The impact of body mass index (BMI) on treatment outcomes in patients with cancer is gaining increasing attention given the limited data available. The aim of this study was to investigate the contribution of BMI on the safety and efficacy profile of palbociclib in 134 patients with metastatic luminal-like breast cancer treated with palbociclib and endocrine therapy (ET). Normal-weight and underweight patients (BMI<25) were compared with overweight and obese (BMI≥25). Detailed clinical and demographic data were collected. Patients with a BMI<25 had a higher incidence of relevant-hematologic toxicities (p = 0.001), dose reduction events (p = 0.003), and tolerated lower dose intensities (p = 0.023) compared to patients with a BMI≥25. In addition, patients with a BMI<25 had significantly shorter progression-free survival (log-rank p = 0.0332). A significant difference was observed in the subgroup of patients for whom systemic palbociclib concentrations were available: patients with a BMI<25 had a 25% higher median minimum plasma concentrations (C_min) compared to BMI≥25. This study provides compelling evidence for a clinically relevant contribution of BMI in discriminating a group of patients who experienced multiple toxicities that appeared to affect treatment adherence and lead to poorer survival. BMI could become a valuable tool for personalizing the starting dose of palbociclib to improve its safety and efficacy.

The use of Pt(IV) complexes as potential anticancer drugs is attractive, because they have higher stability and less side effects than Pt(II) compounds. Moreover, some Pt(IV) complexes can also be activated with light, opening an avenue to photochemotherapy. Our purpose is to widen the library of photoactivatable Pt(IV)-based prodrugs and here we report on the oxidation of the Pt(II) compound [PtCl(4′-phenyl-2,2′:6′,2′′-terpyridine)][CF₃SO₃] (1) with PhICl₂ or H₂O₂. The synthetic procedure avoids the formation of multiple species: the treatment with PhICl₂ produces the Pt(IV) complex with axial chlorides, [PtCl₃(4′-phenyl-2,2′:6′,2′′-terpyridine)][CF₃SO₃] (2), while H₂O₂ oxidation and post-synthesis carboxylation produce [Pt(OCOCH₃)₂Cl(4′-phenyl-2,2′:6′,2′′-terpyridine)][CF₃SO₃] (3), bearing acetates in the axial positions. 2 and 3 are stable in physiological-like buffers and in DMSO in the dark, but undergo photoreduction to 1 upon irradiation at 365 nm. Their stability toward reduction is a fundamental parameter to consider: cyclic voltammetry experiments show that the 2 electron reduction Pt(IV) → Pt(II) occurs at a more negative potential for 3, because of the greater stabilization provided by the acetate axial groups; noteworthily, 3 is stable for hours also in the presence of mM concentration of glutathione. The cytotoxicity of 2 and 3 toward A2780 and A2780cis cell lines reveals that 3 is the least toxic in the dark, but is able to produce cytotoxic effects far higher than cisplatin when irradiated. To shed light on the mechanistic aspects, the interaction with protein and DNA models has been explored through high-resolution mass spectrometry revealing that 2 and 3 behave as prodrugs, but are able to bind to biological targets only after irradiation.

Poly (ADP-ribose) polymerase inhibitors (PARPis) are becoming increasingly meaningful in oncology, and their therapeutic drug monitoring (TDM) might be beneficial for patients. Several bioanalytical methods have been reported for PARPis quantification in human plasma, but advantages might be obtained using dried blood spot (DBS) as a sampling technique. Our aim was to develop and validate a liquid chromatography-tandem mass spectrometric (LC-MS/MS) method for olaparib, rucaparib, and niraparib quantification in both human plasma and DBS matrices. Additionally, we aimed to assess the correlation between the drug concentrations measured in these two matrices. DBS from patients was obtained using Hemaxis DB10 for volumetric sampling. Analytes were separated on a Cortecs-T3 column and detected with electrospray ionization (ESI)-MS in positive ionization mode. Validation was performed according to the latest regulatory guidelines, in the range (ng/mL) 140–7000 for olaparib, 100–5000 for rucaparib, and 60–3000 for niraparib, within the hematocrit (Hct) range 29–45%. The Passing–Bablok and Bland–Altman statistical analyses revealed a strong correlation between plasma and DBS for olaparib and niraparib. However, due to the limited amount of data, it was challenging to establish a robust regression analysis for rucaparib. To ensure a more reliable assessment, additional samples are required. The DBS-to-plasma ratio was used as a conversion factor (CF) without considering any patient-related hematological parameters. These results provide a solid basis for the feasibility of PARPis TDM using both plasma and DBS matrices.

Background: Therapeutic drug monitoring (TDM) of poly(ADP-ribose) polymerase inhibitors (PARPis) is an exploratory practice aimed at improving the quality of treatment through personalized therapy. Currently, there are 4 European Medicines Agency-approved and US Food and Drug Administration–approved PARPis available clinically whose quantification requires validated analytical methods: olaparib, niraparib, rucaparib, and talazoparib. The purpose of this literature review was to highlight the pharmacological features of PARPis that could support their TDM practice and provide a detailed discussion of the available liquid chromatography coupled with tandem mass spectrometry methods for their quantification. Methods: Using several Medical Subject Heading terms, the literature was searched using several research engines, including SciFinder, Web of Science, Google Scholar, and PubMed, to find articles published before August 2022. Results: Exposure-efficacy and exposure-safety profiles, drug–drug interactions, and hepatic/renal impairment of PARPis provide the potential rationale to monitor their concentrations through TDM. Several bioanalytical methods for their quantification have been reported and compared, and a great deal of heterogeneity has been found among methods, regarding both their analytical and regulatory aspects. Conclusions: In addition to reducing toxicity and increasing the efficacy of PARPis therapy, TDM could be beneficial to thoroughly investigate the exposure–response relationships of PARPis and to establish pharmacokinetic thresholds for clinical decisions. Based on the comparison of published bioanalytical methods, their transferability and validation both play a key role in method selection. For future use in clinical TDM, we anticipate that bioanalytical methods should address every analytical need more thoroughly and should be validated with standardized guidelines.

Daratumumab, a pivotal treatment for multiple myeloma, exhibits considerable inter-patient variability in pharmacological clinical outcomes, likely attributed to serum concentration that may underscore the need for its therapeutic drug monitoring. This study aims to develop and validate a straightforward analytical method for quantifying daratumumab in serum, focusing on intact light chain determination, using liquid chromatography high-resolution mass spectrometry. The sample preparation involved immunoglobulin enrichment using Melon gel followed by a reduction step to dissociate the light from the heavy chains of immunoglobulins. The latter were then separated using a MabPac RP 2.1 × 50 mm chromatographic column and the intact light chains were detected and quantified using a Q Exactive Orbitrap mass spectrometer operating in ESI-positive ion mode at 17 500 resolution. The method demonstrated excellent linearity (R² > 0.992) across a serum concentration range of 100 to 2000 μg mL⁻¹ and good precision and accuracy: intra- and interday relative errors ranged from −5.1% to 6.5%, with a relative standard deviation of less than 5.8%. Clinical suitability was confirmed by analyzing 80 clinical samples from multiple myeloma patients treated with 1800 mg of daratumumab. 99% of the samples fell within the analytical range with a mean daratumumab concentration evaluated before the next administration (C_trough) of 398 μg mL⁻¹. These findings highlighted that intact light chain monoclonal antibody quantification could be a valid and robust alternative to either immunoassays or to LC-MS/MS targeting peptides for measuring daratumumab in clinical samples, positioning it as a suitable method for therapeutic drug monitoring applications.

Background: Chronic oral anticancer therapies, are increasingly prescribed and present new challenges including the enhanced risk of overlooked drug-drug interactions (DDIs). Lengthy treatments and patients’ management by different professionals can lead to serious prescribing errors that therapeutic drug monitoring (TDM) can help identifying thus allowing a more effective and safer treatment of patients with polypharmacy. Objectives: This report aims to exemplify how an intensified pharmacological approach could help in the clinical monitoring of patients on chronic treatments. Methods: A patient with gastrointestinal stromal tumor was referred to our clinical pharmacology service due to tumor progression while on imatinib therapy. The investigation was based on TDM, pharmacogenetics, DDI evaluation and Circulating tumor DNA (ctDNA) analysis. The patient underwent repeated blood samplings to measure imatinib and norimatinib plasma concentrations through a validated LC-MS/MS method. Polymorphisms affecting genes involved in imatinib metabolism and transport were investigated using SNPline PCR Genotyping System. Drug-drug interactions were evaluated though Lexicomp. ctDNA analysis was performed on MiSeq platform. Results: TDM analysis revealed that the patient was underexposed to imatinib (C_min = 406 ng/mL; target C_min = 1100 ng/mL). Subsequent DDI analysis highlighted a dangerous interaction with carbamazepine, via CYP3A4 and P-gp strong induction, omitted at the time of imatinib treatment start. No relevant pharmacogenetic variants were identified and appropriate compliance to treatment was ascertained. ctDNA monitoring was performed to assess potential tumor-related resistance to imatinib. Carbamazepine was cautiously switched to a non-interacting antiepileptic drug, restoting IMA plasma concentration (i.e. C_min = 4298 ng/mL). The progression of the disease, which in turn led to the patient’s death, was also witnessed by an increasing fraction of ctDNA in plasma. Conclusion: The active pharmacological monitoring allowed the identification of a dangerous previously over-looked DDI leading to IMA under-exposure. The switch to a different antiepileptic treatment, reversed the effect of DDI, restoring therapeutic IMA plasmatic concentrations. Graphical