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.).

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.

Erlotinib pharmacokinetics: a critical parameter influencing acute toxicity in elderly patients over 75 years-old.

Background Older non-small cell lung cancer (NSCLC) patients under erlotinib are reported to experience more acute toxicity. We hypothesized that modifications in erlotinib pharmacokinetics might explain this observation. Methods A monocentric prospective clinico-pharmacological study included stage IIIb/IV NSCLC consecutive pts. treated with erlotinib. The plasma concentration of erlotinib (Ce) was measured at steady state on day 15. We studied the relationship between age > 75 years, and Ce, using the Mann-Whitney U test and with the occurrence of acute toxicity, using a Fisher's test. Results A total of 53 pts. were analyzed. Median age was 68 years (31-83), 56 % were female. All pts. > 75 years experienced toxicity: all grade acute adverse events were 1.6 fold more frequent (100 % vs 61 %; OR 95 % CI [1.9-INF]; p = 0.003). At day 15, Ce increased with age. Over 75 years old, the mean Ce was 1.5 fold higher: 2091 ng/mL (95 % CI [1476; 2706]) vs 1359 (95 % CI [1029; 1689]; p = 0.024). In pts. over 80 years old, the mean Ce was doubled: 2729 (95 % CI [1961; 3497]) vs 1358 ng/mL (95 % CI [1070; 1646]; p = 0.0019). Reduced lean body mass over 75 years (median 36.6 kg versus 49.1 kg) might account for these differences. Finally, the risk of early erlotinib discontinuation was increased by 11 in older pts. (33 % vs 3 % OR 17.2; 95 % CI [1.7; 892.5] p = .005). Conclusion The risk of overexposure to erlotinib increases with age. Reduced lean body mass may explain erlotinib pharmacokinetics and excessive acute toxicity in the elderly.

ADAM9 expression promotes an aggressive lung adenocarcinoma phenotype.

A disintegrin and metalloproteinase 9 (ADAM9) possesses potent metastasis-inducing capacities and is highly expressed in several cancer cells. Previous work has shown that ADAM9 participates in the adhesive-invasive phenotype in lung cancer cells in vitro. In this study, we evaluated whether ADAM9 expression plays a critical role in metastatic processes in vivo and in angiogenesis. We first found that high ADAM9 expression was correlated with poor lung adenocarcinoma patient prognosis on Prognoscan data base. In vivo model based on intravenous injection in nude mice showed that a stable downregulation of ADAM9 in A549 (TrA549 A9-) cells was associated with a lower number of nodules in the lung, suggesting lower potentials for extravasation and metastasis. On a subcutaneous xenograft we showed that TrA549 A9- produced significantly smaller tumours and exhibited fewer neovessels. In addition, in vitro human umbilical vein endothelial cells exposed to supernatant from TrA549 A9- could reduce the formation of more vessel-like structures. To further understand the mechanism, a human antibody array analysis confirmed that five cytokines were downregulated in TrA549 A9- cells. Interleukin 8 was the most significantly downregulated, and its interaction with CXCR2 was implicated in angiogenesis on an in vitro model. These results emphasize the critical influence of ADAM9 on lung cancer progression and aggressiveness. ADAM9 should at least be a marker of cancer aggressiveness and a potential therapeutic target for cancer treatment.

Plasma vemurafenib exposure and pre-treatment hepatocyte growth factor level are two factors contributing to the early peripheral lymphocytes depletion in BRAF-mutated melanoma patients.

The therapeutic response to vemurafenib, a BRAF serine-threonine kinase inhibitor, exhibits large variations between patients. Evaluation of factors predicting the clinical efficacy of vemurafenib may help to identify patients at high risk of non-response in the early phase of treatment. The aim of this study was to analyze the pharmacokinetics of vemurafenib by a population approach and to evaluate the relationship between plasma drug exposure and pre-treatment plasma hepatocyte growth factor (HGF) levels with clinical effects (progression-free survival (PFS), peripheral lymphocytes depletion) in patients with metastatic BRAFV600 mutated melanoma treated with single agent vemurafenib. Concentration-time data (n=332) obtained in 44 patients were analyzed using the NONMEM program. Pre-treatment plasma levels of HGF (n=36) were assayed by ELISA method. A Cox model was used to identify prognostic factors associated with progression-free survival (PFS), and a linear regression to identify factors contributing to the depletion of peripheral lymphocytes at day 15. Steady-state pharmacokinetics of vemurafenib was described by a one compartment model with first order absorption and first order elimination. None of the tested covariates explained the inter-patient variability in CL/F. A significant decrease in total lymphocytes count was observed within the first 15days (median ratio Day15/Day0=0.66, p<0.0001). Patients with Day15/Day0 ratio below 0.66 had longer PFS (14 vs 4 months, HR=0.41, CI95%=[0.15-0.77], p=0.0095). In the multivariate Cox model analysis, ECOG PS was the only parameter independently associated with PFS (grade 1 vs 0, HR=3.26, CI95%=[1.29-8.22], p=0.01 and grade ≥2 vs 0, HR=4.77, CI95%=[1.52-14.95], p=0.007). Plasma vemurafenib exposure (p=0.046) and pre-treatment HGF levels (p=0.003) were independently associated with the total lymphocyte ratio Day15/Day0. These findings show that plasma vemurafenib exposure and pre-treatment HGF levels are two factors contributing to the early peripheral lymphocytes depletion which itself is associated with PFS.

Arsenic trioxide exerts antitumor activity through regulatory T cell depletion mediated by oxidative stress in a murine model of colon cancer.

Immunotherapy is a promising antitumor strategy that can successfully be combined with current anticancer treatment. In this study, arsenic trioxide (As(2)O(3)) was shown to increase the antitumor immune response in CT26 colon tumor-bearing mice through the modulation of regulatory T cell (T(reg)) numbers. As(2)O(3) induced T(reg)-selective depletion in vitro. In vivo, tumor-bearing mice injected with 1 mg/kg As(2)O(3) showed a significant decrease in the T(reg)/CD4 cell ratio and in absolute T(reg) count versus controls. As(2)O(3) exerted antitumor effects only in immunocompetent mice and enhanced adoptive immunotherapy effects. Inhibition of As(2)O(3)-induced T(reg) depletion by the NO synthase inhibitor N(G)-nitro-l-arginine methyl ester and the superoxide dismutase mimic manganese [III] tetrakis-(5, 10, 15, 20)-benzoic acid porphyrin suggested that it was mediated by oxidative and nitrosative stress. The differential effect of As(2)O(3) on T(reg) versus other CD4 cells may be related to differences in the cells' redox status, as indicated by significant differences in 2'7'dichlorodihydrofluorescein diacetate and 4,5-diaminofluorescein diacetate fluorescence levels. In conclusion, these results show for the first time, to our knowledge, that low doses As(2)O(3) can delay solid tumor growth by depleting T(regs) through oxidative and nitrosative bursts, and suggest that As(2)O(3) could be used to enhance the antitumor activity of adoptive immunotherapy strategies in human cancer.

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.

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.

Bystander effect of vinorelbine alters antitumor immune response.

The bystander effect (BE) is the ability of malignant cells affected by an anticancer agent to induce damage in neighboring cancer cells. In this study, we showed that it could also affect immune cells surrounding the tumor and interfere with the antitumor immune response. We observed that the exposure of human lung cancer cells A549 to vinorelbine induced a BE on neighboring human peripheral blood mononuclear cells (PBMCs) in vitro and on mice splenocytes in vivo. In vitro, the number of PBMCs killed because of their coculture with vinorelbine-pretreated A549 cells was 33% higher than those killed by A549 control cells (p = 0.003). In addition, we showed that when vinorelbine-pretreated A549 cells were injected into immunocompetent mice, splenocyte proliferation ex vivo toward tumor cells decreased by 27% compared with that seen in mice injected with untreated A549 cells (p = 0.03). Finally, in vivo experiment in A549 tumor bearing nude mice showed that adoptive transfer of A549 immune splenocytes was not able to delay tumor growth when vinorelbine-pretreated A549 cells were used for immunization. Inhibition of the BE by the nitric oxide synthase inhibitor, N(G)-nitro-L-arginine methyl ester, and the superoxide dismutase mimic, mangafodipir, suggested that it was mediated by oxidative and nitrosative stress. In conclusion, exposure of cancer cells to vinorelbine alters the antitumor immune response through a BE mediated by cellular oxidative and nitrosative stress. Our results offer new prospects for using oxidative stress modulators to restore the antitumor immune response in patients treated with anticancer agents.

Functional and clinical evidence of the influence of sorafenib binding to albumin on sorafenib disposition in adult cancer patients.

PURPOSE: Sorafenib, an oral multitargeted tyrosine kinase inhibitor, is highly bound to plasma proteins (>99.5%). Little is known about the influence of variations in sorafenib protein binding on its disposition. The aims of this study were to characterize in vitro sorafenib binding properties to albumin using the quenching fluorescence method and investigate the influence of albuminemia and bilirubinemia on sorafenib disposition in 54 adult cancer patients. RESULTS: In vitro estimate of sorafenib dissociation constant (Kd) for albumin was 0.22 µM [CI95 0.20-0.23]. In physiological conditions, sorafenib unbound fraction would increase 1.7-fold as albuminemia decreased from 45 g/L (680 µM) to 30 g/L (453 µM). In presence of bilirubin, apparent Kd of sorafenib was ~1.5-fold greater for bilirubin/albumin molar ratio of 1:4. In clinical settings, median sorafenib clearance (CL) was 1.42 L/h (0.75-2.13 L/h). In univariate analysis, sex, body mass index, and albuminemia were associated with CL (p = 0.04, 0.048, and 0.008, respectively). In multivariate analysis, albuminemia (p = 0.0036) was the single parameter independently associated with CL. CONCLUSION: These findings highlight the major influence of albuminemia on sorafenib clearance and its disposition in 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.

The impact of body composition parameters on severe toxicity of nivolumab.

BACKGROUND: The occurrence of severe, acute limiting toxicity in patients receiving anti-programmed cell death receptor-1 monoclonal antibodies, such as nivolumab, is largely unpredictable. Sarcopenia was found to be associated with anti-cytotoxic T-lymphocyte-associated protein 4 acute toxicity. We explore the clinical and pharmacological parameters influencing nivolumab toxicity, including body composition. METHODS: From June 2015 to January 2017, all consecutive patients treated with nivolumab in our institution were prospectively included. We studied the relationship between muscle mass assessed by computed tomography, nivolumab trough level (Cmin) at day 14 assessed using the enzyme-linked immunosorbent assay method, and the occurrence of immune grade III or IV toxicity or any toxicity leading to treatment discontinuation (immune-related acute limiting toxicity [irALT]). RESULTS: In our population (n = 92) with a majority of lung cancer (72%), forty-five (51.7%) patients were sarcopenic. The median plasma nivolumab Cmin at day 14 was 15.4 µg/mL (interquartile range = 11.8-21.0). In multivariate analysis, hypoalbuminaemia (<35 g/L) was independently associated with low nivolumab Cmin on day 14 (odds ratio [OR] = 0.09; 95% confidence interval [CI] = 0.01-0.59, p = 0.01) and overweight/obesity with high nivolumab Cmin on day 14 (OR = 5.94; 95% CI = 1.25-28.29, p = 0.03). We observed 22 irALTs in 19 patients (21%). The most frequent irALT was respiratory (6.5%) disorders and gastrointestinal (4.3%) disorders. Patients with sarcopenia were at significantly increased risk of experiencing an irALT (OR = 3.84; 95% CI = 1.02-14.46, p = 0.047). No association was found between toxicity and nivolumab plasma Cmin at day 14. CONCLUSIONS: Our results highlight the importance of assessing body composition and suggest that sarcopenia could predict severe immune-related toxicity of nivolumab in real life.

Predictive Value of Soluble PD-1, PD-L1, VEGFA, CD40 Ligand and CD44 for Nivolumab Therapy in Advanced Non-Small Cell Lung Cancer: A Case-Control Study.

A large interindividual variability has been observed in anti Programmed cell Death 1 (anti-PD1) therapies efficacy. The aim of this study is to assess the correlation of soluble PD-1 (sPD-1), soluble Programmed cell Death Ligand 1 (sPD-L1), Vascular Endothelial Growth Factor A (VEGFA), soluble CD40 ligand (sCD40L) and soluble CD44 (sCD44), with survival in nivolumab-treated metastatic non-small cell lung cancer (NSCLC) patients. Plasma biomarkers were assayed at baseline and after two cycles of nivolumab. A cut-off of positivity for sPD-1, sPD-L1 and sCD40L expressions was defined as a plasma level above the lower limit of quantification. Baseline sPD-1 and sPD-L1 levels were subsequently analyzed in a control group of EGFR-mutated (Epidermal Growth Factor Receptor) NSCLC patients. Association between survival and biomarkers was investigated using Cox proportional hazard regression model. Eighty-seven patients were included (51 nivolumab-treated patients, 36 in EGFR-mutated group). In nivolumab group, baseline sPD-1, sPD-L1 and sCD40L were positive for 15(29.4%), 27(52.9%) and 18(50%) patients, respectively. We defined a composite criteria (sCombo) corresponding to sPD-1 and/or sPD-L1 positivity for each patient. In nivolumab group, baseline sCombo positivity was associated with shorter median progression-free survival (PFS) (78 days 95%CI (55-109) vs. 658 days (222-not reached); HR: 4.12 (1.95-8.71), p = 0.0002) and OS (HR: 3.99(1.63-9.80), p = 0.003). In multivariate analysis, baseline sCombo independently correlated with PFS (HR: 2.66 (1.17-6.08), p = 0.02) but not OS. In EGFR-mutated group, all patients were baseline sCombo positive; therefore this factor was not associated with survival. After two cycles of nivolumab, an increased or stable sPD-1 level independently correlated with longer PFS (HR: 0.49, 95%CI (0.30-0.80), p = 0.004) and OS (HR: 0.39, 95%CI (0.21-0.71), p = 0.002). VEGFA, sCD40L and sCD44 did not correlate with survival. We propose a composite biomarker using sPD-1and sPDL-1 to predict nivolumab efficacy in NSCLC patients. A larger validation study is warranted.

Cancer, immune suppression and Coronavirus Disease-19 (COVID-19): Need to manage drug safety (French Society for Oncology Pharmacy [SFPO] guidelines).

The Coronavirus disease (COVID-19) pandemic is disrupting our health environment. As expected, studies highlighted the great susceptibility of cancer patients to COVID-19 and more severe complications, leading oncologists to deeply rethink patient cancer care. This review is dedicated to the optimization of care pathways and therapeutics in cancer patients during the pandemic and aims to discuss successive issues. First we focused on the international guidelines proposing adjustments and alternative options to cancer care in order to limit hospital admission and cytopenic treatment in cancer patients, most of whom are immunocompromised. In addition cancer patients are prone to polypharmacy, enhancing the risk of drug-related problems as adverse events and drug-drug interactions. Due to increased risk in case of COVID-19, we reported a comprehensive review of all the drug-related problems between COVID-19 and antineoplastics. Moreover, in the absence of approved drug against COVID-19, infected patients may be included in clinical trials evaluating new drugs with a lack of knowledge, particularly in cancer patients. Focusing on the several experimental drugs currently being evaluated, we set up an original data board helping oncologists and pharmacists to identify promptly drug-related problems between antineoplastics and experimental drugs. Finally additional and concrete recommendations are provided, supporting oncologists and pharmacists in their efforts to manage cancer patients and to optimize their treatments in this new era related to COVID-19.

Clinical Pharmacokinetics and Pharmacodynamics of Dabrafenib.

Dabrafenib is a potent and selective inhibitor of BRAF-mutant kinase that is approved, as monotherapy or in combination with trametinib (mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor), for unresectable or metastatic BRAF-mutated melanoma, advanced non-small cell lung cancer and anaplastic thyroid cancer harbouring the BRAFV600E mutation. The recommended dose of dabrafenib is 150 mg twice daily (bid) under fasted conditions. After single oral administration of the recommended dose, the absolute oral bioavailability (F) of dabrafenib is 95%. Dabrafenib shows a time-dependent increase in apparent clearance (CL/F) following multiple doses, which is likely due to induction of its own metabolism through cytochrome P450 (CYP) 3A4. Therefore, steady state is reached only after 14 days of daily dose administration. Moreover, the extent of this auto-induction process is dependent on the dose, which explains why dabrafenib systemic exposure at steady state increases less than dose proportionally over the dose range of 75-300 mg bid. The main elimination route of dabrafenib is the oxidative metabolism via CYP3A4/2C8 and biliary excretion. Among the three major metabolites identified, hydroxy-dabrafenib appears to contribute to the pharmacological activity. Age, sex and body weight did not have any clinically significant influence on plasma exposure to dabrafenib. No dose adjustment is needed for patients with mild renal or hepatic impairment, whereas the impacts of severe impairment on dabrafenib pharmacokinetics remain unknown. Considering that dabrafenib is a substrate of CYP3A4/2C8 and is a CYP3A4/2B6/2C inducer, drug-drug interactions are expected with dabrafenib. The relationship between clinical outcomes and plasma exposure to dabrafenib and hydroxy-dabrafenib should be investigated more deeply.

Differential Kinase Activation in Peripheral Blood Mononuclear Cells from Non-Small-Cell Lung Cancer Patients Treated with Nivolumab.

In the era of precision medicine, research of biomarkers for identification of responders to nivolumab therapy is a major challenge. Peripheral blood mononuclear cells (PBMC) could be an interesting surrogate tissue for identifying pharmacodynamic biomarkers. The aim of this exploratory study was to investigate the global serine/threonine kinase (STK) activity in PBMC from non-small-cell lung cancer (NSCLC) patients using a high throughput kinomic profiling method. PamChip® microarrays were used to explore the STK kinomic profile in PBMC from 28 NSCLC patients before nivolumab initiation (D0) and on day 14 (D14) of the first administration. Two clusters of patients (A and B) were identified at D0, median overall survival (OS) tended to be longer in cluster A than in B (402 vs. 112.5 days, respectively; p = 0.15). Interestingly, the PD-L1 tumor cell score (p = 0.045), the count of CD8+ cells (p = 0.023) and the total body weight (p = 0.038) were statistically different between the clusters. On D14, clusters C and D were identified. Greater activity of most STK, especially those of the PI3K/Akt signaling pathway, was noticed among cluster C. No significant difference between C and D was observed regarding OS. Considering the small number of patients, results from this preliminary study are not conclusive. However, the 4-fold longer median OS in cluster A paves the way to further investigate, in a larger cohort of NSCLC patients, the benefit of basal STK kinomic profile in PBMC to identify responders to nivolumab therapy.

Pharmacokinetics and Pharmacodynamics of Once-daily Prolonged-release Tacrolimus in Liver Transplant Recipients.

PURPOSE: Limited published data are available regarding the pharmacokinetic (PK) and pharmacodynamic (PD) variables of prolonged-release tacrolimus (PRT) after liver transplantations. The goal of this study was to compare the PK and PD profiles of PRT in early and stable liver transplant recipients by developing a population PK model of PRT and investigating the profile of calcineurin activity (CNA) in the peripheral blood mononuclear cells. METHODS: A conversion from BID immediate-release tacrolimus (IRT) to once-daily PRT based on a one-to-one daily dose was performed at day 7 (D7) and D90 posttransplantation in groups A (n = 12) and B (n = 12), respectively. Extensive PK samplings, including whole-blood tacrolimus (TAC) concentration, and CNA assessments were performed at D14 and D104 in groups A and B, respectively. TAC concentration-time data (N = 221) were analyzed by using nonlinear mixed effects modeling. FINDINGS: A 2-compartment model with linear elimination and a delayed first-order absorption characterized by 2 transit compartments best described the PK data. Model-predicted dose-normalized (6.0 mg/d) area under the TAC concentration-time curve over the dosing interval in groups A and B was similar (geometric mean, 235.6 ng/mL · h [95% CI, 139.6-598.7] vs 224.6 ng/mL · h [95% CI, 117.6-421.5], respectively; P = 0.94). Area under the CNA versus time curve over the dosing interval did not differ between groups (4897 [3437] and 4079 [1008] pmol/min/106 cells; P = 0.50). In group A, trough CNA at D14 posttransplantation was statistically higher than that measured just before the switch to PRT (ie, D7 posttransplantation) (198 [92] vs 124 [72] pmol/min/106cells, n = 8; P = 0.048); no statistical difference in TAC concentration was observed (P = 0.11). In group B, no statistical difference between D90 and D104 was observed in either trough CNA (149 [78] vs 172 [82] pmol/min/106 cells, n = 6; P = 0.18) or TAC (P = 0.17) concentration. No graft rejection was observed in either of the groups. IMPLICATIONS: This study suggests that one-to-one dosage conversion to once-daily PRT during the early posttransplantation period could result in significant CNA variations but without causing graft rejection. Further investigations in larger cohorts are warranted to confirm these results. ClinicalTrials.gov identifier: NCT02105155.

Is there an Exposure-Response Relationship for Nivolumab in Real-World NSCLC Patients?

Pharmacokinetic/pharmacodynamic data from real-world cohort are sparse in non small-cell lung cancer (NSCLC) patients treated with nivolumab. The aim of this prospective observational study was to explore the exposure-response relationship for effectiveness and toxicity of nivolumab in 81 outpatients with metastatic lung cancer. Nivolumab plasma trough concentrations (Cmin) were assayed at days 14, 28, and 42. Prognostic factors (including Cmin) regarding progression-free survival (PFS) and overall survival (OS) were explored using a multivariate Cox model. A Spearman's rank test was used to investigate the relationship between Cmin and grade >2 immune-related adverse events (irAE). Mean nivolumab Cmin was 16.2 ± 6.0 µg/mL (n = 76), 25.6 ± 10.2 µg/mL (n = 64) and 33.4 ± 11.3 µg/mL (n = 53) at days 14, 28, and 42, respectively. No pharmacokinetic/pharmacodynamic (PK/PD) relationship was observed with either survival or onset of irAE. Multivariable Cox regression analysis identified Eastern Cooperative Oncology Group Performance Status (hazard ratio 1.85, 95%confidence interval 1.02-3.38, p-value = 0.043) and baseline use of corticosteroids (HR 8.08, 95%CI 1.78-36.62, p-value = 0.007) as independent risk factor for PFS and only baseline use of corticosteroids (HR 6.29, 95%CI 1.46-27.08, p-value = 0.013) for OS. No PK/PD relationship for nivolumab was observed in real-world NSCLC patients. This supports the recent use of flat dose regimens without plasma drug monitoring.