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.

The potential of microbiota information to better predict efficiency traits in growing pigs fed a conventional and a high-fiber diet.

BACKGROUND: Improving pigs' ability to digest diets with an increased dietary fiber content is a lever to improve feed efficiency and limit feed costs in pig production. The aim of this study was to determine whether information on the gut microbiota and host genetics can contribute to predict digestive efficiency (DE, i.e. digestibility coefficients of energy, organic matter, and nitrogen), feed efficiency (FE, i.e. feed conversion ratio and residual feed intake), average daily gain, and daily feed intake phenotypes. Data were available for 1082 pigs fed a conventional or high-fiber diet. Fecal samples were collected at 16 weeks, and DE was estimated using near­infrared spectrometry. A cross-validation approach was used to predict traits within the same diet, for the opposite diet, and for a combination of both diets, by implementing three models, i.e. with only genomic (Gen), only microbiota (Micro), and both genomic and microbiota information (Micro+Gen). The predictive ability with and without sharing common sires and breeding environment was also evaluated. Prediction accuracy of the phenotypes was calculated as the correlation between model prediction and phenotype adjusted for fixed effects. RESULTS: Prediction accuracies of the three models were low to moderate (< 0.47) for growth and FE traits and not significantly different between models. In contrast, for DE traits, prediction accuracies of model Gen were low (< 0.30) and those of models Micro and Micro+Gen were moderate to high (> 0.52). Prediction accuracies were not affected by the stratification of diets in the reference and validation sets and were in the same order of magnitude within the same diet, for the opposite diet, and for the combination of both diets. Prediction accuracies of the three models were significantly higher when pigs in the reference and validation populations shared common sires and breeding environment than when they did not (P < 0.001). CONCLUSIONS: The microbiota is a relevant source of information to predict DE regardless of the diet, but not to predict growth and FE traits for which prediction accuracies were similar to those obtained with genomic information only. Further analyses on larger datasets and more diverse diets should be carried out to complement and consolidate these results.

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.

Association Between Severe Nonadherence to Hydroxychloroquine and Systemic Lupus Erythematosus Flares, Damage, and Mortality in 660 Patients From the SLICC Inception Cohort.

OBJECTIVE: The goals of this study were to assess the associations of severe nonadherence to hydroxychloroquine (HCQ), objectively assessed by HCQ serum levels, and risks of systemic lupus erythematosus (SLE) flares, damage, and mortality rates over five years of follow-up. METHODS: The Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort is an international multicenter initiative (33 centers throughout 11 countries). The serum of patients prescribed HCQ for at least three months at enrollment were analyzed. Severe nonadherence was defined by a serum HCQ level <106 ng/mL or <53 ng/mL for HCQ doses of 400 or 200 mg/day, respectively. Associations with the risk of a flare (defined as a Systemic Lupus Erythematosus Disease Activity Index 2000 increase ≥4 points, initiation of prednisone or immunosuppressive drugs, or new renal involvement) were studied with logistic regression, and associations with damage (first SLICC/American College of Rheumatology Damage Index [SDI] increase ≥1 point) and mortality with separate Cox proportional hazard models. RESULTS: Of the 1,849 cohort participants, 660 patients (88% women) were included. Median (interquartile range) serum HCQ was 388 ng/mL (244-566); 48 patients (7.3%) had severe HCQ nonadherence. No covariates were clearly associated with severe nonadherence, which was, however, independently associated with both flare (odds ratio 3.38; 95% confidence interval [CI] 1.80-6.42) and an increase in the SDI within each of the first three years (hazard ratio [HR] 1.92 at three years; 95% CI 1.05-3.50). Eleven patients died within five years, including 3 with severe nonadherence (crude HR 5.41; 95% CI 1.43-20.39). CONCLUSION: Severe nonadherence was independently associated with the risks of an SLE flare in the following year, early damage, and five-year mortality.

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.

Association Between Plasma Rituximab Concentration and the Risk of Major Relapse in Antineutrophil Cytoplasmic Antibody-Associated Vasculitides During Rituximab Maintenance Therapy.

OBJECTIVE: Interindividual variability in response to rituximab remains unexplored in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides. Rituximab pharmacokinetics (PK) and pharmacodynamics (PD) as well as genetic polymorphisms could contribute to variability. This ancillary study of the MAINRITSAN 2 trial aimed to explore the relationship between rituximab plasma concentration, genetic polymorphisms in PK/PD candidate genes, and clinical outcomes. METHODS: Patients included in the MAINRITSAN2 trial (ClinicalTrials.gov identifier: NCT01731561) were randomized to receive a 500-mg fixed-schedule rituximab infusion or an individually tailored regimen. Rituximab plasma concentrations at month 3 (CM3) were assessed. DNA samples (n = 53) were genotyped for single-nucleotide polymorphisms within 88 putative PK/PD candidate genes. The relationship between PK/PD outcomes and genetic variants was investigated using logistic linear regression in additive and recessive genetic models. RESULTS: One hundred and thirty-five patients were included. The frequency of underexposed patients (<4 µg/ml) in the fixed-schedule group was statistically lower compared to that in the tailored-infusion group (2.0% versus 18.0%; P = 0.02, respectively). Low rituximab plasma concentration at 3 months (CM3 <4 µg/ml) was an independent risk factor for major relapse (odds ratio 6.56 [95% confidence interval (95% CI) 1.26-34.09]; P = 0.025) at month 28 (M28). A sensitivity survival analysis also identified CM3 <4 µg/ml as an independent risk factor for major relapse (hazard ratio [HR] 4.81 [95% CI 1.56-14.82]; P = 0.006) and relapse (HR 2.70 [95% CI 1.02-7.15]; P = 0.046). STAT4 rs2278940 and PRKCA rs8076312 were significantly associated with CM3 but not with major relapse onset at M28. CONCLUSION: These results suggest that drug monitoring could be useful to individualize the schedule of rituximab administration within the maintenance phase.

LC-MS/MS method for simultaneous quantification of osilodrostat and metyrapone in human plasma from patients treated for Cushing's Syndrome.

Steroidogenesis inhibitors such as metyrapone (MTP) and osilodrostat (ODT) have a key role in the medical treatment of endogenous Cushing's Syndrome (ECS). Both drugs are characterized by a high inter-individual variability of response and require a dose-titration period to achieve optimal control of cortisol excess. However, PK/PD data remain scarce for both molecules and a pharmacokinetically guided approach could help reaching eucortisolism more rapidly. We aimed to develop and validate a liquid chromatography tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantification of ODT and MTP in human plasma. After addition of isotopically labeled internal standard (IS), plasma pretreatment consisted in protein precipitation with acetonitrile including 1% formic acid (v/v). Chromatographic separation was performed on Kinetex® HILIC (4.6 × 50 mm; 2.6 µm) analytical column with an isocratic elution during the 2.0-min run time. The method was linear from 0.5 to 250 ng/mL for ODT and from 2.5 to 1250 ng/mL for MTP. Intra- and inter-assay precisions were < 7.2%, with an accuracy ranging from 95.9% to 114.9%. The IS-normalized matrix effect ranged from 106.0% to 123.0% (ODT) and from 107.0% to 123.0% (MTP) and the range of the IS-normalized extraction recovery was 84.0-101.0% for ODT and 87.0-101.0% for MTP. The LC-MS/MS method was successfully applied in patients' plasma samples (n = 36), trough concentration of ODT and MTP ranged from 2.7 ng/mL to 8.2 ng/mL and from 10.8 ng/mL to 27.8 ng/mL, respectively. Incurred sample reanalysis exhibits less than 14% difference between the first and the second analysis for both drugs. This accurate and precise method, meeting all validation criteria, can therefore be used for plasma drug monitoring of ODT and MTP within the dose-titration period.

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.

Low-dose mycophenolate mofetil improves survival in a murine model of Staphylococcus aureus sepsis by increasing bacterial clearance and phagocyte function.

Regulators of TLRs signaling pathways play an important role in the control of the pro-inflammatory response that contributes to sepsis-induced tissue injury. Mycophenolate mofetil, an immunosuppressive drug inhibiting lymphocyte proliferation, has been reported to be a regulator of TLRs signaling pathways. Whether MMF used at infra-immunosuppressive doses has an impact on survival and on innate immune response in sepsis is unknown. C57BL/6J mice were infected intraperitoneally with 108 CFU Staphylococcus aureus, and treated or not with low-dose of MMF (20mg/kg/day during 4 days). Survival rate and bacterial clearance were compared. Cytokine levels, quantitative and qualitative cellular responses were assessed. S. aureus - infected mice treated with MMF exhibited improved survival compared to non-treated ones (48% vs 10%, p<0.001). With the dose used for all experiments, MMF did not show any effect on lymphocyte proliferation. MMF treatment also improved local and systemic bacterial clearance, improved phagocytosis activity of peritoneal macrophages resulting in decreased inflammatory cytokines secretion. MMF-treated mice showed enhanced activation of NF-κB seemed with a suspected TLR4-dependent mechanism. These results suggest that infra-immunosuppressive doses of MMF improve host defense during S. aureus sepsis and protects infected mice from fatal outcome by regulating innate immune responses. The signaling pathways involved could be TLR4-dependent. This work brings new perspectives in pathogenesis and therapeutic approaches of severe infections.

Gut microbiota and host genetics contribute to the phenotypic variation of digestive and feed efficiency traits in growing pigs fed a conventional and a high fiber diet.

BACKGROUND: Breeding pigs that can efficiently digest alternative diets with increased fiber content is a viable strategy to mitigate the feed cost in pig production. This study aimed at determining the contribution of the gut microbiota and host genetics to the phenotypic variability of digestive efficiency (DE) traits, such as digestibility coefficients of energy, organic matter and nitrogen, feed efficiency (FE) traits (feed conversion ratio and residual feed intake) and growth traits (average daily gain and daily feed intake). Data were available for 791 pigs fed a conventional diet and 735 of their full-sibs fed a high-fiber diet. Fecal samples were collected at 16 weeks of age to sequence the V3-V4 regions of the 16S ribosomal RNA gene and predict DE with near-infrared spectrometry. The proportions of phenotypic variance explained by the microbiota (microbiability) were estimated under three OTU filtering scenarios. Then, microbiability and heritability were estimated independently (models Micro and Gen) and jointly (model Micro+Gen) using a Bayesian approach for all traits. Breeding values were estimated in models Gen and Micro+Gen. RESULTS: Differences in microbiability estimates were significant between the two extreme filtering scenarios (14,366 and 803 OTU) within diets, but only for all DE. With the intermediate filtering scenario (2399 OTU) and for DE, microbiability was higher (> 0.44) than heritability (< 0.32) under both diets. For two of the DE traits, microbiability was significantly higher under the high-fiber diet (0.67 ± 0.06 and 0.68 ± 0.06) than under the conventional diet (0.44 ± 0.06). For growth and FE, heritability was higher (from 0.26 ± 0.06 to 0.44 ± 0.07) than microbiability (from 0.17 ± 0.05 to 0.35 ± 0.06). Microbiability and heritability estimates obtained with the Micro+Gen model did not significantly differ from those with the Micro and Gen models for all traits. Finally, based on their estimated breeding values, pigs ranked differently between the Gen and Micro+Gen models, only for the DE traits under both diets. CONCLUSIONS: The microbiota explained a significant proportion of the phenotypic variance of the DE traits, which was even larger than that explained by the host genetics. Thus, the use of microbiota information could improve the selection of DE traits, and to a lesser extent, of growth and FE traits. In addition, our results show that, at least for DE traits, filtering OTU is an important step and influences the microbiability.

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.

Quantification of infliximab and adalimumab in human plasma by a liquid chromatography tandem mass spectrometry kit and comparison with two ELISA methods.

Background: This study compared the performance of plasma infliximab and adalimumab quantification using a commercially available kit (mAbXmise kit) and mass spectrometry readout to that of two ELISA methods in patients treated for inflammatory bowel disease. Methods & results: The mAbXmise method based on liquid chromatography tandem mass spectrometry (LC-MS/MS) was linear from 2 to 100 µg/ml. It was validated according to international guidelines. Regarding cross-validation for infliximab (n = 70), the mean bias with LC-MS/MS assay was approximately threefold higher with the commercial ELISA assay compared with the in-house ELISA (-6.1 vs -1.8 µg/ml, respectively). The mean bias between the LC-MS/MS assay and in-house ELISA was -1.2 µg/ml for adalimumab (n = 35). Conclusion: The LC-MS/MS method is a powerful alternative to immunoassays to monitor concentrations of infliximab and adalimumab.