TDM-Based Tailored Dosing of Durvalumab in Lung Cancer Patients: A Comprehensive Population Pharmacokinetic-Pharmacoeconomic Evaluation.

Background: The increasing use of immune checkpoint inhibitors, such as durvalumab, places a significant financial burden on healthcare systems, strains hospital capacities, and contributes to environmental concerns.

Objective: We aimed to develop alternative dosing strategies to optimize durvalumab administration, reduce unnecessary drug use, and ensure sustainable cancer care without sacrificing efficacy.

Methods: Using the population pharmacokinetic model developed by the licensing holder, we designed two alternative dosing strategies for non-small cell lung cancer based on therapeutic drug monitoring.

Effect of CYP3A4 Methylation on Tacrolimus Pharmacokinetics.

Background: Common genetic variants in CYP3A4 together only explain a limited amount of the variability in tacrolimus clearance. This cross-sectional study aimed to explore the extent to which pharmacokinetic variability can be explained by methylation of the CYP3A4 gene.

Methods: Residual tissue material from liver biopsies routinely collected 6 months post-transplantation was used.

A Population Pharmacokinetic Model and Dosing Algorithm to Guide the Tacrolimus Starting and Follow-Up Dose in Living and Deceased Donor Kidney Transplant Recipients.

Introduction: Tacrolimus treatment is complicated by its narrow therapeutic range and large inter- and intra-patient variability. This study aimed to develop a population pharmacokinetic model and dosing algorithm to predict an individual's dose requirement following living and deceased donor kidney transplantation.

Methods: In this international, multicenter, retrospective study, data was collected from patients who had received a living or a deceased donor kidney and received tacrolimus twice daily.

Evaluation of amoxicillin and benzylpenicillin therapy in early-onset neonatal sepsis: a pharmacometric external validation and simulation study.

Background And Objectives: Early-onset sepsis (EOS) poses a significant morbidity and mortality risk in neonates, for which early diagnosis and adequate antibiotic therapy is crucial. Amoxicillin and benzylpenicillin combined with aminoglycosides are often prescribed empirically for neonatal EOS but optimal dosing regimens are lacking. To evaluate the pharmacokinetics (PK), PTA and toxicity of amoxicillin and benzylpenicillin in (pre)term neonates with EOS, and define optimal dosing regimens.

Precision Treatment of Patients With GI Cancer Using Pre-emptive Genotyping/Phenotyping Plus Pharmacokinetic-Guided Dosing of 5-Fluorouracil.

Purpose: The Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends screening for four common variants to prevent severe toxicity in patients with cancer treated with fluoropyrimidines. A 50% starting dose followed by toxicity-based dose titration is advised for patients heterozygous for these variants. In this study, the appropriateness of the CPIC-recommended 5-fluorouracil (5-FU) starting dose was evaluated.

Exploring the Association Between Intra-Patient Variability in Trough Concentration of Pazopanib and Clinical Outcomes in Renal Cell Carcinoma and Soft Tissue Sarcoma Patients.

Pazopanib is an oral tyrosine kinase inhibitor used in patients with either metastatic renal cell carcinoma or soft tissue sarcoma. Pazopanib has a high interindividual variability in pharmacokinetics and pharmacodynamics and a well-established exposure-response relationship. Therefore, therapeutic drug monitoring is recommended to improve the efficacy-toxicity balance.

Alemtuzumab Exposure and T Lymphocyte Depletion: A Population Pharmacokinetic-Pharmacodynamic Model of Alemtuzumab Induction Therapy for Kidney Transplantation.

Alemtuzumab is a T cell-depleting monoclonal antibody that is used for the prevention of kidney transplant rejection. The duration of lymphodepletion after the current standard induction therapy dose is likely longer than necessary, resulting in prolonged T cell lymphopenia with the associated risk of infections. Here, the interplay between alemtuzumab exposure and T cell dynamics was quantitatively evaluated, and the influence of different doses on T cell recovery was investigated.

A Systematic Evaluation of the Dosing Regimens for Approved Targeted Therapies and Immune Checkpoint Inhibitors in Metastatic Renal Cell Carcinoma From a Project OPTIMUS Perspective.

Targeted therapies and immune checkpoint inhibitors (ICIs) have significantly improved survival outcomes in metastatic renal cell carcinoma (mRCC) but are often associated with high rates of adverse events, leading to dose reductions or treatment discontinuation. The FDA's recent initiative, Project OPTIMUS, emphasizes the importance of optimizing dosing regimens in oncology clinical development, and moves beyond the conventional maximum tolerated dose approach. In this study, we aimed to review and redefine the approved dosing strategies for targeted therapies and ICIs in mRCC from the Project OPTIMUS perspective, including pazopanib, axitinib, cabozantinib, sunitinib, everolimus, and nivolumab.

Model-Informed Dose Optimization of Pazopanib in Real-World Patients with Cancer.

Background And Objectives: Pazopanib is approved for metastatic renal cell carcinoma (mRCC) and soft tissue sarcoma (STS) in a dose of 800 mg once daily (QD) taken under fasted conditions. In clinical practice, approximately 60% of patients require dose reductions due to toxicity, with severe liver toxicity necessitating treatment interruptions in over 10% of cases. While a trough concentration (C) target of ≥ 20.

A Comprehensive CYP2D6 Drug-Drug-Gene Interaction Network for Application in Precision Dosing and Drug Development.

Conducting clinical studies on drug-drug-gene interactions (DDGIs) and extrapolating the findings into clinical dose recommendations is challenging due to the high complexity of these interactions. Here, physiologically-based pharmacokinetic (PBPK) modeling networks present a new avenue for exploring such complex scenarios, potentially informing clinical guidelines and handling patient-specific DDGIs at the bedside. Moreover, they provide an established framework for drug-drug interaction (DDI) submissions to regulatory agencies.

Pharmacokinetic modeling of prenatal vitamin D exposure and the impact on offspring asthma and pulmonary function.

Gestational 25-hydroxyvitamin D (25[OH]D) is important in fetal lung development and may influence offspring respiratory outcomes, making accurate exposure assessment essential to understand clinical associations. Therefore, we used the combined data from two large RCTs investigating prenatal vitamin D supplementation, which included early and late prenatal 25(OH)D measurements, to refine a population pharmacokinetic model of vitamin D-25(OH)D and estimate individual area under the curve (AUC) Z-scores. The primary outcome was physician-diagnosed offspring asthma/wheezing at ages 3 and 6 years, and lung function, as a secondary outcome, was evaluated by spirometry at the ages 6 and 8 years.

Everolimus Personalized Therapy: Second Consensus Report by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.

The Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology established the second consensus report to guide therapeutic drug monitoring (TDM) of everolimus (EVR) and its optimal use in clinical practice 7 years after the first version was published in 2016. This version provides information focused on new developments that have arisen in the last 7 years. For the general aspects of the pharmacology and TDM of EVR that have retained their relevance, readers can refer to the 2016 document.

An Evidence-Based Rationale for Dose De-escalation of Subcutaneous Atezolizumab.

Background: Atezolizumab is a programmed death-ligand 1 (PD-L1) checkpoint inhibitor for the treatment of different forms of cancer. The subcutaneous formulation of atezolizumab has recently received approval. However, treatment with atezolizumab continues to be expensive, and the number of patients needing treatment with this drug continues to increase.

Evaluating the Clinical Impact and Feasibility of Therapeutic Drug Monitoring of Pazopanib in a Real-World Soft-Tissue Sarcoma Cohort.

Introduction And Objective: Pazopanib is registered for metastatic renal cell carcinoma and soft-tissue sarcoma (STS). Its variable pharmacokinetic (PK) characteristics and narrow therapeutic range provide a strong rationale for therapeutic drug monitoring (TDM). Prior studies have defined target levels of drug exposure (≥ 20.

Autoantibody-positivity before and seroconversion during treatment with anti-PD-1 is associated with immune-related adverse events in patients with melanoma.

Introduction: Treatment with the immune checkpoint inhibitor anti-programmed cell death protein-1 (PD-1) often causes immune-related adverse events (irAEs). Since irAEs resemble autoimmune diseases, autoantibodies might play a role and could potentially be used to identify patients at risk. Therefore, we investigated the association between autoantibody-positivity and toxicity as well as clinical response in patients with melanoma treated with anti-PD-1.

Immune responsiveness in stable kidney transplantation patients: Complete inhibition of T-cell proliferation but residual T-cell activity during maintenance immunosuppressive treatment.

The recommended immunosuppressive treatment after kidney transplantation consists of tacrolimus, mycophenolate mofetil, and low-dose corticosteroids. Drug concentrations are monitored using therapeutic drug monitoring (TDM), which does not necessarily correlate with pharmacodynamic activity. To find the balance between optimal efficacy and minimal toxicity, it might be more informative to monitor patients' immunological status rather than drug concentrations.

Model-Informed Development of a Cost-Saving Dosing Regimen for Sacituzumab Govitecan.

Background: The antibody-drug conjugate sacituzumab govitecan is approved for metastatic triple-negative breast cancer and has shown promising results in various other types of cancer. Its costs may limit patient access to this novel effective treatment modality.

Objective: The purpose of this study was to develop an evidence-based rational dosing regimen that results in targeted drug exposure within the therapeutic range while minimizing financial toxicity, to improve treatment access.

Population Pharmacokinetics of Cabozantinib in Metastatic Renal Cell Carcinoma Patients: Towards Drug Expenses Saving Regimens.

Introduction: Cabozantinib is one of the preferred treatment options in the latest metastatic renal cell carcinoma (mRCC) guidelines. Cabozantinib is also associated with high drug expenses irrespective of the used dose, because a flat-prizing model has been implemented. In addition, concomitant intake with a high-fat meal increases its bioavailability on average by 57%.

Therapeutic drug monitoring of tacrolimus after kidney transplantation: trough concentration or area under curve-based monitoring?

Measurement of pre-dose tacrolimus concentrations, also referred to as trough concentrations or C0 (in this paper the term C0 will be used), is the most frequently used parameter for therapeutic drug monitoring in patients after solid organ transplantation. C0 is relatively easy to obtain, and can be combined with other lab tests. C0 monitoring is convenient for patient and hospital staff.

Anti-T-lymphocyte globulin exposure is associated with acute graft--host disease and relapse in pediatric acute lymphoblastic leukemia patients undergoing hematopoietic stem cell transplantation: a multinational prospective study.

Anti-T-lymphocyte globulin (ATLG) is used in hematopoietic stem cell transplantation (HSCT) to prevent graft-versus-host disease (GVHD) and graft failure. To date, insight in ATLG pharmacokinetics and -dynamics (PK/PD) is limited, and population PK (POPPK) models are lacking. In this prospective study, we describe ATLG POPPK using NONMEM® and the impact of ATLG exposure on clinical outcome and immune reconstitution in a homogeneous cohort of pediatric acute lymphoblastic leukemia (ALL) patients transplanted with a matched unrelated donor and receiving uniform ATLG dosing.

Best Practice for Therapeutic Drug Monitoring of Infliximab: Position Statement from the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.

Background: Infliximab, an anti-tumor necrosis factor monoclonal antibody, has revolutionized the pharmacological management of immune-mediated inflammatory diseases (IMIDs). This position statement critically reviews and examines existing data on therapeutic drug monitoring (TDM) of infliximab in patients with IMIDs. It provides a practical guide on implementing TDM in current clinical practices and outlines priority areas for future research.

The effect of genetic variants in the transcription factor TSPYL family on the CYP3A4 mediated cyclosporine metabolism in kidney transplant patients.

CYP3A4 activity shows considerable interindividual variability. Although studies indicate 60%-80% is heritable, common single nucleotide variants (SNVs) in CYP3A4 together only explain ~10%. Transcriptional factors, such as the testis-specific Y-encoded-like proteins (TSPYLs) family, have been reported to regulate the expression of CYP enzymes including CYP3A4 in vitro.