LC-MS/MS method development and validation for novel targeted anticancer therapies adagrasib, capmatinib, ensartinib, entrectinib, larotrectinib, lorlatinib, pralsetinib, selpercatinib and sotorasib.

A reversed-phase liquid chromatography-tandem mass spectrometry method was developed and validated for quantifying nine novel oral targeted anticancer agents mainly indicated for non-small cell lung cancer: adagrasib, capmatinib, ensartinib, entrectinib, larotrectinib, lorlatinib, pralsetinib, selpercatinib and sotorasib in human plasma for therapeutic drug monitoring. Chromatographic separation used an Acquity BEH C18 column with step gradient of 0.1 % formic acid in water and acetonitrile-methanol (50:50, v/v), at a 0.

Assessing Safety of the Transition to Generic Imatinib in Patients with Gastrointestinal Stromal Tumours.

Introduction: Following patent expiration of branded imatinib (Glivec®), all Dutch patients with gastrointestinal stromal tumours (GIST) switched from Glivec to generic forms. Following this switch, many patients reported new symptoms. Therefore, we conducted this observational study to assess safety of generic imatinib among patients with GIST in the Netherlands.

Validated LC-MS/MS Method for Quantifying the Antiparasitic Nitroimidazole DNDI-0690 in Preclinical Target Site PK/PD Studies.

Understanding the target site pharmacokinetics (PK) of the nitroimidazole analog DNDI-0690, a potential drug for the neglected parasitic disease leishmaniasis, is important due to the diversity of infected tissue sites and potential drug penetration variability. An ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed and validated for quantifying DNDI-0690 in murine biomatrices (plasma, liver, spleen, skin, and skin microdialysate). The method used three protein precipitation sample preparation procedures, tailored for different biomatrices, utilizing a surrogate biomatrix approach.

Imatinib Desensitization After a Type IV Hypersensitivity Reaction in a Gastrointestinal Stromal Tumor Patient-A Case Report.

Background: Imatinib treatment is approved for several indications, including chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST). Although adverse events are common, hypersensitivity reactions are not. Because there is a clear clinical benefit of imatinib treatment, re-introduction of imatinib after a hypersensitivity reaction should be considered.

Stabilization of Abiraterone in Human Plasma Using the Esterase Inhibitor Bis(4-nitrophenyl) Phosphate: A Short Communication.

Background: Abiraterone, an active metabolite of abiraterone acetate, is used for the treatment of prostate cancer. Therapeutic drug monitoring (TDM) of abiraterone could improve treatment outcomes. However, its stability in plasma for only 4 hours at room temperature, is making the TDM implementation difficult in clinical practice.

Folinic Acid Prophylaxis and Dose Adjustments Enable Safe Treatment with Pemetrexed in Patients with Renal Impairment.

Pemetrexed is a cornerstone in chemo(immunotherapy) of non-small cell lung cancer and mesothelioma; however, it is contraindicated in patients with renal impairment due to severe toxicity concerns. Therefore, a large proportion of patients is withheld from effective chemo(immunotherapy). We performed an intra-patient 3 + 3 dose escalation renal impairment study (eGFR < 45 mL/min).

Quantitative analysis of DNDI-6174 using UPLC-MS/MS: A preclinical target site pharmacokinetic study.

Leishmaniasis is a neglected parasitic infection that continues to pose a significant global health challenge, with currently limited effective treatment options. DNDI-6174 is a novel orally-active, investigational drug with antileishmanial properties. Herein, a novel ultra-high performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) method was developed and validated to quantify DNDI-6174 in relevant murine biomatrices, i.

Phase I Study of Sorafenib Combined with Gemcitabine and Carboplatin in Patients with Advanced Solid Tumors.

Introduction: A combination of targeted anticancer drugs with cytotoxic therapy can potentially overcome multidrug resistance. The multi-target kinase inhibitor sorafenib demonstrates synergistic activity when combined with chemotherapeutics in preclinical models. This phase I trial aimed to assess safety, tolerability, efficacy, and pharmacokinetics of sorafenib with gemcitabine and carboplatin.

Implementing Pre-Emptive Pharmacogenetics: Impact of Early Pharmacogenetic Screening in a Pediatric Oncology Cohort of 1,151 Subjects.

In pediatric oncology, pharmacogenetic guidelines are underutilized and the potential impact of pre-emptive pharmacogenetic screening remains largely unexplored despite this field's need for individualized approaches. While comprehensive pharmacogenetic guidelines are not yet available for all anticancer drugs, evidence-based recommendations exist for a subset of supportive care drugs and anticancer drugs, including thiopurines, irinotecan, capecitabine, and 5-fluorouracil. In this study, we evaluate the potential impact of pre-emptive pharmacogenetic screening by retrospectively identifying opportunities for dose or treatment adjustments within a national pediatric oncology cohort.

Pharmacokinetic boosting of olaparib: Study protocol of a multicentre, open-label, randomised, non-inferiority trial (PROACTIVE-B).

Background: Pharmacokinetic (PK) boosting is the intentional use of a drug-drug interaction to enhance systemic drug exposure. PK boosting of the anticancer drug olaparib, a CYP3A-substrate, has the potential to reduce PK variability, side effects and financial burden associated with this drug. After establishing adequate pharmacokinetic exposure with boosting in the PROACTIVE-A study, the PROACTIVE-B study is designed to evaluate non-inferiority for both efficacy and toxicity of the boosted therapy compared to the standard monotherapy of olaparib.

Added prognostic value of circulating tumor cell numbers in CSF of patients with leptomeningeal metastasis from epithelial tumors.

Background: Leptomeningeal metastases (LM) from solid tumors are described in up to 10 % of patients, and median survival rates are low. Advanced techniques for circulating tumor cell enumeration in cerebrospinal fluid (CSF) can help in diagnosing patients with LM but also could have value in prognostication. Our aim was to investigate whether the number of circulating tumor cells (CTCs) in CSF are of added value in survival prediction in LM patients.

Advancing Therapeutic Drug Monitoring for Oral Targeted Anticancer Drugs: From Hospital-Based Towards Home-Sampling.

Home-sampling for therapeutic drug monitoring (TDM) for oral targeted anticancer drugs offers a promising alternative to traditional hospital-based sampling methods, though it presents challenges. This review aims to summarize the state-of-the-art of home-sampling methods for TDM and evaluates the analytical and clinical validation challenges. A comprehensive search was conducted across Embase, Medline, and Scopus.

The feasibility of using real world data as external control arms in oncology trials.

Before real world data (RWD)-derived external control arms (ECAs) can be applied in clinical trials within the field of oncology, it must be determined whether these ECAs can function as appropriate and reliable control arms. This review provides an overview of studies in which RWD-derived ECAs were constructed and compared to a randomized clinical trial (RCT) arm. RWD-derived ECAs had similar survival outcomes as the RCT arm of comparison in six of the eight included studies.

Clinical Application of Volumetric Absorptive Microsampling for Therapeutic Drug Monitoring of Oral Targeted Anticancer Drugs.

Background: Therapeutic Drug Monitoring optimizes oral anticancer drug treatment by measuring plasma levels. Volumetric absorptive microsampling (VAMS) allows home sampling with a minimal blood sample. However, methods for converting whole blood into plasma are required to interpret these results.

Feasibility and efficacy of therapeutic drug monitoring of abiraterone in metastatic castration resistant prostate cancer patients.

Background: Previous studies demonstrated better outcomes for mCRPC (metastatic castration resistant prostate cancer) patients with higher abiraterone exposure (minimal plasma concentration (C) > 8.4 ng/mL), but around 40% of patients experience exposure below this target. Pharmacokinetic (PK)-guided interventions following Therapeutic Drug Monitoring (TDM) could optimise exposure and outcomes.

Population Pharmacokinetics of Cobicistat and its Effect on the Pharmacokinetics of the Anticancer Drug Olaparib.

Objectives: Pharmacokinetic (PK) boosting is the intentional use of strong inhibitors of metabolic enzymes or transporters to boost the systemic exposure of a therapeutic drug. PK boosting is expanding to therapeutic areas outside human immunodeficiency virus (HIV) therapy. Data on the PK of the booster cobicistat and its effect on CYP3A-substrates outside of HIV therapy are lacking.

Pharmacokinetic exposure and treatment outcomes of lenvatinib in patients with renal cell carcinoma and differentiated thyroid carcinoma.

Purpose: After initial approval of lenvatinib for radioiodine-refractory differentiated thyroid cancer (DTC), it has also shown promising outcomes in among others metastatic renal cell carcinoma (mRCC). Given that trial populations typically do not represent routine clinical care populations, questions arise about how applicable trial outcomes are in clinical practice. This study aims to compare the pharmacokinetics (PK), toxicity patterns, and survival data of lenvatinib in a real-world cohort with DTC and mRCC to those observed in pivotal clinical trials.

A Population Pharmacokinetic Study to Evaluate Doxorubicin Exposure Across All Age Groups.

Background: The effect of age on doxorubicin pharmacokinetics remains inconclusive, especially in patients at the extremes of the age spectrum. We developed a population pharmacokinetic model to further investigate the impact of age on the pharmacokinetics of doxorubicin.

Methods: A three-compartment model, incorporating allometric scaling was developed to describe doxorubicin pharmacokinetics across all ages.

Platinum retention in plasma, urine, and normal colonic mucosa in cisplatin-treated testicular cancer survivors.

Testicular cancer survivors (TCS) treated with platinum-based chemotherapy have increased cancer risk. Platinum retention in healthy tissue may contribute to carcinogenesis. We assessed total platinum concentrations in plasma, urine, and normal colonic mucosa samples in TCS treated with cisplatin.

Treatment sequences and survival outcomes in advanced HR + HER2- breast cancer patients: a real-world cohort.

Purpose: Palliative treatment options for HR + HER2- advanced breast cancer (ABC) patients have increased, but data is lacking about the optimal treatment sequence. We used real-world data from a comprehensive cancer center to describe applied treatment sequences and we determined treatment-related and survival outcomes.

Methods: Patients aged 18 years and older with HR + HER2- ABC treated with systemic treatment were included in this historic cohort study.

Early Prediction and Impact Assessment of CYP3A4-Related Drug-Drug Interactions for Small-Molecule Anticancer Drugs Using Human-CYP3A4-Transgenic Mouse Models.

Early detection of drug-drug interactions (DDIs) can facilitate timely drug development decisions, prevent unnecessary restrictions on patient enrollment, resulting in clinical study populations that are not representative of the indicated study population, and allow for appropriate dose adjustments to ensure safety in clinical trials. All of these factors contribute to a streamlined drug approval process and enhanced patient safety. Here we describe a new approach for early prediction of the magnitude of change in exposure for cytochrome P450 (P450) CYP3A4-related DDIs of small-molecule anticancer drugs based on the model-based extrapolation of human-CYP3A4-transgenic mice pharmacokinetics to humans.