Treatment patterns of patients with HR+/HER2- metastatic breast cancer receiving CDK4/6 inhibitor-based regimens: a cohort study in the French nationwide healthcare database.

PURPOSE: To assess real-world treatment patterns in patients diagnosed with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer (mBC) who received cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in combination with an aromatase inhibitor (AI) or fulvestrant at first line. METHODS: Patient characteristics, treatment history, and outcomes data were extracted from the French 'Système National des Données de Santé' (SNDS) database for patients diagnosed with HR+/HER2- mBC between January 2014 and June 2019 and who received combination therapy with a CDK4/6 inhibitor and endocrine therapy. Kaplan-Meier methodology was used to assess time to next treatment (TTNT) and time to treatment discontinuation (TTTD). RESULTS: The cohort comprised 6061 patients including 4032 patients who received CDK4/6 inhibitors + AIs and 2029 patients who received CDK4/6 inhibitors + fulvestrant. Median follow-up was 13.5 months (IQR 9.5-18.1). The median TTTD of first line treatment with CDK4/6 inhibitors + AIs and CDK4/6 inhibitors + fulvestrant was 17.3 months (95% CI 16.8-17.9) and 9.7 months (95% CI 9.0-10.2), respectively. Chemotherapy was the most common second line therapy. Median TTTD of subsequent treatment lines was progressively shorter following first line treatment with CDK4/6 inhibitors + AIs (2nd line: 4.6 months (95% CI 4.4-4.9) and with CDK4/6 inhibitors + fulvestrant (2nd line: 4.7 months (95% CI 4.3-5.1). TTNT was longer than TTTD across lines of therapy. CONCLUSION: This real-world analysis confirms the effectiveness of CDK4/6 inhibitor-based regimens in French patients and highlights the frequent use of chemotherapy as second line therapy.

Incidence of stroke, subsequent clinical outcomes and health care resource utilization in people with type 2 diabetes: a real-world database study in France: "INSIST" study.

BACKGROUND: People with type 2 diabetes (T2D) are at elevated risk of cardiovascular disease (CVD) including stroke, yet existing real-world evidence (RWE) on the clinical and economic burden of stroke in this population is limited. The aim of this cohort study was to evaluate the clinical and economic burden of stroke among people with T2D in France. METHODS: We conducted a retrospective RWE study using data from the nationally representative subset of the French Système National des Données de Santé (SNDS) database. We assessed the incidence of stroke requiring hospitalization between 2012 and 2018 among T2D patients. Subsequent clinical outcomes including CVD, stroke recurrence, and mortality were estimated overall and according to stroke subtype (ischemic versus hemorrhagic). We also examined the treatment patterns for glucose-lowering agents and CVD agents, health care resource utilization and medical costs. RESULTS: Among 45,331 people with T2D without baseline history of stroke, 2090 (4.6%) had an incident stroke requiring hospitalization. The incidence of ischemic stroke per 1000 person-years was 4.9-times higher than hemorrhagic stroke (6.80 [95% confidence interval (CI) 6.47-7.15] versus 1.38 [1.24-1.54]). During a median follow-up of 2.4 years (interquartile range 0.6; 4.4) from date of index stroke, the rate of CVD, stroke recurrence and mortality per 1000 person-years was higher among hemorrhagic stroke patients than ischemic stroke patients (CVD 130.9 [107.7-159.0] versus 126.4 [117.2-136.4]; stroke recurrence: 86.7 [66.4-113.4] versus 66.5 [59.2-74.6]; mortality 291.5 [259.1-327.9] versus 144.1 [134.3-154.6]). These differences were not statistically significant, except for mortality (adjusted hazard ratio 1.95 [95% CI 1.66-2.92]). The proportion of patients prescribed glucagon-like peptide-1 receptor agonists increased from 4.2% at baseline to 6.6% during follow-up. The proportion of patients prescribed antihypertensives and statins only increased slightly following incident stroke (antihypertensives: 70.9% pre-stroke versus 76.7% post-stroke; statins: 24.1% pre-stroke versus 30.0% post-stroke). Overall, 68.8% of patients had a subsequent hospitalization. Median total medical costs were €12,199 (6846; 22,378). CONCLUSIONS: The high burden of stroke among people with T2D, along with the low proportion of patients receiving recommended treatments as per clinical guidelines, necessitates a strengthened and multidisciplinary approach to the CVD prevention and management in people with T2D.

Survival and treatment patterns of patients with relapsed or refractory multiple myeloma in France - a cohort study using the French National Healthcare database (SNDS).

Over the past decade, several drugs have been approved for the treatment of relapsed or refractory multiple myeloma (RRMM). This retrospective study, using the French National Healthcare database (SNDS), describes the treatment patterns and outcomes of patients with RRMM treated in real-world clinical practice in France. Patients were adults, with a diagnosis of multiple myeloma, who initiated second-line (2L) treatment approved for use in France between 2014 and 2018; this included bortezomib, carfilzomib, daratumumab, ixazomib, lenalidomide, or pomalidomide. Data were analyzed overall, by first-line (1L) autologous stem cell transplant (ASCT) status and by lenalidomide treatment status at 2L. In total, 12987 patients with RRMM were included in the study (mean age 69.5 years); 27% received an ASCT at 1L, and 30% received a lenalidomide-sparing regimen at 2L. Overall, and among the ASCT and non-ASCT subgroups, most patients received a bortezomib-based regimen at 1L, whereas lenalidomide-based regimens were most common at 2L. Among patients who received a lenalidomide-sparing regimen at 2L, this was most often a proteasome inhibitor-based regimen. Mortality rate was 26.1/100 person-years, and median (95% confidence interval) survival from 2L initiation was 32.4 (31.2-33.6) months. Survival differed by various factors, shorter survival was reported in the non-ASCT group, those receiving a lenalidomide-sparing regimen at 2L, older patients (≥ 70 years), and those with multiple comorbidities. This analysis provides insight into the real-world use of approved novel MM treatments and highlights an ongoing unmet need to improve outcomes, particularly for selected patient groups.

The Yin-Yang of CYP3A4: a Bayesian meta-analysis to quantify inhibition and induction of CYP3A4 metabolism in humans and refine uncertainty factors for mixture risk assessment.

Quantifying differences in pharmacokinetics (PK) and toxicokinetics (TK) provides a science-based approach to refine uncertainty factors (UFs) for chemical risk assessment. Cytochrome P450 (CYP) 3A4-the major hepatic and intestinal human CYP-and the P-glycoprotein (Pgp) transporter share a vast range of common substrates for which PK may be modulated through inhibition or induction in the presence of grapefruit juice (GFJ) or St. John's wort (SJW), respectively. Here, an extensive literature search was performed on PK interactions for CYP3A4 and Pgp substrates after oral co-exposure to GFJ and SJW. Relevant data from 109 publications, extracted for both markers of acute (Cmax) and chronic [clearance and area under the plasma concentration-time curve (AUC)] exposure, were computed into a Bayesian hierarchical meta-analysis model. Bioavailability (F) and substrate fraction metabolised by CYP3A4 (Fm) were identified as the variables exhibiting the highest impact on the magnitude of interaction. The Bayesian meta-regression model developed provided good predictions for magnitudes of inhibition (maximum 5.3-fold with GFJ) and induction (maximum 2.3-fold with SJW). Integration of CYP3A4 variability, F, Fm and magnitude of interaction provided the basis to derive a range of CYP3A4 and Pgp-related UFs. Such CYP3A4 and Pgp-related UFs can be derived in the absence of human data using in vitro TK evidence for CYP3A4/Pgp inhibition or induction as conservative in silico options. The future development of quantitative in vitro-in vivo extrapolation models for mixture risk assessment is discussed with particular attention to integrating human in vitro and in vivo P/TK data on interactions with pathway-related variability.

Clinical and Economic Burden Associated With Acute Graft-Versus-Host Disease After Allogeneic Hematopoietic Cell Transplantation in Germany.

BACKGROUND: Acute graft-vs-host disease (aGVHD) is a serious complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), yet there are limited data on the clinical and economic burden of aGVHD in Germany. This real-world study aimed to evaluate clinical and economic outcomes among patients in Germany with or without aGVHD after allo-HSCT. METHODS: This retrospective cohort study used administrative claims extracted from the German statutory health insurance database. Eligible adult patients underwent allo-HSCT between 1 January 2009 and 31 December 2017 for any hematological malignancy. Clinical (severe infections and mortality) and economic (health care resource use [HCRU] and costs) outcomes were compared in "aGVHD" patients and "no GVHD" patients. Propensity score matching (1:1) was used to balance covariates between the aGVHD and no GVHD groups. RESULTS: After propensity score matching, 95 aGVHD and 95 no GVHD patients were included in the analysis. The aGVHD group had significantly higher odds of mortality than the no GVHD group (odds ratio [OR] 2.2; 95% CI 1.2-4.0). Odds of severe infection were similar between the 2 groups (OR 1.7; 95% CI 0.9-3.3). Patients in the aGVHD group had significantly more overnight hospitalizations per patient-year (mean [SD]: 3.7 [3.0] and 2.7 [2.5], P = .029), and total direct costs were 1.6-fold higher than those in the no GVHD group. CONCLUSION: Among patients who underwent allo-HSCT, aGVHD was associated with significantly higher mortality, HCRU, and costs, highlighting the need for effective prophylaxis and treatment options to prevent or reduce the incidence of aGVHD.

Clinical burden and healthcare resource utilization associated with managing transfusion-dependent ß-thalassemia in France.

OBJECTIVE: To describe the clinical burden and healthcare resource utilization associated with managing transfusion-dependent ß-thalassemia (TDT) in France. METHODS: We used the French National Health Data System (système national des données de santé) to identify eligible patients from January 1, 2012, to March 1, 2019. Inclusion criteria were a diagnosis of ß-thalassemia, ≥8 red blood cell (RBC) transfusion episodes per year in ≥2 consecutive years following the diagnosis, and ≥1 year of follow-up data. Patients were excluded if medical records showed evidence of sickle cell disease, α-thalassemia, hereditary persistence of fetal hemoglobin, or hematopoietic stem cell transplant. Clinical complications, mortality, treatment use, and healthcare resource utilization were evaluated. RESULTS: Overall, 331 eligible patients with TDT were identified. Mean age was 26.1 (standard deviation [SD]: 18.0) years, and 50.5% were male. Common clinical complications were endocrine (26.0%), hepatobiliary (22.7%), and cardiopulmonary (18.7%). Fifteen (4.5%) patients died during follow-up, with a mortality rate of 1.16 deaths per 100 person-years (mean age of death: 52.5 years [SD: 22]). Patients had a mean of 13.5 (SD: 5.2) RBC transfusion episodes and 11.2 (SD: 5.3) iron chelation therapy treatments per year. Healthcare resource utilization was substantial, with a mean of 14.8 inpatient hospitalizations (including 13.8 mean inpatient day cases) and 16.9 outpatient prescriptions per patient per year. CONCLUSIONS: Patients with TDT in France experience significant clinical complications, elevated mortality, and substantial healthcare resource utilization driven by frequent RBC transfusion episodes and inpatient hospitalizations. These results reinforce the need for disease-modifying therapies for this patient population.

Healthcare Resource Utilization and Cost Burden of BCG-Treated Non-Muscle Invasive Bladder Cancer Patients in Germany: A Retrospective Claims Analysis.

Background: Intermediate and high-risk non-muscle-invasive bladder cancer (NMIBC) is typically managed with transurethral resection of the bladder tumour (TURBT) followed by intravesical Bacillus Calmette-Guérin (BCG) immunotherapy; however, NMIBC patients can become refractory or unresponsive to BCG treatment, and/or progress to muscle-invasive bladder cancer (MIBC). Healthcare resource utilization (HCRU) and costs in these patient populations are high. Methods: A retrospective longitudinal cohort design of adult (≥18 years) patients with bladder cancer and BCG treatment (01/01/2012-31/12/2017) was conducted using data from a representative subset of the German statutory health insurance database. During the follow-up period after last BCG, patients were categorized into subgroups of No further NMIBC treatment, Continuous treatment for NMIBC, or MIBC evidence; HCRU and costs were tabulated for each subgroup and for the entire cohort. Results: A total of 1049 patients met the study inclusion criteria (mean age, 70.9 years; 84.8% male). Across the different subgroups, patients showing MIBC evidence had more than two times higher hospitalization rates compared to the other subgroups. Overall, the entire BCG-treated cohort's total direct medical cost including hospitalizations, outpatient care and drugs was €33.9 million and €9250 per patient-year. Cost for patients with MIBC evidence was much higher, at €17,983 per patient-year, than patients with No further NMIBC treatment (€6617) and patients with Continuous treatment for NMIBC (€7786). Across the subgroups, hospitalization was the largest driver of cost and contributed the most to cost for those with MIBC evidence. Conclusion: The overall cost burden of this BCG-treated cohort of 1049 patients is high (€38 million whereof 4.1 million are indirect costs) over a mean follow-up of 3.9 years; economic burden is especially substantial for patients who fail BCG treatment and those who progress.

Low Molecular Weight Heparin Treatment Patterns and Outcomes in Cancer Patients with Acute Venous Thromboembolism: A Nationwide Cohort Study in France.

Patients with cancer have an increased risk of developing venous thromboembolism (VTE) and an increased risk of death from VTE. Until recently, the standard of care for treatment of VTE in cancer patients was low molecular weight heparins (LMWH). To determine treatment patterns and outcomes, we performed an observational study using a nationwide health database. Treatment patterns, rates of bleeding, and VTE recurrence at 6 and 12 months were assessed in cancer patients with VTE in France prescribed LMWH in 2013-2018. Of 31,771 patients administered LMWH (mean age 66.3 years), 51.0% were male, 58.7% had pulmonary embolism, and 70.9% had metastatic disease. At 6 months LMWH persistence was 81.6%, VTE recurrence had occurred in 1256 patients (4.0%) at a crude rate per 100 person-months (PM) of 0.90, and bleeding had occurred in 1124 patients (3.5%) at a crude rate per 100 PM of 0.81. At 12 months, VTE recurrence had occurred in 1546 patients (4.9%) at a crude rate per 100 PM of 0.71 and bleeding had occurred in 1438 patients (4.5%) at a crude rate per 100 PM of 0.66. Overall, VTE-related clinical event rates were high among patients administered LMWH, suggesting an unmet medical need.

Clinical and economic burden associated with graft-versus-host disease following allogeneic hematopoietic cell transplantation in France.

The real-world clinical and economic burden of graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplantation has not been comprehensively studied in France. Clinical outcomes, healthcare resource utilization and costs associated with acute GVHD (aGVHD), chronic GVHD (cGVHD), acute plus chronic GVHD (a+cGVHD) versus no GVHD were compared using French administrative claims data. After propensity score matching, 1934, 408, and 1268 matched pairs were retained for the aGVHD, cGVHD, and a+cGVHD cohorts, respectively. Compared with patients with no GVHD, odds of developing severe infection were greater in patients with aGVHD (odds ratio: 1.7 [95% confidence interval: 1.4, 2.1]). Compared with patients with no GVHD, mortality rates were higher in patients with aGVHD (rate ratio (RR): 1.6 [1.4, 1.7]) and with a+cGVHD (RR: 1.1 [1.0, 1.2]) but similar in patients with cGVHD (RR: 0.9 [0.7, 1.1]). Mean overnight hospital admission rates per patient-year were significantly higher in patients with aGVHD and a+cGVHD compared with no GVHD. Total direct costs (range €174,482-332,557) were 1.2, 1.5, and 1.9 times higher for patients with aGVHD, cGVHD, and a+cGVHD, respectively, versus patients with no GVHD. These results highlight the significant unmet need for effective treatments of patients who experience GVHD.

Quantification of steroids and endocrine disrupting chemicals in rat ovaries by LC-MS/MS for reproductive toxicology assessment.

Reproductive function is controlled by a finely tuned balance of androgens and estrogens. Environmental toxicants, notably endocrine disrupting chemicals (EDCs), appear to be involved in the disruption of hormonal balance in several studies. To further describe the effects of selected EDCs on steroid secretion in female rats, we aim to simultaneously investigate the EDC concentration and the sex hormone balance in the ovaries. Therefore, an effective method has been developed for the quantification of the sex steroid hormones (testosterone, androstenedione, estradiol, and estrone) and four endocrine disrupting chemicals (bisphenol A, atrazine, and the active metabolites of methoxychlor and vinclozolin) in rat ovaries. The sample preparation procedure is based on the so-called "quick, easy, cheap, effective, rugged, and safe" approach, and an analytical method was developed to quantify these compounds with low detection limits by liquid chromatography coupled with a tandem mass spectrometer. This analytical method, applied to rat ovary samples following subacute EDC exposure, revealed some new findings for toxicological evaluation. In particular, we showed that EDCs with the same described in vitro mechanisms of action have different effects on the gonadal steroid balance. These results highlight the need to develop an integrative evaluation with the simultaneous measurement of EDCs and numerous steroids for good risk assessment.

Multi-residue analysis of free and conjugated hormones and endocrine disruptors in rat testis by QuEChERS-based extraction and LC-MS/MS.

Endocrine disrupting compounds (EDCs) are suspected to be responsible for many disorders of the human reproductive system. To establish a causality relationship between exposure to endocrine disruptors and disease, experiments on animals must be performed with improved or new analytical tools. Therefore, a simple, rapid, and effective multi-residue method was developed for the determination of four steroid hormones (i.e., testosterone, androstenedione, estrone, and estradiol), glucuronide and sulfate conjugates of estrone and estradiol and four endocrine disruptors in rat testis (i.e., bisphenol A, atrazine, and active metabolites of methoxychlor and vinclozolin). The sample preparation procedure was based on the Quick, Easy, Cheap, Effective, Rugged, and Safe (QuEChERS) approach. An analytical method was then developed to quantify these compounds at ultra-trace levels by liquid chromatography coupled to tandem mass spectrometry. The QuEChERS extraction was optimized with regard to the acetonitrile/water ratio used in the extraction step, the choice of the cleanup method and the acetonitrile/hexane ratio used in the cleanup step. The optimized extraction method exhibited recoveries between 89% and 108% for all tested compounds except the conjugates (31% to 58%). The detection limits of all compounds were below 20 ng g(-1) of wet weight of testis. The method was subsequently applied to determine the levels of hormones and EDCs in seven rat testis samples.

Comparative Analysis of All-Cause Health Care Resource Utilization and Costs Among Venous Thrombosis Patients Without Cancer Prescribed Apixaban or VKAs in France.

INTRODUCTION: The direct oral anticoagulant (DOAC) apixaban has shown to have non-inferior efficacy and better safety than vitamin K antagonists (VKAs) in patients with venous thromboembolism (VTE). We determined whether healthcare resource use (HCRU) and direct all-cause medical and non-medical costs in patients with VTE in France differed between VKAs and apixaban. METHODS: A retrospective cohort study was conducted using French national health data from January 2013-June 2018 for anticoagulant-naïve adults hospitalized with VTE. All-cause costs and HCRU per patient per month (PPPM) were compared between apixaban and VKA cohorts created by 1:1 propensity score matching. Two-part models with bootstrapping were used to calculate marginal effects for costs and HCRU. RESULTS: The matched VKA and apixaban cohorts each comprised 7503 patients. Compared to VKAs, patients prescribed apixaban had significantly lower (P < 0.0001) mean all-cause costs PPPM for outpatient visits (€438.54 vs. €455.58), overall laboratory tests (€21.26 vs. €83.73), and hospitalizations (€249.48 vs. €343.82), but significantly higher (P < 0.0001) mean all-cause costs PPPM for overall drugs (€97.06 vs. €69.56) and medical procedures (€42.12 vs. €35.50). Mean total all-cause direct medical costs (€687.93 vs. €798.70) and total all-cause direct medical and non-medical costs (€771.60 vs. €883.66) were significantly lower (P < 0.0001) for apixaban. Mean HCRU PPPM showed similar trends. Subgroup analyses showed that, among patients with recurrent VTE, patients prescribed apixaban had significantly lower (P < 0.0001) all-cause costs PPPM for total medical costs (€17.26 vs. €18.12) and total all-cause direct medical and non-medical costs (€18.37 vs. €19.20) than patients prescribed VKAs. Similarly, among patients with bleeding, patients prescribed apixaban had significantly lower (P < 0.0001) all-cause costs PPPM for total medical costs (€15.34 vs. €32.61) and total all-cause direct medical and non-medical costs (€16.23 vs. €34.63) than patients prescribed VKAs. CONCLUSION: Compared to VKAs, apixaban may be cost-saving in the treatment of patients hospitalized for acute VTE.

Effectiveness and Safety of Oral Anticoagulants in the Treatment of Acute Venous Thromboembolism: A Nationwide Comparative Cohort Study in France.

INTRODUCTION: Data from clinical trials indicate that direct oral anticoagulants (DOACs) are noninferior and safer than conventional therapy (low-molecular-weight heparin followed by a vitamin K antagonist [VKA]) for treating venous thromboembolism (VTE), which includes deep vein thrombosis and pulmonary embolism (PE). This study compared the effectiveness and safety of DOACs and conventional therapy in a real-world setting. METHODS: This observational study used French national claims data of adult, treatment-naïve patients diagnosed with VTE (majority PE) who were hospitalized and treated for VTE with a DOAC (apixaban or rivaroxaban) or VKAs during 2013 to 2018. Patients with active cancer were excluded. After propensity score matching for each DOAC-VKA comparison, risks of bleeding, recurrent VTE, and all-cause mortality were compared at 6 months. Cox proportional hazards regression was used to estimate adjusted hazard ratios of the endpoints. RESULTS: A total of 58,137 patients were included (10,775 VKAs, 10,440 apixaban, 36,922 rivaroxaban). Propensity score-matched cohort sizes were 7,503 for apixaban and 9,179 for rivaroxaban. The hazard ratio (95% confidence interval) was significantly lower for apixaban than VKAs for bleeding requiring hospitalization (0.43 [0.32-0.59]), all-cause death (0.61 [0.51-0.74]), and first recurrent VTE (0.67 [0.52-0.85]). The hazard ratio was also significantly lower for rivaroxaban than VKAs for all-cause death (0.63 [0.53-0.74]) but not for bleeding requiring hospitalization (0.86 [0.69-1.07]) or first recurrent VTE (0.91 [0.74-1.13]). CONCLUSION: Apixaban was associated with superior safety and effectiveness than VKAs. All-cause mortality was lower in both DOACs than VKAs. Our results support recommendations to use DOACs over VKAs for the treatment of VTE.

Exploring the treatment gap among patients with osteoporosis-related fractures in France.

The use of anti-osteoporosis treatment following a diagnosis of osteoporosis with fracture or a relevant fragility fracture remains low in France. Initiating an anti-resorptive may reduce the incidence of a subsequent fracture by 60%. PURPOSE: To describe real-world osteoporosis treatment patterns in individuals with a fragility fracture in France and to explore the impact of initiating treatment on the risk of subsequent fracture. METHODS: A retrospective cohort study, using the national French Health Insurance claims database. Males and females 50 years and over, with a hospital discharge diagnosis of osteoporosis with fracture or a relevant fragility fracture between 2011 and 2014, were included and followed until death or the end of 2016, whichever came first. The primary outcome was the proportion of patients receiving anti-osteoporosis treatments prior to and post-index fracture. Change in fracture rates before and after treatment initiation was assessed in an exploratory analysis. RESULTS: A total of 574,133 patients (138,567 males, 435,566 females) had a qualifying index fracture. The proportion of patients receiving any anti-osteoporosis treatment increased pre-index fracture to post-index fracture from 2.2 to 5.6% among males, and from 11.8 to 18.2% among females. Oral bisphosphonates were the most prescribed anti-osteoporosis treatment for both males and females among post-index fractures (60.6% and 68.8% of patients initiating treatment). Following initiation of anti-resorptives, the incidence of subsequent fracture was reduced by 60% (rate ratio (RR): 0.40, 95% confidence interval [CI]: 0.34-0.45). CONCLUSION: Anti-osteoporosis treatment following an index fracture in France remains low. Improved identification and pharmacologic management of patients at risk of fragility fractures are necessary to reduce the risk of subsequent fractures.

Inter-phenotypic differences in CYP2C9 and CYP2C19 metabolism: Bayesian meta-regression of human population variability in kinetics and application in chemical risk assessment.

Quantifying variability in pharmacokinetics (PK) and toxicokinetics (TK) provides a science-based approach to refine uncertainty factors (UFs) for chemical risk assessment. In this context, genetic polymorphisms in cytochromes P450 (CYPs) drive inter-phenotypic differences and may result in reduction or increase in metabolism of drugs or other xenobiotics. Here, an extensive literature search was performed to identify PK data for probe substrates of the human polymorphic isoforms CYP2C9 and CYP2C19. Relevant data from 158 publications were extracted for markers of chronic exposure (clearance and area under the plasma concentration-time curve) and analysed using a Bayesian meta-regression model. Enzyme function (EF), driven by inter-phenotypic differences across a range of allozymes present in extensive and poor metabolisers (EMs and PMs), and fraction metabolised (Fm), were identified as exhibiting the highest impact on the metabolism. The Bayesian meta-regression model provided good predictions for such inter-phenotypic differences. Integration of population distributions for inter-phenotypic differences and estimates for EF and Fm allowed the derivation of CYP2C9- and CYP2C19-related UFs which ranged from 2.7 to 12.7, and were above the default factor for human variability in TK (3.16) for PMs and major substrates (Fm >60%). These results provide population distributions and pathway-related UFs as conservative in silico options to integrate variability in CYP2C9 and CYP2C19 metabolism using in vitro kinetic evidence and in the absence of human data. The future development of quantitative extrapolation models is discussed with particular attention to integrating human in vitro and in vivo PK or TK data with pathway-related variability for chemical risk assessment.

Clinical impact and room for improvement of intensity and adherence to lipid lowering therapy: Five years of clinical follow-up from 164,565 post-myocardial infarction patients.

BACKGROUND: In patients at risk of cardiovascular (CV) events, the effectiveness of lipid-lowering therapies (LLT) is affected by both intensity and adherence. Our study evaluated the association between LLT intensity (statin and/or ezetimibe) and adherence, and CV events in patients with a history of myocardial infarction (MI) in France. METHODS: Using the French national healthcare database (SNDS), we included patients with a history of MI, an initial LLT prescription in 2011-2013, and a second prescription within one year. LLT intensity was defined using the expected percent reduction in low-density lipoprotein cholesterol; adherence was measured as the proportion of days covered. Cox proportional hazards models were used to assess associations between intensity and/or adherence, and the risk of major adverse CV event (MACE). RESULTS: 164,565 patients were included; mean (SD) age, 66·3 (13·8) years; 73·6% men. Following an MI, only half of patients were treated with high-intensity LLT and approximately 40% of those on LLT remained non-adherent during follow-up (mean (SD) follow-up, 2·6 (1·4) years). Each 10% increase in treatment intensity, adherence, or adherence-adjusted intensity was respectively associated with a 16% (HR 0.84, 95%CI 0.84-0.85), 7% (HR 0.93, 95%CI 0.93-0.94), and 15% (HR 0.85, 95%CI 0.84-0.86) decrease in the risk of MACE. CONCLUSIONS: Among patients with a history of MI, prescriptions of high-intensity LLT were limited and adherence to LLT was low. Higher intensity and/or adherence to statins was associated with a significantly lower risk of MACE, highlighting the importance of compliance with clinical guidelines to improve patient outcomes.

Generic physiologically-based toxicokinetic modelling for fish: Integration of environmental factors and species variability.

One of the goals of environmental risk assessment is to protect the whole ecosystem from adverse effects resulting from exposure to chemicals. Many research efforts have aimed to improve the quantification of dose-response relationships through the integration of toxicokinetics. For this purpose, physiologically-based toxicokinetic (PBTK) models have been developed to estimate internal doses from external doses in a time-dependent manner. In this study, a generic PBTK model was developed and adapted for rainbow trout (Onchorhynchus mykiss), zebrafish (Danio rerio), fathead minnow (Pimephales promelas), and three-spined stickleback (Gasterosteus aculeatus). New mechanistic approaches were proposed for including the effects of growth and temperature in the model. Physiological parameters and their inter-individual variability were estimated based on the results of extensive literature searches or specific experimental data. The PBTK model was implemented for nine environmental contaminants (with log kow from -0.9 to 6.8) to predict whole-body concentrations and concentrations in various fish's organs. Sensitivity analyses were performed for a lipophilic and a hydrophilic compound to identify which parameters have most impact on the model's outputs. Model predictions were compared with experimental data according to dataset-specific exposure scenarios and were accurate: 50% of predictions were within a 3-fold factor for six out of nine chemicals and 75% of predictions were within a 3-fold factor for three of the most lipophilic compounds studied. Our model can be used to assess the influence of physiological and environmental factors on the toxicokinetics of chemicals and provide guidance for assessing the effect of those critical factors in environmental risk assessment.

Investigating combined toxicity of binary mixtures in bees: Meta-analysis of laboratory tests, modelling, mechanistic basis and implications for risk assessment.

Bees are exposed to a wide range of multiple chemicals "chemical mixtures" from anthropogenic (e.g. plant protection products or veterinary products) or natural origin (e.g. mycotoxins, plant toxins). Quantifying the relative impact of multiple chemicals on bee health compared with other environmental stressors (e.g. varroa, viruses, and nutrition) has been identified as a priority to support the development of holistic risk assessment methods. Here, extensive literature searches and data collection of available laboratory studies on combined toxicity data for binary mixtures of pesticides and non-chemical stressors has been performed for honey bees (Apis mellifera), wild bees (Bombus spp.) and solitary bee species (Osmia spp.). From 957 screened publications, 14 publications provided 218 binary mixture toxicity data mostly for acute mortality (lethal dose: LD50) after contact exposure (61%), with fewer studies reporting chronic oral toxicity (20%) and acute oral LC50 values (19%). From the data collection, available dose response data for 92 binary mixtures were modelled using a Toxic Unit (TU) approach and the MIXTOX modelling tool to test assumptions of combined toxicity i.e. concentration addition (CA), and interactions (i.e. synergism, antagonism). The magnitude of interactions was quantified as the Model Deviation Ratio (MDR). The CA model applied to 17% of cases while synergism and antagonism were observed for 72% (MDR > 1.25) and 11% (MDR < 0.83) respectively. Most synergistic effects (55%) were observed as interactions between sterol-biosynthesis-inhibiting (SBI) fungicides and insecticide/acaricide. The mechanisms behind such synergistic effects of binary mixtures in bees are known to involve direct cytochrome P450 (CYP) inhibition, resulting in an increase in internal dose and toxicity of the binary mixture. Moreover, bees are known to have the lowest number of CYP copies and other detoxification enzymes in the insect kingdom. In the light of these findings, occurrence of these binary mixtures in relevant crops (frequency and concentrations) would need to be investigated. Addressing this exposure dimension remains critical to characterise the likelihood and plausibility of such interactions to occur under field realistic conditions. Finally, data gaps and further work for the development of risk assessment methods to assess multiple stressors in bees including chemicals and non-chemical stressors in bees are discussed.

Toxicokinetic models and related tools in environmental risk assessment of chemicals.

Environmental risk assessment of chemicals for the protection of ecosystems integrity is a key regulatory and scientific research field which is undergoing constant development in modelling approaches and harmonisation with human risk assessment. This review focuses on state-of-the-art toxicokinetic tools and models that have been applied to terrestrial and aquatic species relevant to environmental risk assessment of chemicals. Both empirical and mechanistic toxicokinetic models are discussed using the results of extensive literature searches together with tools and software for their calibration and an overview of applications in environmental risk assessment. These include simple tools such as one-compartment models, multi-compartment models to physiologically-based toxicokinetic (PBTK) models, mostly available for aquatic species such as fish species and a number of chemical classes including plant protection products, metals, persistent organic pollutants, nanoparticles. Data gaps and further research needs are highlighted.

Modeling bioavailability to organs protected by biological barriers.

Computational pharmacokinetic (PK) modeling gives access to drug concentration vs. time profiles in target organs and allows better interpretation of clinical observations of therapeutic or toxic effects. Physiologically-based PK (PBPK) models in particular, based on mechanistic descriptions of the body anatomy and physiology, may also help to extrapolate in vitro or animal data to human. Once in the systemic circulation, a chemical has access to the microvasculature of every organ or tissue. However, its penetration in the brain, retina, thymus, spinal cord, testis, placenta,… may be limited or even fully prevented by dynamic physiological blood-tissue barriers. Those barriers are both physical (involving tight junctions between adjacent cells) and biochemical (involving metabolizing enzymes and transporters). On those cases, correct mechanistic characterization of the passage (or not) of molecules through the barrier can be crucial for improved PBPK modeling and prediction. In parallel, attempts to understand and quantitatively characterize the processes involved in drug penetration of physiological barriers have led to the development of several in vitro experimental models. Data from such assays are very useful to calibrate PBPK models. We review here those in vitro and computational models, highlighting the challenges and perspectives for in vitro and computational models to better assess drug availability to target tissues.