Reasons for non-feasibility of therapeutic drug monitoring of oral targeted therapies in oncology - an analysis of the closed cohorts of a multicentre prospective study.

BACKGROUND: Therapeutic drug monitoring (TDM) - performing dose adjustments based on measured drug levels and established pharmacokinetic (PK) targets - could optimise treatment with drugs that show large interpatient variability in exposure. We evaluated the feasibility of TDM for multiple oral targeted therapies. Here we report on drugs for which routine TDM is not feasible. METHODS: We evaluated drug cohorts from the Dutch Pharmacology Oncology Group - TDM study. Based on PK levels taken at pre-specified time points, PK-guided interventions were performed. Feasibility of TDM was evaluated, and based on the success and practicability of TDM, cohorts could be closed. RESULTS: For 10 out of 24 cohorts TDM was not feasible and inclusion was closed. A high incidence of adverse events resulted in closing the cabozantinib, dabrafenib/trametinib, everolimus, regorafenib and vismodegib cohort. The enzalutamide and erlotinib cohorts were closed because almost all PK levels were above target. Other, non-pharmacological reasons led to closing the palbociclib, olaparib and tamoxifen cohort. CONCLUSIONS: Although TDM could help personalising treatment for many drugs, the above-mentioned reasons can influence its feasibility, usefulness and clinical applicability. Therefore, routine TDM is not advised for cabozantinib, dabrafenib/trametinib, enzalutamide, erlotinib, everolimus, regorafenib and vismodegib. Nonetheless, TDM remains valuable for individual clinical decisions.

Results of the first international quality control programme for oral targeted oncolytics.

AIMS: With the rising number of oral targeted oncolytics and growing awareness of the benefits of therapeutic drug monitoring (TDM) within the field of oncology, it is expected that the requests for quantifying concentrations of these drugs will increase. It is important to (cross-)validate available assays and ensure its quality, as results may lead to altered dosing recommendations. Therefore, we aimed to evaluate the performance of laboratories measuring concentrations of targeted oral oncolytics in a one-time international quality control (QC) programme. METHODS: Participating laboratories received a set of plasma samples containing low, medium and high concentrations of imatinib, sunitinib, desethylsunitinib, pazopanib, cabozantinib, olaparib, enzalutamide, desmethylenzalutamide and abiraterone, with the request to report their results back within five weeks after shipment. Accuracy was defined acceptable if measurements where within 85%-115% from the weighed-in reference concentrations. Besides descriptive statistics, an exploratory ANOVA was performed. RESULTS: Seventeen laboratories from six countries reported 243 results. Overall, 80.7% of all measurements were within the predefined range of acceptable accuracy. Laboratories performed best in quantifying imatinib and poorest in quantifying desethylsunitinib (median absolute inaccuracy respectively 4.0% (interquartile range (IQR) 1.8%-6.5%) and 15.5% (IQR 8.8%-34.9%)). The poorest performance of desethylsunitinib might be caused by using the stable-isotope-labelled sunitinib instead of desethylsunitinib as an internal standard, or due to the light-induced cis(Z)/trans(E) isomerization of (desethyl)sunitinib. Overall, drug substance and performing laboratory seemed to influence the absolute inaccuracy (F = 16.4; p < 0.001 and F = 35.5; p < 0.001, respectively). CONCLUSION: Considering this is the first evaluation of an international QC programme for oral targeted oncolytics, an impressive high percentage of measurements were within the predefined range of accuracy. Cross-validation of assays that are used for dose optimization of oncolytics will secure the performance and will protect patients from incorrect advices.

Exploring the contribution of genetic variants to high sunitinib exposure in patients with cancer.

AIMS: Sunitinib exhibits considerable interindividual variability in exposure. While the target total plasma concentration of sunitinib and its active metabolite is 50-87.5 ng/mL for the intermittent dosing schedule, ~10-21% of patients experience higher exposures (>87.5 ng/mL), correlated with an increased risk for toxicity. Previous research identified single nucleotide variants (SNVs) in genes from the sunitinib pharmacokinetic pathway to be associated with efficacy and toxicity. However, significant interindividual variability in exposure remains unexplained. Our aim was to identify genetic variants associated with supratherapeutic exposure of sunitinib. METHODS: This was a genome-wide association study. Cases were identified during routine therapeutic drug monitoring and consisted of patients with dose-normalized sunitinib plasma concentrations >87.5 ng/mL (intermittent dosing) or >75 ng/mL (continuous dosing). Controls were sampled from the historical cohort EuroTARGET who tolerated the standard dose of 50 mg in an intermittent schedule. SNVs were tested for an association with sunitinib exposure. A P-value ≤5 × 10-8 was considered significant and a P-value between 5 × 10-8 and 5 × 10-6 was considered suggestive. RESULTS: Sixty-nine cases and 345 controls were included for association analysis. One SNV (rs6923761), located on the gene glucagon-like peptide 1 receptor, was significantly associated with increased sunitinib exposure (P = 7.86 × 10-19). Twelve SNVs were suggestive for an association with sunitinib exposure (P ≤ 5 × 10-6). CONCLUSIONS: While rs6923671 is associated with high sunitinib exposure, the underlying mechanism is not yet clarified and warrants further investigation. We could not confirm the earlier found associations between SNVs in candidate genes involved in the pharmacokinetic pathway of sunitinib and its efficacy and toxicity.

The QT interval prolongation potential of anticancer and supportive drugs: a comprehensive overview.

Patients with cancer are prone to prolongation of the corrected QT interval (QTc) due to the use of anticancer drugs with QTc-prolonging potential in combination with electrolyte imbalances caused by, for example, gastrointestinal side-effects. However, most anticancer drugs were approved with little information on their QTc-prolonging potential and the added risk of torsade de pointes. The absence of this information on the drug label poses a considerable challenge to clinicians regarding the measures that need to be taken to safely start anticancer treatment. In this Review, we provide a comprehensive overview of the evidence for the QTc-prolonging properties of 205 anticancer drugs and 14 antiemetic drugs available from drug labels, assessment reports, and published studies. We classify the drugs as low-risk, moderate-risk, or high-risk for QTc prolongation. We also discuss the clinical relevance of these findings and include practical recommendations to guide clinicians to select the drugs with the least QTc-prolonging properties and to adequately monitor susceptible patients.

Body weight gain in clozapine-treated patients: Is norclozapine the culprit?

The antipsychotic drug clozapine is associated with weight gain. The proposed mechanisms include blocking of serotonin (5-HT2a/2c ), dopamine (D2 ) and histamine (H1 ) receptors. Clozapine is metabolized by cytochrome P450 1A2 (CYP1A2) to norclozapine, a metabolite with more 5-HT2c -receptor and less H1 blocking capacity. We hypothesized that norclozapine serum levels correlate with body mass index (BMI), waist circumference and other parameters of the metabolic syndrome. We performed a retrospective cross-sectional study in 39 patients (female n = 8 (20.5%), smokers n = 18 (46.2%), average age 45.8 ± 9.9 years) of a clozapine outpatient clinic in the Netherlands between 1 January 2017 and 1 July 2020. Norclozapine concentrations correlated with waist circumference (r = 0.354, P = .03) and hemoglobin A1c (HbA1c) (r = 0.34, P = .03). In smokers (smoking induces CYP1A2), norclozapine concentrations correlated with waist circumference (r = 0.723, P = .001), HbA1c (r = 0.49, P = .04) and BMI (r = 0.63, P = .004). Elucidating the relationship between norclozapine and adverse effects of clozapine use offers perspectives for interventions and treatment options.

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 (≥ 20.5 mg/L) linked to prolonged progression-free survival (PFS), but the added value of using TDM remains unclear. This study investigates the effect of TDM of pazopanib in patients with STS on survival outcomes and dose-limiting toxicities (DLTs) and evaluates the feasibility of TDM-guided dosing. METHODS: A TDM-guided cohort was compared to a non-TDM-guided cohort for PFS, overall survival (OS) and DLTs. PK samples were available from all patients, though not acted upon in the non-TDM-guided cohort. We evaluated the feasibility of TDM by comparing the proportion of underdosed patients in our TDM cohort with data from previous publications. RESULTS: A total of 122 STS patients were included in the TDM-guided cohort (n = 95) and non-TDM-guided cohort (n = 27). The average exposure in the overall population was 30.5 mg/L and was similar in both groups. Median PFS and OS did not differ between the TDM-guided cohort and non-TDM-guided cohort (respectively 5.5 vs 4.4 months, p = 0.3, and 12.6 vs 10.1 months, p = 0.8). Slightly more patients in the non-TDM-guided cohort experienced DLTs (54%) compared to the TDM-guided cohort (44%). The proportion of underdosed patients (13.3%) was halved compared to historical data (26.7%). CONCLUSION: TDM reduced the proportion of patients with subtherapeutic exposure levels by ~ 50%. Nonetheless, the added value of TDM for achieving target trough levels of ≥ 20.5 mg/L for pazopanib on survival outcomes could not be confirmed in STS patients.

Measuring Tumour Imatinib Concentrations in Gastrointestinal Stromal Tumours: Relevant or Redundant?

Imatinib plasma trough concentrations are associated with efficacy for patients treated for advanced or metastatic KIT-positive gastrointestinal stromal tumours (GISTs). This relationship has not been studied for patients treated in the neoadjuvant setting, let alone its correlation with tumour drug concentrations. In this exploratory study we aimed to determine the correlation between plasma and tumour imatinib concentrations in the neoadjuvant setting, investigate tumour imatinib distribution patterns within GISTs, and analyse its correlation with pathological response. Imatinib concentrations were measured in both plasma and in three regions of the resected primary tumour: the core, middle part, and periphery. Twenty-four tumour samples derived from the primary tumours of eight patients were included in the analyses. Imatinib tumour concentrations were higher compared to plasma concentrations. No correlation was observed between plasma and tumour concentrations. Interpatient variability in tumour concentrations was high compared to interindividual variability in plasma concentrations. Although imatinib accumulates in tumour tissue, no distribution pattern of imatinib in tumour tissue could be identified. There was no correlation between imatinib concentrations in tumour tissue and pathological treatment response.

Adverse Drug Reactions from Real-World Data in Inflammatory Bowel Disease Patients in the IBDREAM Registry.

INTRODUCTION: Inflammatory bowel disease (IBD) frequently requires chronic immunosuppressive treatment and active involvement from patients during treatment decision making. Information about the risk of developing adverse drug reactions (ADRs) to IBD therapies is required in this process. OBJECTIVE: The aim of this study was to describe the ADRs reported in IBD patients from real-world data, using the Dutch nationwide IBDREAM registry, and compare the occurrence and cumulative incidences with the Summary of Product Characteristics (SmPC) of the associated drugs. METHODS: In this retrospective multicentre study, ADRs related to IBD medication were assessed. Only reports associated with the use of drugs used for the maintenance treatment of IBD were included. All ADRs were verified by healthcare professionals and coded by trained pharmacovigilance assessors. RESULTS: In total, 3080 ADRs were reported in 1179 patients. Twenty-three new drug-ADR associations related to the use of azathioprine, mercaptopurine, infliximab, oral mesalamine and thioguanine were reported in the IBDREAM registry that were not mentioned in the corresponding SmPCs. The most frequently reported new association was pyrexia for azathioprine (3.1%) and mercaptopurine (4.9%). In addition, there were seven ADRs with a higher cumulative incidence in IBDREAM compared with the SmPC, and included, among others, arthralgia during mercaptopurine use (2.5%), and diarrhoea (1.4%), alopecia (1.2%) and infections (1.6%) during azathioprine use. CONCLUSIONS: Based on real-world data, ADR reporting demonstrated new ADRs and higher incidences of ADRs to IBD therapies. This information will contribute to drug safety by updating the SmPCs, allowing better risk assessment and communication towards patients.

Frequency of real-world reported adverse drug reactions in rheumatoid arthritis patients.

OBJECTIVES: To describe the cumulative incidences of adverse drug reactions (ADRs) associated with disease-modifying anti-rheumatic drugs (DMARDs) in rheumatoid arthritis (RA) patients from real-world data (RWD), using the DREAM-RA registry, and to compare these with incidence frequencies mentioned in the Summary of Product Characteristics (SmPC). METHODS: All ADRs in patients with recorded use of adalimumab, etanercept, hydroxychloroquine, leflunomide, oral and subcutaneous methotrexate, and sulfasalazine from a single center participating in the DREAM-RA registry (n = 1,098 patients) that were directly sent to the Netherlands Pharmacovigilance Center Lareb were assessed. Cumulative incidences were calculated, described and compared to the most recently revised SmPCs. RESULTS: In total, 14 ADRs (≥5 case reports) associated with the use of one of the included DMARDs were reported with a higher estimated cumulative incidence compared to the SmPC. For hydroxychloroquine and sulfasalazine, 5 ADRs (≥5 case reports) mentioned with an 'unknown' incidence in the SmPC were reported as 'common' in this study. CONCLUSIONS: Although ADR data in the DREAM-RA registry were partly comparable with data in the SmPCs, RWD from this patient registry provided an added value to the currently available information on the incidences of ADRs associated with DMARDs in RA patients as described in SmPCs.