Rob ter Heine

Accessible tools for pharmacokinetic education and routine clinical pharmacokinetic analysis remain limited. Commercial software carries licensing costs and on the other hand existing open-source alternatives lack integrated workflows spanning study planning through bioequivalence assessment and are not user-friendly. We developed NCA Assistant, a browser-based application for non-compartmental pharmacokinetic analysis, bioequivalence testing, and power and sample size calculations within a single platform designed for pharmacokinetic research and teaching. NCA Assistant was designed with Anthropic Claude AI as coding assistant, with multi-expert prompting. The app was developed in R/Shiny with a hub-based architecture connecting six workflow modules. Core computations rely on established R packages for non-compartmental analysis, power and sample size calculations and analysis of variance. For the interface, there was an emphasis for transparency through interactive visualization, configurable analysis settings and exportable audit trails. The application supports extravascular and intravenous dosing scenarios, handles both single-subject and batch analyses and accommodates standard crossover, replicate, and parallel bioequivalence designs.A dedicated visualization module generates publication-ready concentration–time plots. Features include interactive terminal half-life review with point selection override and configurable thresholds for elimination half-life calculation. A validation package, consisting of draft validation documents and a validation script, accompanies the application and is supplied in the supplemental materials. NCA Assistant provides an accessible entry point for pharmacokinetic data analysis suitable for graduate training and routine clinical pharmacology applications, with extensibility for use in more regulated environments.

Introduction: Currently, no established guidelines exist for dosing chemotherapy or immunotherapy in patients with achondroplasia. Case: A 69-year old female with congenital achondroplasia was diagnosed with stage IV non-small cell lung carcinoma type adenocarcinoma, with high Tumor Mutational Burden and 20% programmed death-ligand 1 expression. The patient received carboplatin dose based on renal function utilizing measured creatinine clearance, pemetrexed based on body surface area and pembrolizumab at a fixed dose of 100mg for body weight <65 kg. The doses of carboplatin and pemetrexed were adjusted after the first cycle based on therapeutic drug monitoring (TDM). The treatment was generally well tolerated, with the exception of grade 2 neutropenia, which resolved after a one-week delay of the third treatment cycle. A favorable clinical response was achieved after four treatment cycles. Conclusion: Given the uncertainty regarding the accuracy of dosing algorithms in patients with congenital achondroplasia, TDM may support dose optimization and attainment of adequate drug exposure.

Background: Therapeutic drug monitoring (TDM) may optimize dosing of mycophenolate mofetil (MMF) in patients with nephrotic syndrome, but it is not routinely implemented. When performed, TDM typically relies on total mycophenolic acid (MPA) concentrations, although only unbound MPA is pharmacologically active. This study aimed to develop a population pharmacokinetic (PK) model characterizing the PK and pharmacodynamics (PD) of total and unbound MPA in plasma and saliva of paediatric nephrotic syndrome patients following oral MMF. Methods: PK/PD data from 62 children (47 full and 21 limited sampling curves) were analysed using nonlinear mixed-effects modelling. Results: A two-compartment model with first-order absorption best describes unbound MPA PK. Protein binding was captured using a nonlinear saturable binding equation. The final population PK parameter estimates (for unbound MPA) were absorption rate constant (k _a ), 1.81 h ⁻¹ (relative standard error (RSE): 8%); apparent clearance (Cl/F), 2550 L h ⁻¹ (RSE: 8%); apparent central volume (V _c /F), 1590 L (RSE: 27%); apparent peripheral volume (V _p /F), 239,000 L (RSE: 52%); apparent intercompartmental clearance (Q/F), 1940 L h ⁻¹ (RSE: 13%); maximal binding capacity (B _max ), 196 µmol (RSE: 44%); dissociation constant (K _d ), 0.75 µmol L ⁻¹ (RSE: 49%). Saliva and unbound plasma MPA showed a proportional relationship (saliva/plasma ratio: 1.34, RSE: 24%). The PK–PD relationship between unbound MPA and inosine monophosphate dehydrogenase (IMPDH) activity was described by a sigmoid inhibitory effect model with a baseline parameter. The population estimates were baseline effect, 66.4 (RSE: 21%); unbound plasma concentration for 50% inhibition, 0.0251 (RSE: 27%); shape parameter, 0.559 (RSE:22%). A limited sampling strategy allowed acceptable prediction of unbound MPA area under the concentration–time curve from 0 to 12 hours (AUC _0–12 h ) but not IMPDH activity. Conclusion: The developed model provides a foundation for model-informed precision dosing of MMF in children with nephrotic syndrome.

Aim: Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, acquired haematopoietic stem cell disorder. Crovalimab, a complement C5‐inhibitor, is approved for PNH and can be self‐administered subcutaneously every 4 weeks, offering a more convenient route than intravenous C5‐inhibitors. Since exposure often exceeds pharmacokinetic targets and varies with body weight, we aimed to explored individualized dosing of crovalimab using clinical trial simulations to optimize therapy. Methods: We compared standard, weight‐based and therapeutic drug monitoring (TDM)‐guided regimens in treatment‐naïve PNH patients over 52 weeks by means of clinical trial simulations based on the population pharmacokinetic model developed by the market authorization holder. Results: Maintenance‐phase crovalimab concentrations were generally supratherapeutic with substantial variability. Weight‐based dosing reduced this variability, while TDM‐guided dosing further minimized it and allowed dose intervals to be prolonged in 24% of patients to a mean of 5.0 weeks, while maintaining exposure comparable to the standard regimen. Conclusion: Individualized dosing of crovalimab may reduce exposure variability and enable less frequent dosing, supporting the feasibility of more flexible cost‐effective and patient‐tailored treatment regimens.

Introduction: Polypharmacy (concurrent use of ≥ 5 medications) is common in patients with non-small cell lung cancer and increases the risk of potentially inappropriate medication use, particularly in those with advanced disease. Deprescribing may reduce medication-related harm; however, its implementation in oncology remains limited and is insufficiently informed by stakeholder perspectives. Aim: This study aimed to determine the prevalence of potentially inappropriate medications in patients with advanced non-small cell lung cancer and explore the attitudes and beliefs of patients, caregivers, and healthcare professionals regarding deprescribing to inform feasible implementation strategies for routine clinical practice. Method: A retrospective analysis was conducted in a cohort of 817 patients with stage IV non-small cell lung cancer to identify potentially inappropriate medications using the OncoSTRIP checklist. Perspectives on deprescribing were collected using validated questionnaires: the revised Patients’ Attitudes Toward Deprescribing (rPATD) for patients and caregivers and the Comprehensive Healthcare Providers’ Opinions, Preferences, and Attitudes Toward Deprescribing (CHOPPED) for medical clinicians and pharmacists, which were completed by 37 patients, 15 caregivers, 24 medical clinicians (physicians and specialist nurses), and 24 pharmacists. Results: Potentially inappropriate medications were algorithm-flagged in 793 of the 817 (97.1%) patients. Among these, 1,686 (40.8%) were confirmed by clinical evidence, while 2,448 (59.2%) were unconfirmed (defined as medications flagged by the checklist but lacking sufficient electronic health record data, such as laboratory values or specific indications, to definitively justify their use). The primary classifications were the risk of adverse drug events (47.3%) and unnecessary therapy (30.0%). Most patients (33, 89.2%) and caregivers (11, 73.3%) were willing to discontinue their medications if advised by a physician. Perceived barriers influenced medical clinicians’ and pharmacists’ willingness: medical clinicians were most affected by collaboration- and competence-related concerns, whereas pharmacists were constrained by competence- and patient-related factors. Conclusion: The high algorithm-flagged prevalence of potentially inappropriate medications with 40.8% confirmed by clinical evidence, in patients with advanced non-small cell lung cancer underscores the urgent need for deprescribing. Successful implementation requires a patient-centered approach, active involvement of patients and caregivers, interprofessional collaboration, and targeted strategies to address systemic and professional barriers to ensure safe and sustainable medication optimization.

Background: The increasing use of pembrolizumab in oncological treatments results in substantial healthcare costs and the subcutaneous (SC) pembrolizumab formulation remains expensive. To evaluate alternative SC pembrolizumab dosing strategies that reduce costs while maintaining equivalent exposure and improving patient convenience.Methods: A previously published population pharmacokinetic model was used to evaluate alternative dosing strategies achieving exposure equivalent to the intravenous (IV) 2 mg/kg Q3W dosing (reference) compliant with FDA guidelines and reducing costs (Dutch price). First, extended fixed dosing intervals irrespective of bodyweight were investigated. Second, body-weight-adjusted dosing intervals were evaluated. Finally, we explored to inject SC formulation (790 mg) intravenously.Results: Identified alternative regimens included SC 790 mg Q7W for all patients; SC 790 mg Q8W (85 kg); and IV administration of 790 mg Q9W using the SC formulation. The extended-interval SC regimen (790 mg Q7W) would reduce annual cost to €85,000 (-14%). A bodyweight-adjusted SC strategy would reduce yearly cost from €99,166 to €85,000 (-14%; 55 - 85 kg) and to €74,375 (-25%; <55 kg). Using the SC formulation intravenously can potentially save annual costs by €33,055 (-33%). In addition, extracting 5 doses of 150 mg Q3W out of one 790 mg SC dose could reduce the annual costs even to €39,666 (-60%).Conclusions: Dose interval extension of subcutaneous pembrolizumab maintains equivalent exposure and complies with regulatory requirements. Intravenous administration of the subcutaneous formulation is a promising highly cost-effective intervention but requires prospective safety investigation before implementation.