Letter to the editor regarding the paper by A. Boileve et al.: Safety of direct oral anticoagulants in patients with advanced solid tumors receiving anti­VEGF agents: a retrospective study.

Concomitant direct oral anticoagulants (DOACs) and tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (anti-VEGF TKI) have been associated with a higher risk of bleeding. Nevertheless, concomitant administration seems frequent in clinical practice in patients with cancer-associated thrombosis and appears to be safe according to the retrospective study by Boileve A. et al. But the risk of an additional pharmacokinetic interaction between anti-VEGF TKI and DOACs must be considered, in case of P-glycoprotein (P-gp) inhibition by the TKI. We describe a case report with a major bleeding event in a renal metastatic cancer patient treated with cabozantinib and rivaroxaban. This case highlights the difficult therapeutic decision in a complex patient with cancer-associated thrombosis, who refused the anticoagulant subcutaneous route. Accumulation of bleeding risk factors (genito-urinary tumor localization) was additive to several pharmacodynamic interactions (acetylsalicylic acid, venlafaxine) and a potential pharmacokinetic interaction between cabozantinib and rivaroxaban. Indeed, cabozantinib-related P-glycoprotein inhibition could have led to a supratherapeutic level of rivaroxaban, contributing partly to the bleeding event. Before combining an anti-VEGF TKI and DOACs, a multidisciplinary pretherapeutic assessment seems crucial to evaluate the patient's bleeding risk factors, pharmacodynamic interactions, and the risk of pharmacokinetic interactions mediated by P-gp.

Intra-individual Dose Escalation of Abiraterone According to Its Plasma Exposure in Patients with Progressive Metastatic Castration-Resistant Prostate Cancer: Results of the OPTIMABI Trial.

BACKGROUND AND OBJECTIVE: Trough abiraterone concentration (ABI Cmin) of 8.4 ng/mL has been identified as an appropriate efficacy threshold in patients treated for metastatic castration-resistant prostate cancer (mCRPC). The aim of the phase II OPTIMABI study was to evaluate the efficacy of pharmacokinetics (PK)-guided dose escalation of abiraterone acetate (AA) in underexposed patients with mCRPC with early tumour progression. METHODS: This multicentre, non-randomised study consisted of two sequential steps. In step 1, all patients started treatment with 1000 mg of AA once daily. Abiraterone Cmin was measured 22-26 h after the last dose intake each month during the first 12 weeks of treatment. In step 2, underexposed patients (Cmin < 8.4 ng/mL) with tumour progression within the first 6 months of treatment were enrolled and received AA 1000 mg twice daily. The primary endpoint was the rate of non-progression at 12 weeks after the dose doubling. During step 1, adherence to ABI treatment was assessed using the Girerd self-reported questionnaire. A post-hoc analysis of pharmacokinetic (PK) data was conducted using Bayesian estimation of Cmin from samples collected outside the sampling guidelines (22-26 h). RESULTS: In the intention-to-treat analysis (ITT), 81 patients were included in step 1. In all, 21 (26%) patients were underexposed in step 1, and 8 of them (38%) experienced tumour progression within the first 6 months. A total of 71 patients (88%) completed the Girerd self-reported questionnaire. Of the patients, 62% had a score of 0, and 38% had a score of 1 or 2 (minimal compliance failure), without a significant difference in mean ABI Cmin in the two groups. Four patients were enrolled in step 2, and all reached the exposure target (Cmin > 8.4 ng/mL) after doubling the dose, but none met the primary endpoint. In the post-hoc analysis of PK data, 32 patients (39%) were underexposed, and ABI Cmin was independently associated with worse progression-free survival [hazard ratio (HR) 2.50, 95% confidence interval (CI) 1.07-5.81; p = 0.03], in contrast to the ITT analysis. CONCLUSION: The ITT and per-protocol analyses showed no statistical association between ABI underexposure and an increased risk of early tumour progression in patients with mCRPC, while the Bayesian estimator showed an association. However, other strategies than dose escalation at the time of progression need to be evaluated. Treatment adherence appeared to be uniformly good in the present study. Finally, the use of a Bayesian approach to recover samples collected outside the predefined blood collection time window could benefit the conduct of clinical trials based on drug monitoring. OPTIMABI trial is registered as National Clinical Trial number NCT03458247, with the EudraCT number 2017-000560-15).

Improving olaparib exposure to optimize adverse effects management.

Background: Olaparib is an inhibitor of the human poly-(ADP-ribose)-polymerase enzymes (PARP1/2) needed to repair single-strand DNA breaks. It is used in breast, ovarian, prostate and pancreatic cancer. Objectives: This work aimed to describe the pharmacokinetics/pharmacodynamics (PK/PD) relationship between olaparib plasma concentrations and common adverse effects (i.e. anaemia and hypercreatininaemia), in a real-life setting, to propose a target concentration for therapeutic drug monitoring. Methods: Two PK/PD models describing the evolution of haemoglobinaemia and creatininaemia as a function of time were developed, based on data from, respectively, 38 and 37 patients receiving olaparib. The final model estimates were used to calculate the incidence of anaemia and creatinine increase according to plasma trough concentrations for 1000 virtual subjects to define target exposure. Results: The final models correctly described the temporal evolution of haemoglobinaemia and creatininaemia for all patients. The haemoglobinaemia PK/PD model is inspired by Friberg's model, and the creatininaemia PK/PD model is an indirect response model. Model parameters were in agreement with physiological values and close to literature values for similar models. The mean (population) plasma haemoglobin concentration at treatment initiation, as estimated by the model, was 11.62 g/dL, while creatinine concentration was 71.91 µmol/L. Using simulations, we have identified a target trough concentration of 3500-4000 ng/mL, above which more than 20% of patients would report grade ≥3 anaemia. Conclusion: Based on real-world data, we were able to properly describe the time course of haemoglobinaemia and plasma creatininaemia during olaparib treatment.

Extending the dosing intervals of nivolumab: model-based simulations in unselected cancer patients.

BACKGROUND: Reducing nivolumab dose intensity could increase patients' life quality and decrease the financial burden while maintaining efficacy. The aims of this study were to develop a population PK model of nivolumab based on data from unselected metastatic cancer patients and to simulate extended-interval regimens allowing to maintain minimal effective plasma concentrations (MEPC). METHODS: Concentration-time data (992 plasma nivolumab concentrations, 364 patients) were modeled using a two-compartment model with linear elimination clearance in Monolix software. Extended-interval regimens allowing to maintain steady-state trough concentrations (Cmin,ss) above the MEPC of 2.5 mg/L or 1.5 mg/L in >90% of patients were simulated. RESULTS: Increasing 3-times the dosing interval from 240 mg every two weeks (Q2W) to Q6W and 2-times from 480 mg Q4W to Q8W resulted in Cmin,ss above 2.5 mg/L in 95.8% and 95.4% of patients, respectively. 240 mg Q8W and 480 mg Q10W resulted in Cmin,ss above 1.5 mg/L in 91.0% and 91.8% of patients, respectively. Selection of a 240 mg Q6W regimen would decrease by 3-fold the annual treatment costs compared to standard regimen of 240 mg Q2W (from 78,744€ to 26,248€ in France). CONCLUSIONS: Clinical trials are warranted to confirm the non-inferiority of extended-interval compared to standard regimen.

Exposure-response relationship of cabozantinib in patients with metastatic renal cell carcinoma treated in routine care.

BACKGROUND: Interindividual pharmacokinetic variability may influence the clinical benefit or toxicity of cabozantinib in metastatic renal cell carcinoma (mRCC). We aimed to investigate the exposure-toxicity and exposure-response relationship of cabozantinib in unselected mRCC patients treated in routine care. METHODS: This ambispective multicenter study enrolled consecutive patients receiving cabozantinib in monotherapy. Steady-state trough concentration (Cmin,ss) within the first 3 months after treatment initiation was used for the PK/PD analysis with dose-limiting toxicity (DLT) and survival outcomes. Logistic regression and Cox proportional-hazards models were used to identify the risk factors of DLT and inefficacy in patients, respectively. RESULTS: Seventy-eight mRCC patients were eligible for the statistical analysis. Fifty-two patients (67%) experienced DLT with a median onset of 2.1 months (95%CI 0.7-8.2). In multivariate analysis, Cmin,ss was identified as an independent risk factor of DLT (OR 1.46, 95%CI [1.04-2.04]; p = 0.029). PFS and OS were not statistically associated with the starting dose (p = 0.81 and p = 0.98, respectively). In the multivariate analysis of PFS, Cmin, ss > 336 ng/mL resulted in a hazard ratio of 0.28 (95%CI, 0.10-0.77, p = 0.014). By contrast, Cmin, ss > 336 ng/mL was not statistically associated with longer OS. CONCLUSION: Early plasma drug monitoring may be useful to optimise cabozantinib treatment in mRCC patients treated in monotherapy, especially in frail patients starting at a lower than standard dose.

Pazopanib pharmacokinetically guided dose optimization in three cancer patients with gastrointestinal resection.

PURPOSE: Pazopanib is approved in advanced renal cell carcinoma (RCC) and soft-tissue sarcoma at a flat-fixed dose despite a large pharmacokinetics interindividual variability and a narrow therapeutic index. To our knowledge, pazopanib exposure in patients with gastrointestinal resections (GIR) has not been described. This report focuses on feasibility of pharmacokinetics-guided dose escalation in these patients and clinical implications for their management. METHOD: A retrospective data collection was performed for three patients with GIR treated with pazopanib, including pazopanib plasma concentrations (high-performance liquid chromatography with UV detection) and treatment adherence (Girerd score). CASE PRESENTATION: First patient (55-year-old man, RCC, gastric bypass surgery) pazopanib Cmin,ss at day 39 was 4.1 mg/L. Dose escalation to 1800 mg/day fractionated allowed to reach Cmin,ss of 18.5 mg/L (target threshold in RCC patients: 20.5 mg/L). Patient 2 (50-year-old woman, metastatic myxofibrosarcoma, gastric band) showed Cmin,ss of 4.0 mg/L at day 13. In patient 3 (49-year-old man, gastric malignant peripheral nerve sheath tumor, gastrectomy), Cmin,ss at day 13 was 2.7 mg/L. For these two patients, intake with food and dose fractioning only slightly increased pazopanib Cmin,ss to 12.0 mg/L and 6.5 mg/L, respectively (therapeutic threshold in sarcoma patients: 27 mg/L). Treatment adherence was good in all patients. CONCLUSION: Optimal pazopanib exposure cannot be achieved in patients with GIR, and thus, other therapeutic strategies should be encouraged. Pretherapeutic assessment seems crucial to evaluate factors as bariatric surgery that may impact pazopanib concentrations. Therapeutic drug monitoring could be helpful to optimize pazopanib response in these patients.

Pharmacokinetics/Pharmacodynamics of Dabrafenib and Trametinib for Redifferentiation and Treatment of Radioactive Iodine-Resistant Mutated Advanced Differentiated Thyroid Cancer.

Background: BRAF and MEK inhibitors are cornerstones of the redifferentiation strategy in metastatic radioactive iodine (RAI)-resistant mutant thyroid cancers. We explored the exposure-toxicity relationship for dose-limiting toxicity (DLT) onset in patients treated with dabrafenib and/or trametinib and investigated whether plasma exposure was associated with RAI reuptake. Methods: We conducted a retrospective monocentric study in which we reviewed the electronic medical records of patients treated in our institution with a tumor redifferentiation strategy, for whom plasma concentration of dabrafenib, its active metabolite hydroxy-dabrafenib, and trametinib was measured. Trough concentrations (Cminpred) and total plasma drug exposure (area under the curve, AUC) of dabrafenib (AUCDAB), hydroxy-dabrafenib (AUCOHD), and trametinib (AUCTRA) were estimated. Results: Of the 22 patients treated in a redifferentiation strategy between March 2014 and December 2021, 15 were included in this study. A dabrafenib- or trametinib-related DLT was experienced by 8 (62%) and 9 (64%) patients, respectively. Patients who experienced a trametinib-related DLT exhibited a significantly higher last AUCTRA than the average AUCTRA of patients who had no DLT (390, IQR: 67 vs. 215, IQR: 91 ng/mL·h-1, respectively; p = 0.008). Patients who experienced a dabrafenib-related DLT had a higher AUCDAB than observed in other patients (9265 ng/mL·h-1 vs. 6953 ng/mL·h-1, respectively; p = 0.09). No clinical and demographical characteristic was associated with the DLT onset. Overall, 9 of 15 (60%) patients demonstrated tumor redifferentiation. Patients in whom RAI reuptake was achieved had significant lower AUCDAB (6990 ng/mL·h-1 vs. 9764 ng/mL·h-1, p = 0.014; respectively) compared with patients who did not. Moreover, the relative exposure ratio of AUCOHD/DAB was significantly higher in patients who achieved RAI reuptake (1.11 vs. 0.71, respectively; p = 0.0047). Conclusions: Our data suggest a relationship between DLT onset and trametinib plasma exposure, as well as an association between achievement of RAI reuptake and dabrafenib plasma exposure (AUC and ratio of AUCOHD/DAB). These data imply that the use of plasma drug monitoring could be helpful in guiding clinical practice in redifferentiation treatment.

Hydroxychloroquine sulfate: A novel treatment for lipin-1 deficiency?

BACKGROUND: Lipin-1 deficiency is a life-threatening disease that causes severe rhabdomyolysis (RM) and chronic symptoms associated with oxidative stress. In the absence of treatment, Hydroxychloroquine sulfate (HCQ) was administered to patients off label use on a compassionate basis in order to improve their physical conditions. METHODS: Eleven patients with LPIN1 mutations were treated with HCQ. Clinical and biological efficacy and tolerance were assessed, including pain and quality of life, physical capacities, cardiopulmonary parameters, creatine kinase levels and plasma proinflammatory cytokines. To explore a dose-dependent effect of HCQ, primary myoblasts from 4 patients were incubated with various HCQ concentrations in growth medium (GM) or during starvation (EBSS medium) to investigate autophagy and oxidative stress. FINDINGS: Under HCQ treatment, patient physical capacities improved. Abnormal cardiac function and peripheral muscle adaptation to exercise were normalized. However, two patients who had the highest mean blood HCQ concentrations experienced RM. We hypothesized that HCQ exerts deleterious effects at high concentrations by blocking autophagy, and beneficial effects on oxidative stress at low concentrations. We confirmed in primary myoblasts from 4 patients that high in vitro HCQ concentration (10 µM) but not low concentration (1 µM and 0.1 µM) induced autophagy blockage by modifying endolysosomal pH. Low HCQ concentration (1 µM) prevented reactive oxygen species (ROS) and oxidized DNA accumulation in myoblasts during starvation. INTERPRETATION: HCQ improves the condition of patients with lipin-1 deficiency, but at low concentrations. In vitro, 1 µM HCQ decreases oxidative stress in myoblasts whereas higher concentrations have a deleterious effect by blocking autophagy.

Predictive factors associated with pemetrexed acute toxicity.

PURPOSE: Pemetrexed has shown efficacy as monotherapy or in combination with platinum salts in the treatment of non-small cell lung cancer and mesothelioma. However, severe hematological toxicities induced by pemetrexed-based chemotherapy have been observed. Some studies have suggested that drug interactions may be associated with pemetrexed toxicity. The objective of this study was to determine predictive factors, including drug interactions, associated with pemetrexed toxicity. METHODS: This retrospective open monocentric study included patients consecutively treated with pemetrexed after a multidisciplinary risk assessment. Patients who experienced toxicity of grade 3 or 4 according to the Common Terminology Criteria for Adverse Events v5.0, or a grade 2 leading to a change in management, during the first four courses of pemetrexed, were assigned to the early limiting toxicities (ELT) group. Univariate and multivariable logistic regression models were used to test the association variables with the occurrence of ELT. RESULTS: Seventy-four patients were included in this study (median age: 67 years, with non-small cell lung cancer adenocarcinoma (88%), mesothelioma (7%), or others (5%). Thirty-six patients (49%) were assigned to the ELT group (27 grades 3 and 4; 9 grade 2 with management modification). Three baseline factors were associated with pemetrexed ELT in univariate and multivariate analysis: cystatin clearance (p = 0.0135), albumin level (p = 0.0333), and proton pump inhibitors use (p = 0.035). CONCLUSION: To conclude, ELT induced by pemetrexed-based treatments occur frequently in cancer patients in a real-world setting. A pretherapeutic assessment before pemetrexed initiation should include three major checkpoints: use of proton pump inhibitors, sarcopenia, and denutrition evaluation.

Therapeutic Drug Monitoring of Tyrosine Kinase Inhibitors in the Treatment of Advanced Renal Cancer.

Seven tyrosine kinase inhibitor compounds with anti-angiogenic properties remain key drugs to treat advanced renal cell carcinoma. There is a strong rationale to develop therapeutic drug monitoring for these drugs. General considerations of such monitoring of the several groups of anticancer drugs are given, with a focus on oral therapy. Pharmacokinetics and the factors of inter- and intraindividual variabilities of these tyrosine kinase inhibitors are described together with an exhaustive presentation of their pharmacokinetic/pharmacodynamic relationships. The latter was observed in studies where every patient was treated with the same dose, and the results of several prospective studies based on dose individualization support the practice of increasing individual dosage in case of low observed plasma drug concentrations. Finally, the benefits and limits of therapeutic drug monitoring as a routine practice are discussed.

Cardiac toxicity associated with pharmacokinetic drug-drug interaction between crizotinib and sofosbuvir/velpatasvir: A case report.

This case report describes a pharmacokinetic drug-drug interaction between crizotinib, a tyrosine kinase inhibitor, and sofosbuvir/velpatasvir, a direct-acting antiviral drug, leading to cardiac toxicity. A 75-year-old man, with no cardiovascular history but a diagnosis of metastatic nonsmall cell lung cancer with mesenchymal-epithelial transition exon-14 deletion and hepatitis C virus infection genotype 1A, received both crizotinib and sofosbuvir/velpatasvir. Crizotinib was well tolerated, but 1 week after sofosbuvir/velpatasvir initiation, the patient experienced bilateral lower-limb oedema and class III New York Heart Association dyspnoea. We assumed that increased exposure to crizotinib could account for this cardiac toxicity. Drug causality was probable according to the Naranjo scale. We hypothesized a reciprocal interaction between crizotinib and velpatasvir, mediated by both cytochrome 3A4 (CYP3A4) and P-glycoprotein (P-gp). Clinicians should be aware of the risk of drug-drug interactions between direct-acting antiviral agents that inhibit CYP3A4 (glecaprevir) and/or P-gp (voxilaprevir, velpatasvir) and anticancer tyrosine kinase inhibitors that are mostly CYP3A4 and/or P-gp substrates (gefitinib, afatinib, erlotinib, crizotinib, ceritinib, lorlatinib, brigatinib, capmatinib etc.).

High plasma concentrations of acyl-coenzyme A binding protein (ACBP) predispose to cardiovascular disease: Evidence for a phylogenetically conserved proaging function of ACBP.

Autophagy defects accelerate aging, while stimulation of autophagy decelerates aging. Acyl-coenzyme A binding protein (ACBP), which is encoded by a diazepam-binding inhibitor (DBI), acts as an extracellular feedback regulator of autophagy. As shown here, knockout of the gene coding for the yeast orthologue of ACBP/DBI (ACB1) improves chronological aging, and this effect is reversed by knockout of essential autophagy genes (ATG5, ATG7) but less so by knockout of an essential mitophagy gene (ATG32). In humans, ACBP/DBI levels independently correlate with body mass index (BMI) as well as with chronological age. In still-healthy individuals, we find that high ACBP/DBI levels correlate with future cardiovascular events (such as heart surgery, myocardial infarction, and stroke), an association that is independent of BMI and chronological age, suggesting that ACBP/DBI is indeed a biomarker of "biological" aging. Concurringly, ACBP/DBI plasma concentrations correlate with established cardiovascular risk factors (fasting glucose levels, systolic blood pressure, total free cholesterol, triglycerides), but are inversely correlated with atheroprotective high-density lipoprotein (HDL). In mice, neutralization of ACBP/DBI through a monoclonal antibody attenuates anthracycline-induced cardiotoxicity, which is a model of accelerated heart aging. In conclusion, plasma elevation of ACBP/DBI constitutes a novel biomarker of chronological aging and facets of biological aging with a prognostic value in cardiovascular disease.

Monitoring of Dabrafenib and Trametinib in Serum and Self-Sampled Capillary Blood in Patients with BRAFV600-Mutant Melanoma.

Patients treated with dabrafenib and trametinib for BRAFV600-mutant melanoma often experience dose reductions and treatment discontinuations. Current knowledge about the associations between patient characteristics, adverse events (AE), and exposure is inconclusive. Our study included 27 patients (including 18 patients for micro-sampling). Dabrafenib and trametinib exposure was prospectively analyzed, and the relevant patient characteristics and AE were reported. Their association with the observed concentrations and Bayesian estimates of the pharmacokinetic (PK) parameters of (hydroxy-)dabrafenib and trametinib were investigated. Further, the feasibility of at-home sampling of capillary blood was assessed. A population pharmacokinetic (popPK) model-informed conversion model was developed to derive serum PK parameters from self-sampled capillary blood. Results showed that (hydroxy-)dabrafenib or trametinib exposure was not associated with age, sex, body mass index, or toxicity. Co-medication with P-glycoprotein inducers was associated with significantly lower trough concentrations of trametinib (p = 0.027) but not (hydroxy-)dabrafenib. Self-sampling of capillary blood was feasible for use in routine care. Our conversion model was adequate for estimating serum PK parameters from micro-samples. Findings do not support a general recommendation for monitoring dabrafenib and trametinib but suggest that monitoring can facilitate making decisions about dosage adjustments. To this end, micro-sampling and the newly developed conversion model may be useful for estimating precise PK parameters.

Exposure-Response Analysis of Osimertinib in Patients with Advanced Non-Small-Cell Lung Cancer.

High interindividual variability (IIV) of the clinical response to epidermal growth factor receptor (EGFR) inhibitors such as osimertinib in non-small-cell lung cancer (NSCLC) might be related to the IIV in plasma exposure. The aim of this study was to evaluate the exposure−response relationship for toxicity and efficacy of osimertinib in unselected patients with advanced EGFR-mutant NSCLC. This retrospective analysis included 87 patients treated with osimertinib. Exposure−toxicity analysis was performed in the entire cohort and survival analysis only in second-line patients (n = 45). No significant relationship between occurrence of dose-limiting toxicity and plasma exposure was observed in the entire cohort (p = 0.23, n = 86). The median overall survival (OS) was approximately two-fold shorter in the 4th quartile (Q4) of osimertinib trough plasma concentration (>235 ng/mL) than in the Q1−Q3 group (12.2 months [CI95% = 8.0−not reached (NR)] vs. 22.7 months [CI95% = 17.1−34.1]), but the difference was not statistically significant (p = 0.15). To refine this result, the exposure−survival relationship was explored in a cohort of 41 NSCLC patients treated with erlotinib. The Q4 erlotinib exposure group (>1728 ng/mL) exhibited a six-fold shorter median OS than the Q1−Q3 group (4.8 months [CI95% = 3.3-NR] vs. 22.8 months (CI95% = 10.6−37.4), p = 0.00011). These results suggest that high exposure to EGFR inhibitors might be related to worse survival in NSCLC patients.

Population Pharmacokinetics of Palbociclib and Its Correlation with Clinical Efficacy and Safety in Patients with Advanced Breast Cancer.

Neutropenia is the most frequent dose-limiting toxicity reported in patients with metastatic breast cancer receiving palbociclib. The objective of this study was to investigate the pharmacokinetic-pharmacodynamic (PK/PD) relationships for toxicity (i.e., absolute neutrophil count, ANC) and efficacy (i.e., progression-free survival, PFS). A semi-mechanistic PK/PD model was used to predict neutrophils' time course using a population approach (NONMEM). Influence of demographic and clinical characteristics was evaluated. Cox proportional hazards models were developed to evaluate the influence of palbociclib PK on PFS. A two-compartment model with first-order absorption and a lag time adequately described the 255 palbociclib concentrations provided by 44 patients. The effect of the co-administration of proton-pump inhibitors in fasting conditions increased palbociclib clearance by 56%. None of the tested covariates affected the PD parameters. Model-based simulations confirmed the concentration-dependent and non-cumulative properties of palbociclib-induced neutropenia, reversible after treatment withdrawal. The ANC nadir occurred approximately at day 24 of each cycle. Cox analyses revealed a trend for better PFS with increasing palbociclib exposure in older patients. By characterizing palbociclib-induced neutropenia, this model offers support to clinicians to rationally optimize treatment management through patient-individualized strategies.

Relation between Plasma Trough Concentration of Pazopanib and Progression-Free Survival in Metastatic Soft Tissue Sarcoma Patients.

Background: Pazopanib (PAZ) is an oral angiogenesis inhibitor approved to treat soft tissue sarcoma (STS) but associated with a large interpatient pharmacokinetic (PK) variability and narrow therapeutic index. We aimed to define the specific threshold of PAZ trough concentration (Cmin) associated with better progression-free survival (PFS) in STS patients. Methods: In this observational study, PAZ Cmin was monitored over the treatment course. For the primary endpoint, the 3-month PFS in STS was analyzed with logistic regression. Second, we performed exposure−overall survival (OS) (Cox model plus Kaplan−Meier analysis/log-rank test) and exposure−toxicity analyses. Results: Ninety-five STS patients were eligible for pharmacokinetic/pharmacodynamic (PK/PD) assessment. In the multivariable analysis, PAZ Cmin < 27 mg/L was independently associated with a risk of progression at 3 months (odds ratio (OR) 4.21, 95% confidence interval (CI) (1.47−12.12), p = 0.008). A higher average of PAZ Cmin over the first 3 months was associated with a higher risk of grade 3−4 toxicities according to the NCI-CTCAE version 5.0 (OR 1.07 per 1 mg/L increase, CI95 (1.02−1.13), p = 0.007). Conclusion: PAZ Cmin ≥ 27 mg/L was independently associated with improved 3-month PFS in STS patients. Pharmacokinetically-guided dosing could be helpful to optimize the clinical management of STS patients in daily clinical practice.

Cross-Validation of a Multiplex LC-MS/MS Method for Assaying mAbs Plasma Levels in Patients with Cancer: A GPCO-UNICANCER Study.

BACKGROUND: Different liquid chromatography tandem mass spectrometry (LC-MS/MS) methods have been published for quantification of monoclonal antibodies (mAbs) in plasma but thus far none allowed the simultaneous quantification of several mAbs, including immune checkpoint inhibitors. We developed and validated an original multiplex LC-MS/MS method using a ready-to-use kit to simultaneously assay 7 mAbs (i.e., bevacizumab, cetuximab, ipilimumab, nivolumab, pembrolizumab, rituximab and trastuzumab) in plasma. This method was next cross-validated with respective reference methods (ELISA or LC-MS/MS). METHODS: The mAbXmise kit was used for mAb extraction and full-length stable-isotope-labeled antibodies as internal standards. The LC-MS/MS method was fully validated following current EMA guidelines. Each cross validation between reference methods and ours included 16-28 plasma samples from cancer patients. RESULTS: The method was linear from 2 to 100 µg/mL for all mAbs. Inter- and intra-assay precision was <14.6% and accuracy was 90.1-111.1%. The mean absolute bias of measured concentrations between multiplex and reference methods was 10.6% (range 3.0-19.9%). CONCLUSIONS: We developed and cross-validated a simple, accurate and precise method that allows the assay of up to 7 mAbs. Furthermore, the present method is the first to offer a simultaneous quantification of three immune checkpoint inhibitors likely to be associated in patients.

Association between Olaparib Exposure and Early Toxicity in BRCA-Mutated Ovarian Cancer Patients: Results from a Retrospective Multicenter Study.

Factors associated with olaparib toxicity remain unknown in ovarian cancer patients. The large inter-individual variability in olaparib pharmacokinetics could contribute to the onset of early significant adverse events (SAE). We aimed to retrospectively analyze the pharmacokinetic/pharmacodynamic relationship for toxicity in ovarian cancer patients from "real life" data. The clinical endpoint was the onset of SAE (grade III/IV toxicity or dose reduction/discontinuation). Plasma olaparib concentration was assayed using liquid chromatography at any time over the dosing interval. Trough concentrations (CminPred) were estimated using a population pharmacokinetic model. The association between toxicity and clinical characteristics or CminPred was assessed by logistic regression and non-parametric statistical tests. Twenty-seven patients were included, among whom 13 (48%) experienced SAE during the first six months of treatment. Olaparib CminPred was the only covariate significantly associated with increased risk of SAE onset (odds ratio = 1.31, 95%CI = [1.10; 1.57], for each additional 1000 ng/mL). The ROC curve identified a threshold of CminPred = 2500 ng/mL for prediction of SAE onset (sensitivity/specificity 0.62 and 1.00, respectively). This study highlights a significant association between olaparib plasma exposure and SAE onset and identified the threshold of 2500 ng/mL trough concentration as potentially useful to guide dose adjustment in ovarian cancer patients.

Prevalence of drug-drug interactions in sarcoma patients: key role of the pharmacist integration for toxicity risk management.

BACKGROUND: The risk of drug-drug interactions (DDI) has become a major issue in cancer patients. However, data in sarcoma patients are scarce. We aimed to evaluate the frequency and the factors associated with DDI with antitumor treatments, and to evaluate the impact of a pharmacist evaluation before anticancer treatment. PATIENTS AND METHODS: We performed a retrospective review of consecutive sarcoma patients starting chemotherapy (CT) or Tyrosine kinase inhibitor (TKI). A pharmacist performed medication reconciliation and established an early toxicity risk assessment. Potential DDI with antitumor drugs were identified using Micromedex electronic software. RESULTS: One hundred and twenty-two soft-tissue and 80 bone sarcoma patients (103 males, median age 50 years,) were included before CT (86%) or TKI (14%). The median number of medications was 3; 34 patients (22% of patients with medication reconciliation) reported complementary medicine use. 37 potential DDI classified as major, were identified (12% of the 243 pre-therapeutic assessments). In multivariate analysis, TKI (p < 0.0001), proton pump inhibitor (p = 0.026) and antidepressant (p < 0.001) were identified as risk factors of DDI (p < 0.02). Only marital status (p = 0.003) was associated with complementary medicine use. A pharmacist performed 157 medication reconciliations and made 71 interventions among 59 patients (37%). In multivariate analysis, factors associated with pharmacist intervention were: complementary medicines (p = 0.004), drugs number (p = 0.005) and treatment with TKI (p = 0.0002) CONCLUSIONS: Clinical interventions on DDI are more frequently required among sarcoma patients treated with TKI than CT. Multidisciplinary risk assessment including a medication reconciliation by a pharmacist could be crucial to prevent DDI with TKI.

Analysis of Pembrolizumab in Human Plasma by LC-MS/HRMS. Method Validation and Comparison with Elisa.

Pembrolizumab is a humanized immunoglobulin G4-kappa anti-PD1 antibody used in the treatment of different solid tumors or haematological malignancies. A liquid chromatography coupled with a high resolution mass spectrometry (orbitrap technology) method was fully developed, optimized, and validated for quantitative analysis of pembrolizumab in human plasma. A mass spectrometry assay was used for the first time a full-length stable isotope-labelled pembrolizumab-like (Arginine 13C6-15N4 and Lysine 13C6-15N2) as an internal standard; the sample preparation was based on albumin depletion and trypsin digestion and, finally, one surrogate peptide was quantified in positive mode. The assay showed good linearity over the range of 1-100 µg/mL, a limit of quantification at 1 µg/mL, excellent accuracy from 4.4% to 5.1%, and also a between-day precision below 20% at the limit of quantification. In parallel, an in-house ELISA was developed with a linearity range from 2.5 to 50 µg/mL. Then, results were obtained from 70 plasma samples of cancer patients that were treated with pembrolizumab and quantified with both methods were compared using the Passing-Bablok regression analysis and Bland-Altman plotting. The LC-MS/HRMS method is easy to implement in the laboratory for use in the context of PK/PD studies, clinical trials, or therapeutic drug monitoring.