissues. Here we employ seconds-resolved measurements collected simultaneously in blood and subcutaneous ISF to study this relationship for methotrexate (MTX), a drug that requires TDM to optimize efficacy and minimize toxicity, particularly in high-dose chemotherapies. However, the relation between MTX pharmacokinetics in plasma versus those in ISF remains poorly understood.

Aims: Here, we determine the relationship between plasma and ISF concentrations of MTX following intravenous infusion employing electrochemical aptamer-based (EAB) sensors.

Methods: EAB sensors functionalized with an MTX-detecting aptamer were placed in the jugular vein and subcutaneously (ISF) in live rats. Following rapid intravenous infusion of MTX, the sensors were electrochemically interrogated to generate seconds-resolved measurements in situ.

Results: Plasma and ISF MTX concentrations showed a modest correlation (R2 = 0.37), which improved considerably post-Cmax in the ISF (R2 = 0.66). Body-mass adjusted dose correlated with plasma Cmax (R2 = 0.75), but was a poor predictor of overall drug exposure (AUC) in plasma and ISF. In contrast, ISF AUC strongly correlates with plasma AUC (R2 = 0.80, p = 0.0070), suggesting ISF measurements as a potential proxy for predicting plasma exposure.

Conclusions:The strong relationship between plasma and ISF pharmacokinetics suggests the potential value of EAB sensors as a means of predicting plasma drug exposure with high-precision through minimally-invasive subcutaneous measurements.