Trough Plasma Levels Research Articles

M204. ULTRA-RESISTANT SCHIZOPHRENIA IS ASSOCIATED WITH A DELAY TO INITIATE CLOZAPINE AND WITH LESS ABDOMINAL OBESITY. SEX DIFFERENCES IN INSULINEMIA AND LEPTIN LEVELS ARE OBSERVED BETWEEN RESPONDERS AND NOT RESPONDERS

Background30% patients suffering from schizophrenia fail to obtain therapeutic benefit even after two appropriate antipsychotic trials and are considered resistant. The recommended treatment in these cases is clozapine (CLZ), but only 40% of patients with resistant schizophrenia show clinical response, a condition called ultra-resistance (UR) and defined as the lack of antipsychotic response after 8 to 12 weeks of treatment with at least 400 mg/day of clozapine or plasma levels ≥ 350 ng/ml. The objective of the present study is to identify factors associated with UR in in a group of patients from Argentina.MethodsA paired case-control study was conducted, being cases those patients with UR schizophrenia and controls those who responded to CLZ; both groups were matched by age and sex. The response to CLZ was measured using the PANSS (UR was defined with a total score ≥ 80). The following parameters were compared between groups: months of untreated psychosis, months until the introduction of clozapine, body mass index (BMI), waist circumference, fasting blood glucose, insulinemia, triglyceridemia, HDL cholesterol, ultrasensitive C-reactive protein (CRP) and plasma leptin levels. Clozapine and nor-clozapine plasma trough levels were measured by HPLC-MS/MS.Results9 men (M) and 7 women (W) with the diagnosis of UR schizophrenia were matched with the same number of responders (R) to clozapine. Total PANSS scores (mean ± SD) for each group were as follows: W-R 48.9 ± 11; W-UR 88.4 ± 6 (p < 0.0001); M-R 60.5 ± 7; M-UR 112.8 ± 23 (p < 0.0001). CLZ dose was significantly higher both in W-UR and in M-UR than in paired controls (p < 0.05). Nonsignificant differences were observed for nor-CLZ plasma concentration among groups. Clozapinemia was not different among men but it was significantly higher in W-UR in comparison with W-R (p < 0.05).Significant differences were detected in the amount of months that passed before initiation of CLZ both for women (W-R 140.9 ± 124, W-UR 255.6 ± 153, p < 0.005) and men (M-R 104.0 ± 51. 6 versus M-UR 174.6± 65; p < 0.05). Body mass index (kg/m2) was significantly lower in UR patients: W-R 35.3 ± 6 versus W-UR 26.9 ± 3 (p < 0.05) and M-R 30.6 ± 5 versus M-UR 22.7 ± 4 (p <.005). Waist circumference (cm) was also significantly lower in UR independently of sex: W-R 110.6 ± 12 versus W-UR 98.5 ± 8 (p < 0.05); M-R 113.9 ± 15 versus M-UR 87.4 ± 9 (p <0 .005). Insulinemia (UI/ml) was significantly lower in M-UR than in M-R (16.1± 8 versus 9.4 ± 7, p<0.005) but not in women. Also significant differences were found in leptin levels (pg/ml) in men but not in women (M-R 1824.0 ± 1139 versus M-UR 477.6 ± 692; p < 0.05). No differences were observed in the number of antipsychotics received before CLZ, months of untreated psychosis, fasting glycemia, trygliceridemia, HDL cholesterol, CRP, HbA1c and diastolic or systolic arterial blood pressure.DiscussionTime to CLZ initiation could be a critical factor predisposing to UR. The absence of clozapine-induced abdominal obesity and changes in BMI are also to be associated with poor clinical response, independently of plasma drug levels. Differences between ultra-resistant men and women concerning insulin and leptin plasma levels should be further investigated. As far as we know, this is the first paired case-control study aimed to investigate factors associated with CLZ resistance in schizophrenia.

The Effect of Proton Pump Inhibitor Withdrawal on Dabigatran Etexilate Plasma Levels in Patients With Atrial Fibrillation: A Washout Study.

Several studies demonstrated that proton pump inhibitors (PPIs) co-administrated with dabigatran in patients with atrial fibrillation (AF) decreased dabigatran trough and peak plasma levels. However, it is still unknown whether this interaction is reversible or not, and whether the withdrawal of PPI would lead to normalization of dabigatran plasma levels. The aim of this study was to determine the effect of PPI withdrawal on dabigatran plasma levels in patients with AF. This pilot prospective study enrolled 23 AF patients on long-term dabigatran and PPI therapy (omeprazole 20 mg twice daily or pantoprazole 40 mg once daily). Dabigatran trough and peak levels (ng/mL) were tested on PPI and after a 2-week period of PPI withdrawal with Hemoclot Thrombin Inhibitor Assay. The analysis of dabigatran plasma levels demonstrated significant elevation in trough dabigatran levels after 2 weeks of PPI withdrawal (97.2 ± 79.7 vs. 163.8 ± 105.5 ng/mL; P < 0.05). Moreover, significantly higher peak dabigatran levels were observed after 2 weeks of PPI withdrawal (142.4 ± 102.8 vs. 255 ± 129.5 ng/mL; P ≤ 0.001). This study showed that a 2-week period of PPI withdrawal lead to a significant increase in dabigatran trough and peak plasma levels in patients with AF.

Real Life Experience in Clinical Practice with Recombinant Coagulation FVIII-Fc Fusion Protein

Introduction: Efmoroctocog alfa (Elocta®) is a recombinant coagulation FVIII-Fc (rFVIIIFc), a fully recombinant fusion protein produced in human embryonic kidney cells, with an extended half-life used for the treatment and prevention of bleeding in patients with severe hemophilia A. Using rFVIIIFc for the treatment of severe hemophilia A patients received the approval of reimbursement in Spain at the end of 2016. Therefore, there are no many comparative data published about real life use of rFVIIIFc. Objective: This work aims to describe characteristics of the treatment of severe hemophilia A patients with rFVIIIFc and to compare its results with those previously obtained employing other FVIII products. Methods: This was an open-label non-interventional retrospective study reviewing patient characteristics and treatment outcomes before and after the use of rFVIIIFc. The La Paz University Hospital Ethics Committee approved the experimental protocol. Patients with severe hemophilia A without inhibitors being treated with rFVIIIFc since at least six months before study approval by Ethics Committee were included. The following data were collected for patients included in the study: dose (IU/kg) and prophylaxis treatment regimen, number of spontaneous and traumatic bleedings, annual bleeding rate (ABR) and FVIII trough level. The statistical analysis on the variables listed above comparing before and after rFVIIIFc usage was performed by the Biostatistics Unit of La Paz University Hospital with the statistical package SPSS v.18.0 (SPSS Inc., Chicago, IL, USA). Results: Twenty two severe hemophilia A patients (median age: 20 years old, ranging from 6 to 63 years) on prophylaxis with rFVIIIFc were considered to be included in this study, but two were excluded due to lack of data. Median follow-up period was 14 months (ranging from 6 to 28 months). Nineteen severe hemophilia A patients have been previously treated with rFVIII (two of them with other extended half-life product) and one with plasma-derived FVIII. Eight of the ten severe hemophilia A patients who presented an ABR greater than 0 with previous treatments reduced their ABR when treated with rFVIIIFc (Table 1). Among those patients with an ABR=0 with previously used FVIII products, only one increased to an ABR=1 when treated with Elocta® due to a traumatic bleeding. Table 1 shows ABR across all patients before and after rFVIIIFc. There was no difference in dose per injection between other FVIII products and rFVIIIFc (median dose for patients treated with other FVIII products: 46.0 IU/kg, ranging from 26 to 65 IU/kg; median dose for patients treated with rFVIIIFc: 46.5 IU/kg, ranging from 26 to 65 IU/kg). Nevertheless, a reduction was observed in administration frequency. Among the twelve patients who received treatment with other FVIII products every 48 hours, eleven came to receive rFVIIIFc 3 times a week and the one previously receiving a plasma-derived FVIII, to twice a week. Five of the patients receiving treatment 3 times a week reduced its frequency to twice per week. Three patients maintained the same schedule of administration. To note, one of the two patients receiving another prolonged half-life product maintained the schedule of treatment and the other reduced its frequency from every 48 hours to 3 times a week. FVIII trough level in plasma (% of FVIII), expressed as median (25th-75th percentile), was 1.1 (0.1-4.0) for rFVIIIFc treatment and 0.2 (0.0-1.9) for other FVIII products (p=0.06). Conclusions: 85% of the severe hemophilia A patients from our cohort reduced the weekly dose administration after beginning treatment with rFVIIIFc. Most of the patients increased plasma trough level of FVIII with rFVIIIFc. 45% of patients reduced and 40% kept their ABR=0 when they changed rFVIIIFc. These data suggest that treatment with rFVIIIFc gives a higher protection to severe hemophilia A patients. However, further research with larger sample size is required to investigate this. This work was supported by SOBI. NB holds a tenure track grant from FIS-FONDOS FEDER (CP14/00024). Disclosures Álvarez Roman: Takeda: Research Funding; Amgen: Consultancy, Speakers Bureau; NovoNordisk: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; CSL Behring: Consultancy, Speakers Bureau; Sobi: Consultancy, Speakers Bureau. Fernandez-Bello:Novartis, Pfizer, ROCHE, Stago: Speakers Bureau. Martín:SOBI: Research Funding; Novartis, Pfizer, ROCHE, Novo Nordisk: Speakers Bureau. Rivas Pollmar:Novartis, Pfizer, ROCHE, Novo Nordisk: Speakers Bureau; SOBI: Research Funding. García Barcenilla:Bayer, Pfizer, Takeda, Novartis: Speakers Bureau; SOBI: Research Funding. Canales:SOBI: Research Funding; iQone: Honoraria; Karyopharm: Honoraria; Novartis: Honoraria; Takeda: Speakers Bureau; Gilead: Honoraria; Celgene: Honoraria; Janssen: Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Honoraria, Speakers Bureau; Sandoz: Honoraria. Butta:Roche, Pfizer: Speakers Bureau; Novartis: Consultancy. Jimenez-Yuste:Bayer, CSL Behring, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche, Sobi, Shire: Consultancy, Honoraria, Other: reimbursement for attending symposia/congresses , Research Funding, Speakers Bureau.

Analysis of correlation between plasma trough level and response of generic imatinib in the treatment of Chinese patients with chronic myeloid leukemia

目的评价我国慢性髓性白血病慢性期（CML-CP）患者接受国产伊马替尼（商品名：格尼可）治疗后伊马替尼及其代谢物血浆谷浓度水平与疗效的关系。方法以2012年10月11日至2013年5月8日入组编号为YMTN1.0临床研究的21例接受国产伊马替尼治疗的CML-CP患者为研究对象，评价其血浆药物谷浓度与疗效、年龄、体重、体表面积的关系。伊马替尼及其代谢物浓度检测采用高效液相色谱-串联质谱法。结果①伊马替尼及其代谢物血浆谷浓度分别为（1 185.07±417.91）µg/L和（251.53±76.50）µg/L。②伊马替尼及其代谢物血浆谷浓度与患者年龄、体重和体表面积均无明显相关性（P值均>0.05）。③伊马替尼稳态血浆谷浓度高于1 000 µg/L的患者其完全及主要分子学反应率显著高于未达1 000 µg/L的患者（42%对0，P<0.01）。结论接受国产伊马替尼治疗的CML-CP患者中，伊马替尼及其代谢产物稳态血浆谷浓度存在较大个体差异，伊马替尼血浆谷浓度与患者获得分子学疗效有一定的相关性。

Quantitative tracking of inflammatory activity at the peak and trough plasma levels of tofacitinib, a Janus kinase inhibitor, via in vivo 18 F-FDG PET.

To assess the capability of in vivo positron emission tomography (PET) using 18 F-fluorodeoxyglucose (18 F-FDG) to quantify changes in inflammatory activity in response to tofacitinib, a Janus kinase (JAK) inhibitor, over a timeframe of a few hours to few days in a preclinical model of rheumatoid arthritis (RA). Twenty-four mice with collagen-induced arthritis in the following groups were assessed: Group 1, where the changes in PET measures for the extremity joints were evaluated at the peak and trough plasma drug levels after administration of a single dose of tofacitinib (4hours apart); Group 2, where joint PET measures were assessed before treatment and after 6days of administration of a daily dose of tofacitinib; and group 3 (controls), where joint PET measures were derived from the same mice, 6days apart. At about peak plasma levels of the drug after a single tofacitinib administration, there was a reduction in PET measures compared to pretreatment values, suggesting decreased inflammatory activity. These measures were equivalent to those obtained after 6days of daily dosing by tofacitinib. However, PET measures at trough plasma levels of the drug from tofacitinib administration were significantly higher than those at peak plasma drug levels and equivalent to pretreatment measures. There were insignificant changes in PET measures for the control animals. 18 F-FDG PET can detect changes in inflammatory activity occurring in response to the JAK inhibitor tofacitinib: (a) during peak and trough plasma drug levels, that is within mere hours of treatment; and (b) over a span of days.

Association of Hepatic Nuclear Factor 4 Alpha Gene Polymorphisms With Free Imatinib Plasma Levels and Adverse Reactions in Chinese Gastrointestinal Stromal Tumor Patients.

As the first-line treatment of gastrointestinal stromal tumor (GIST), the pharmacokinetic and pharmacodynamic of imatinib (IM) were characterized by marked interindividual variability. Pharmacogenetics of IM involved metabolic enzymes and transporters have been extensively reported, but the results remained inconsistent. This study investigated the effect of genetic variants in hepatocyte nuclear factor 4 alpha (HNF4α, encoded by gene NR2A1), a pivotal transcriptional regulator of drug disposition genes, on dose-adjusted IM-free plasma levels and related adverse reactions in Chinese GIST patients. Five common polymorphisms of NR2A1 (rs3818247, rs1884613, rs2071197, rs2425640, and rs736824) were genotyped in 70 Chinese GIST patients who had been administered IM 300-600 mg/d. The free IM trough plasma levels were determined based on a method of ultrafiltration coupled with high performance liquid chromatography-tandem mass spectrometry. There were wide interpatient variations in free plasma levels of IM (range, 9.50-67.50 ng/mL), in which significant sex differences were observed (P < 0.01). The dose-adjusted IM-free plasma levels showed a significant negative correlation with body surface area (r = -0.302, P = 0.012). Although there were no significant effects of NR2A1 polymorphisms on dose-adjusted IM-free plasma levels among the study population, polymorphism in rs736824 was found to be significantly associated with dose-adjusted IM-free plasma levels in male subjects (P = 0.031). For the IM-related adverse reaction, polymorphisms in rs3818247 were found to be significantly associated with periorbital edema (P = 0.032). In addition, no significant correlations were found between IM-free plasma levels and IM-related adverse reactions, except for the correlation of IM-free plasma levels with periorbital edema among male patients (P = 0.013). The research demonstrated that NR2A1 polymorphisms may act as contributors of IM pharmacokinetics and responses in Chinese GIST patients. This represents an attractive opportunity for IM therapy optimization, worth testing in clinical trials.

Genetic Polymorphisms and Adverse Events on Unbound Imatinib and Its Active Metabolite Concentration in Patients With Gastrointestinal Stromal Tumors

Imatinib is a first-line drug for the treatment of gastrointestinal stromal tumors (GIST). This study aims to investigate the influence of different kinds of protein concentrations and genetic polymorphisms of metabolizing enzymes and drug transporters on unbound imatinib and its active metabolite N-desmethyl-imatinib concentration, as well as the relationship between adverse drug reactions (ADRs) and drug concentration. A total of 62 Chinese patients with GIST were genotyped for five single nucleotide polymorphisms (SNPs). Total and unbound 3h and trough concentration of imatinib and N-desmethyl-imatinib in GIST patients were determined by an LC-MS/MS method combined with an equilibrium dialysis. Single-Use Red Plate with inserts was used to separate the unbound drug. When the protein concentration became higher, the unbound imatinib and N-desmethyl-imatinib plasma concentration got higher (p < 0.05). Patients with GA genotype in rs755828176 had significantly higher unbound N-desmethyl-imatinib dose-adjusted trough plasma concentrations (p = 0.012). Patients with CC genotype in rs3814055 had significantly higher unbound imatinib dose-adjusted trough plasma concentrations (p = 0.040). The mean total imatinib C3h of patients with ADRs (3.10 ± 0.96 µg/ml) was significantly higher than that of patients without ADRs (p = 0.023). The mean total N-desmethyl-imatinib C3h of patients (0.64 ± 0.21 µg/ml) with ADRs was significantly higher than that of patients without ADRs (p = 0.004). The mean unbound N-desmethyl-imatinib C3h of patients with ADRs (6.49 ± 2.53 ng/ml) was significantly higher than that of patients without ADRs (p = 0.042). The total and unbound C3h of imatinib and N-desmethyl-imatinib in patients with ADRs was significantly higher than that in patients without ADRs (p < 0.05). Protein concentrations have great influence on the unbound imatinib and N-desmethyl-imatinib concentrations. The genetic polymorphisms of CYP3A4 rs755828176 and NR1I2 rs3814055 were significantly associated with unbound imatinib and N-desmethyl-imatinib dose-adjusted trough plasma levels. The total and unbound imatinib or N-desmethyl-imatinib concentration in patients with GIST was also significantly correlated with ADRs.

Treatment of Candida infections with fluconazole in adult liver transplant recipients: Is TDM-guided dosing adaptation helpful?

Fluconazole represents a common antifungal option for the treatment of Candida infections in liver transplant recipients. Although adequate antifungal exposure is known to correlate with favorable outcomes in patients with invasive candidiasis, therapeutic drug monitoring (TDM) of fluconazole is currently not recommended. We conducted a retrospective study including adult liver transplant recipients receiving fluconazole for invasive candidiasis and undergoing TDM. We assessed the correlation between clinical variables, fluconazole trough plasma levels (Cmin ), and outcome. Twenty-seven patients (74% males; median age 57years) were included. Abdominal candidiasis was the most frequent infection (56%). Median duration of fluconazole therapy was 17days (IQR 9-21). Fluconazole median Cmin was 11.0mg/L (range 2.4-30.6mg/L). Five (19%) patients required TDM-guided fluconazole dose increase. All-cause in hospital mortality was 33%. Fluconazole Cmin >11mg/L significantly correlated with clinical success (OR 8.78, 95% CI 1.13-67.8, P=0.04). Our study identified decreased fluconazole Cmin as a factor associated with negative outcomes in liver transplant recipients with Candida infection. TDM of fluconazole may be advisable in this patient population.

PB1919 EFFECT OF OCT1 GENE POLYMORPHISM ON RESPONSE TO IMATINIB MESYLATE IN CML PATIENTS

Background: Imatinib mesylate (IM) has been shown to be highly efficacious in the treatment of Chronic Myeloid Leukemia (CML). Continuous and adequate dosing is essential for optimal outcomes. There is a considerable variability in the level of molecular responses achieved with IM therapy. These differences could result from variable drug level which may be due to genetic factors. The human organic cation transporter 1 (OCT1; SLC22A1) has been reported to be the main influx transporter responsible for active uptake of IM into CML cells. Aims: We hypothesized that the SNPs of this gene could predict the outcomes of IM therapy in CML patients. Methods: Fifty patients with CML at chronic phase were studied. All patients were monitored at outpatient clinic of the National Cancer Institute, Cairo University, Egypt. The study was approved by the NCI Ethical Committee for Clinical Research. Written Informed consent was obtained. The polymorphism of SLC22A1 gene was studied using PCR-RFLP technique. Imatinib mesylate level was determined using HPLC-massspectroscopy. Results: The mean IM trough plasma level in patients who achieved unfavorable response (n = 25) was 1019 ± 638 ng/mL, and in patients who achieved favorable response (n = 25) 1353 ± 611 ng/mL (p = 0.04). In regard to SLC22A1 rs(628031) gene, heterogeneous & variant allele (GA&AA) was significantly correlated to unfavorable response while wild allele GG is linked to favorable response(p = 0.0006). No significant correlation was detected between SLC22A1 gene polymorphism and drug level (p = 0.08). Summary/Conclusion: In patients with CML treated with IM, one of the significant factors affecting response was OCT1 polymorphism. This may influence the interindividual variation observed among Egyptian CML patients. Although a prospective study with a larger patient population is necessary to validate this finding. In patients with CML treated with IM, one of the significant factors affecting response was OCT1 polymorphism. This may influence the interindividual variation observed among Egyptian CML patients. Although a prospective study with a larger patient population is necessary to validate this finding.

PF190 PLASMA LEVELS AND OUTCOMES OF PROPHYLACTIC POST-TRANSPLANT PONATINIB ADMINISTRATION IN PATIENTS WITH PHILADELPHIA CHROMOSOME-POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA (PH+ALL)

Background: Some retrospective studies demonstrated that the administration of first- and second-generation tyrosine kinase inhibitors (TKIs) to patients with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ALL) after allogeneic hematopoietic cell transplantation (allo-HCT) led to better overall survival (OS) and progression-free survival (PFS). However, most patients become intolerant, making it difficult to continue treatment. Experimental data show that third-generation TKI ponatinib is effective against various BCR-ABL1 mutations, including T315I, at plasma levels of 21.3 ng/mL. In addition, a recent study demonstrated that a reduced dose of ponatinib might result in a lower incidence of cardiovascular adverse events (AEs). However, few studies have examined ponatinib maintenance after allo-HCT to prevent relapse. We herein investigate the efficacy and safety of maintenance with low-dose ponatinib after allo-HCT to prevent relapse and evaluated plasma concentration of ponatinib. Aims: The purpose of this study was to examine whether ponatinib maintenance after allo-HCT was tolerable and contributed to superior OS and PFS. Methods: We retrospectively analyzed data of consecutive patients with Ph+ALL who underwent allo-HCT at our institution between January 2008 and December 2018. The initial ponatinib dose was 15 mg daily; thereafter, it was at the physicians’ discretion. Plasma trough levels of ponatinib were measured using liquid chromatography tandem mass spectrometry on and after day 8 following the first administration. We compared outcomes between patients who did or did not receive ponatinib maintenance using 1:2 nearest neighbor propensity matching based on factors such as age, number of transplants, and minimal residual disease (MRD). Results: A total of 31 patients aged 19–65 years (median, 46) were included. Of them, 29 achieved complete remission and 24 had a negative MRD status before allo-HCT, while 10 had prior history of BCR-ABL1 mutations including T315I (n = 7). Seven patients received ponatinib maintenance for a median of 48 days (range, 36–124) after allo-HCT. The median follow-up times for all patients and for those on ponatinib maintenance were 553 (range, 34–3,836) days and 240 (69–405) days, respectively. Two-year OS and PFS in the ponatinib maintenance group tended to be better than those in the non-ponatinib group after propensity matching (n = 21) as shown in Figure 1 (100% vs. 62.5%, P = 0.206; 100% vs. 55.1%, P = 0.120, respectively). In the ponatinib group, median plasma concentration during 15 mg daily administration of ponatinib was 15.6 ng/mL (range, 4.8–23.3). The plasma level exceeded 21.3 ng/mL in only one patient and was below 10 ng/mL in two patients. The initial ponatinib dose was continued in six patients and changed to 30 mg in one patient. Although grades 3–4 non-hematologic AEs occurred in three patients, all were reversible. No cardiovascular AEs occurred during follow-up. One patient developed acute skin graft-versus-host disease shortly after ponatinib administration. In the ponatinib group, 93.5% of intended doses were administered. We found no relationship between plasma ponatinib concentrations and AEs or drug interruption.Summary/Conclusion: Our results suggest that prophylactic post-transplant ponatinib administration in patients with Ph+ALL is relatively safe and effective. It would be worthwhile to prospectively evaluate ponatinib maintenance efficacy after allo-HCT in a large patient cohort.

Relative Factors Analysis of Imatinib Trough Concentration in Chinese Patients with Gastrointestinal Stromal Tumor

Aims: Imatinib plasma trough levels (IM C_min) have been reported to have a considerable clinical impact in patients with gastrointestinal stromal tumors (GISTs). We therefore have investigated the factors affecting IM plasma concentration in Chinese GIST patients. Methods: IM C_min in 190 patients with GIST who were taking IM were measured. Results: In patients treated with IM 300 mg/day (n = 16), 400 mg/day (n = 168), and > 400 mg/day (500: n = 1, 600: n = 5), IM C_min was 1,564.54 ± 596.15, 1,521.26 ± 610.33, and 2,540.31 ± 1,298.14 ng/mL, respectively. Of the 168 patients treated with IM 400 mg/day, IM C_min was significantly lower in males (1,353.94 ± 492.89 ng/mL) than in females (1,680.79 ± 669.03 ng/mL, p < 0.01), and in patients with gastrectomy (1,439.60 ± 587.66 ng/mL) than those without gastrectomy (1,649.88 ± 620.12 ng/mL) (p = 0.033). High IM C_min was correlated with low body weight (p = 0.004) and low body surface area (p < 0.001). Conclusion: IM C_min at steady state was significantly associated with body weight and body surface area. Monitoring of IM C_min might be particularly important for the optimal treatment with IM of male patients and those who have undergone gastrectomy.

Safety, Pharmacokinetics, and Pharmacodynamics of ME-401, an Oral, Potent, and Selective Inhibitor of Phosphatidylinositol 3-Kinase P110δ, Following Single Ascending Dose Administration to Healthy Volunteers

PurposeME-401 is a novel selective inhibitor of phosphatidylinositol 3 kinase p110δ, an enzyme often found overexpressed and overactive in B-cell malignancies. The current study was performed to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending oral doses of ME-401 in healthy volunteers. MethodsThis analysis was an open-label, nonrandomized study in healthy male volunteers. Three sequential groups were dosed. Each group received single doses of ME-401 on two occasions; the doses tested ranged from 10 to 150 mg. Blood was drawn at various time points to analyze plasma concentrations of ME-401 and inhibition of basophil activation, a marker of phosphatidylinositol 3 kinase p110δ inhibition. FindingsFifteen subjects received a single dose of ME-401 on two occasions. Three adverse events that were considered possibly related to the study drug were reported: one event of pain, one event of headache, and one event of upper abdominal pain. ME-401 exhibited dose proportionality up to 60 mg, and supra-proportional increases in exposure were observed above doses of 60 mg. In addition, there was a dose-proportional increase in the inhibition of basophil activation up to 60 mg. Mean t1/2 ranged from 9.36 to 29.23 hours across the dose range. A 60 mg dose of ME-401 approached 90% inhibition of basophil activation, and thereafter no further increase to the percent inhibition of basophil activation was observed for higher doses. Once-daily dosing of 60 mg ME-401 was forecasted to result in trough plasma levels exceeding the concentration needed for 90% inhibition of basophil activation. ImplicationsThis first-in-human study showed that ME-401 was well tolerated after single doses up to 150 mg. Pharmacologic activity was confirmed after administration of single ascending oral doses of 10 to 150 mg. ME-401 60 mg, administered once daily, was selected as the starting dose for patient studies. ClinicalTrials.gov identifier: NCT02521389.

Abstract 1309: Network as a biomarker to predict drug candidates: Mapping driver dysregulated target networks onto pharmacologic data-derived drug networks identifies cardiac glycosides as the potential treatment of Group 3 medulloblastomas

Abstract Background: Medulloblastoma is a heterogeneous group of tumors that consists of four subtypes with distinct genomic signatures. Two of these subgroups are defined by a single dysfunctional signaling pathway, WNT and SHH respectively, which has raised the prospect of taking a rational target based approach to the development of new therapies. Conversely, the other 2 sub-types, Groups 3 and 4, which compose 60-65% of total medulloblastoma cases, are associated with much more complicated genetic, epigenetic and genomic contents and display significant intragroup heterogeneity. In addition, Group 3 are associated with the worst prognosis among all the subgroups and are frequently metastatic at presentation which makes the need for novel approaches to drug discovery for these tumors particularly acute. Results: We developed a computational systems biology method that incorporates novel algorithms for driver signaling network identification (DSNI) and drug functional network-(DFN) based drug repositioning to integrate multiple types of genomics profiles for Group 3 MB patients with human cancer signaling pathways resources and gene expression profiles of 1,309 drugs in CMAP with drug structure information and effects. By applying the DSNI-DFN method on Groups 3 MB data we identified five members of the cardiac glycoside family, a group of Na/K pump inhibitors best known for their role in the treatment of heart failure, as potential inhibitors of driver dysregulated network of the Groups 3 MB. We were subsequently able to validate this finding in cell culture where all 5 compounds lead to significant growth inhibition of Group 3 derived medulloblastoma cell lines. Members of the cardiac glycoside family showed efficacy in vivo in animal models inhibiting proliferation. Digoxin significantly prolonged survival in both PDOX models of Group 3 medulloblastoma (ICb-2055) at a dose which resulted in plasma trough levels similar to those targeted in cardiac patients receiving digoxin. Digoxin-treated mice (n=10) had a median survival of 180 days compared to a median survival of 102 in untreated controls (n=8) (P&amp;lt;0.0001). Furthermore, in the Group 3 model digoxin showed survival extension comparable to ionizing radiation which represents a major component of the current standard care for medulloblastoma. Taken together, these data demonstrate that digoxin has a strong in vivo anti-tumor effect against preformed PDOX tumors derived from Groups 3 medulloblastoma. Conclusions: Our findings represent both an exciting potential new therapy for Group 3 medulloblastoma and validation of an approach that can be applied to identify driver dysregulated networks and predict drugs for a wide variety of genomically complex tumors. Citation Format: Lei Huang, Sarah Garrett Injac, Xiaonan Li, Adesina Adekunle, Hong Zhao, Ching Lau, Stephen Wong. Network as a biomarker to predict drug candidates: Mapping driver dysregulated target networks onto pharmacologic data-derived drug networks identifies cardiac glycosides as the potential treatment of Group 3 medulloblastomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1309.

Biopsy-proven vancomycin-induced acute kidney injury: a case report and literature review

BackgroundVancomycin is the first-line antibiotic for methicillin-resistant Staphylococcus aureus and coagulase-negative strains. The risk of vancomycin-induced acute kidney injury increases with plasma vancomycin levels. Vancomycin-induced acute kidney injury is histologically characterized by acute interstitial nephritis and/or acute tubular necrosis. However, only 12 biopsy-proven cases of vancomycin-induced acute kidney injury have been reported so far, as renal biopsy is rarely performed for such cases. Current recommendations for the prevention or treatment of vancomycin-induced acute kidney injury are drug monitoring of plasma vancomycin levels using trough level and drug withdrawal. Oral prednisone and high-flux haemodialysis have led to the successful recovery of renal function in some biopsy-proven cases.Case presentationWe present the case of a 41-year-old man with type 1 diabetes mellitus, who developed vancomycin-induced acute kidney injury during treatment for Fournier gangrene. His serum creatinine level increased to 1020.1 μmol/L from a baseline of 79.6 μmol/L, and his plasma trough level of vancomycin peaked at 80.48 μg/mL. Vancomycin discontinuation and frequent haemodialysis with high-flux membrane were immediately performed following diagnosis. Renal biopsy showed acute tubular necrosis and focal acute interstitial nephritis, mainly in the medullary rays (medullary ray injury). There was no sign of glomerulonephritis, but mild diabetic changes were detected. He was discharged without continuing haemodialysis (serum creatinine level, 145.0 μmol/L) 49 days after initial vancomycin administration.ConclusionsThis case suggests that frequent haemodialysis and renal biopsy could be useful for the treatment and assessment of vancomycin-induced acute kidney injury, particularly in high-risk cases or patients with other renal disorders.

Evaluating the Effect of a Web-Based E-Learning Tool for Health Professional Education on Clinical Vancomycin Use: Comparative Study.

BackgroundInternet-based learning for health professional education is increasing. It offers advantages over traditional learning approaches, as it enables learning to be completed at a time convenient to the user and improves access where facilities are geographically disparate. We developed and implemented the Vancomycin Interactive (VI) e-learning tool to improve knowledge on the clinical use of the antibiotic vancomycin, which is commonly used for treatment of infections caused by methicillin-resistant Staphylococcus aureus (MRSA).ObjectiveThe aims of this study were to evaluate the effect of the VI e-learning tool on (1) survey knowledge scores and (2) clinical use of vancomycin among health professionals.MethodsWe conducted a comparative pre-post intervention study across the 14 hospitals of two health districts in New South Wales, Australia. A knowledge survey was completed by nurses, doctors, and pharmacists before and after release of a Web-based e-learning tool. Survey scores were compared with those obtained following traditional education in the form of an email intervention. Survey questions related to dosing, administration, and monitoring of vancomycin. Outcome measures were survey knowledge scores among the three health professional groups, vancomycin plasma trough levels, and vancomycin approvals recorded on a computerized clinical decision support system.ResultsSurvey response rates were low at 26.87% (577/2147) preintervention and 8.24% (177/2147) postintervention. The VI was associated with an increase in knowledge scores (maximum score=5) among nurses (median 2, IQR 1-2 to median 2, IQR 1-3; P<.001), but not among other professional groups. The comparator email intervention was associated with an increase in knowledge scores among doctors (median 3, IQR 2-4 to median 4, IQR 2-4; P=.04). Participants who referred to Web-based resources while completing the e-learning tool achieved higher overall scores than those who did not (P<.001). The e-learning tool was not shown to be significantly more effective than the comparator email in the clinical use of vancomycin, as measured by plasma levels within the therapeutic range.ConclusionsThe e-learning tool was associated with improved knowledge scores among nurses, whereas the comparator email was associated with improved scores among doctors. This implies that different strategies may be required for optimizing the effectiveness of education among different health professional groups. Low survey response rates limited conclusions regarding the tool’s effectiveness. Improvements to design and evaluation methodology may increase the likelihood of a demonstrable effect from e-learning tools in the future.

Posaconazole oral dose and plasma levels in pediatric hematology-oncology patients.

Posaconazole is a triazole with limited pharmacokinetic information in children. This study assessed the correlation between posaconazole oral solution daily dosage/kg/body weight and trough plasma level. A total of 97 hematology-oncology pediatric patients with ≥1 posaconazole plasma concentration level (PPC) assessment in the first 6weeks after the start of posaconazole treatment were included. Posaconazole was used as prophylaxis in 84 of 97 (87%) patients and as therapy in 13 of 97 (13%). The median daily dose/kg/bw ranged from 10 to 12mg in the prophylaxis group and 12.5 to 16.5mg in the therapy group. The median value of PPC for the prophylaxis group was 0.9 and 0.8μg/mL at the first and second/third determinations, respectively. Posaconazole prophylaxis failed in 4 of 84 patients (5%). The median value of PPC for the therapy group was 1.5 and 1.4μg/mL at the first/second and the third determination, respectively. Posaconazole-related side effects were reported in 6 patients and all regressed with the suspension of the drug. In the prophylaxis group, the use of proton-pump inhibitors was significantly associated with a lower PPC, P = 0.04. Posaconazole may be a valuable antifungal agent in children despite the incomplete knowledge of its pharmacokinetic characteristics.

CX-1158-101: A first-in-human phase 1 study of CB-1158, a small molecule inhibitor of arginase, as monotherapy and in combination with an anti-PD-1 checkpoint inhibitor in patients (pts) with solid tumors.

3005 Background: Arginase is secreted by myeloid-derived suppressor cells (MDSCs) and polymorphonuclear cells (PMNs) in the tumor microenvironment, depleting arginine, an amino acid required for T-cell activation and proliferation. CB-1158 is an oral small molecule inhibitor of arginase. CB-1158 reverses PMN- and MDSC-mediated suppression of T-cells in ex vivo human models, and increases plasma and tumor arginine levels in mouse syngeneic tumor models leading to increased pro-inflammatory markers and activated CD8 T-cells in the tumor. CB-1158 has single agent efficacy in mouse tumor models and synergistically enhances the antitumor efficacy of checkpoint inhibitors. Methods: This is an ongoing phase 1 study to evaluate safety and tolerability of CB-1158 as a monotherapy and in combination with anti-PD-1 in pts with solid tumors. Pharmacokinetics (PK), anti-tumor effects, and biomarkers, including plasma arginine, arginase activity, and effects on immune function in blood and in tumors will be evaluated. CB-1158 was administered BID orally in 28-day cycles. Escalating doses were administered to cohorts for safety evaluation. Additional pts were enrolled at dose levels determined to be safe to support biomarker objectives. Results: Nine pts have been enrolled across two monotherapy dose escalation cohorts (50 and 100 mg) and biomarker cohorts. CB-1158 was rapidly absorbed (Tmax = 4 h) and was cleared with a half-life of 6 h. At doses of 50 and 100 mg, steady-state plasma trough levels were 1.6 and 4.5 µM, sufficient to achieve &gt; 90% arginase inhibition, and plasma arginine levels increased 2.4- and 4-fold, respectively. CB-1158 has been well tolerated with no DLTs or drug-related Grade 3 AEs. Dose escalation is ongoing and updated safety, PK and biomarker data will be presented. Conclusions: CB-1158 is a first-in-class inhibitor of the myeloid-derived immunosuppressive enzyme arginase. CB-1158 has been well tolerated and achieves on-target inhibition resulting in increases in plasma arginine, an amino acid required for T-cell immune responses. Clinical trial information: NCT02903914.

Influence of MDR1 and CYP3A5 genetic polymorphisms on trough levels and therapeutic response of imatinib in newly diagnosed patients with chronic myeloid leukemia

Polymorphisms in genes coding for imatinib transporters and metabolizing enzymes may affect imatinib pharmacokinetics and clinical response. Aim of this study was to assess the influence of polymorphisms in MDR1 and CYP3A5 genes on imatinib trough levels, cytogenetic and molecular response in patients with CML. Newly diagnosed patients with chronic-phase CML started on imatinib therapy were enrolled and followed up prospectively for 24 months. The following single nucleotide polymorphisms were genotyped; C1236T, C3435T, G2677T/A in MDR1 gene and A6986G in CYP3A5 gene. Genotyping was done using PCR-RFLP method and validated by direct gene sequencing. Trough levels of imatinib were measured using LC–MS/MS. Cytogenetic response was assessed by conventional bone-marrow cytogenetics. Molecular response was assessed by qRTPCR using international scale. A total of 173 patients were included, out of which 71 patients were imatinib responders, while 102 were non-responders. Marked inter-individual variability in trough levels of imatinib was seen. Patients with GG genotype for CYP3A5-A6986G (P=0.016) and TT genotype for MDR1-C3435T (P=0.013) polymorphisms had significantly higher trough levels of imatinib. Patients with AA genotype for CYP3A5-A6986G [RR=1.448, 95% CI (1.126, 1.860), P=0.029] and CC genotype for MDR1-C1236T [RR=1.397, 95% CI (1.066, 1.831), P=0.06] &MDR1-C3435T [RR=1.508, 95% CI (1.186, 1.917), P=0.018] polymorphisms were at high risk for failure of imatinib therapy. Patients with CGC haplotype for MDR1 polymorphisms had significantly lower imatinib trough levels and were at a higher risk of imatinib failure [RR=1.547, 95% CI (1.324, 1.808), P<0.001]. GG vs. non-GG genotype for CYP3A5-A6986G [adjusted OR: 0.246; 95% CI (0.116, 0.519); P<0.001] and TT vs. non-TT genotype for MDR1-C1236T [adjusted OR: 0.270; 95% CI (0.110, 0.659); P=0.004] &MDR1-C3435T [adjusted OR: 0.289; 95% CI (0.135, 0.615); P=0.001] polymorphisms were independent factors predicting imatinib response in multivariate analysis. To conclude, MDR1 and CYP3A5 genetic polymorphisms significantly influence plasma trough levels and therapeutic response of imatinib in patients with CML. Genotyping of these polymorphisms could be of value to individualize the therapy and optimize the clinical outcomes.

Development and validation of an ELISA method for the quantification of nivolumab in plasma from non-small-cell lung cancer patients

Nivolumab, an anti PD-1 monoclonal antibody, has been approved for the treatment of previously treated advanced or metastatic non-small-cell lung cancer (NSCLC). The aim of this study was to develop and validate an ELISA method for the quantification of nivolumab in plasma from patients with NSCLC in order to perform future pharmacokinetic/pharmacodynamic (PK/PD) studies. A home-made ELISA was developed and validated according to the general recommendations for the immunoassays. Then, the ELISA method was applied to quantify plasma trough levels (Cmin) of nivolumab (3mg/kg every two weeks) in 27 NSCLC patients at days 14, 28 and 42 after start of treatment. Blood samples were collected just before the infusion on days 0 (baseline), 14, 28 and 42 after start of treatment. The dynamic calibration range for nivolumab assay was 5–100μg/mL. Within- and between-day imprecision for quality controls (5, 20 and 75μg/mL) were less than 5 and 12%, respectively. The mean (±standard deviation) nivolumab Cmin was 17.3±4.8μg/mL (coefficient of variation, CV=27.8%), 25.0±9.7μg/mL (CV=38.8%) and 33.0±12.9μg/mL (CV=39.1%) on days 14, 28 and 42, respectively. IgG (p=0.002) and ALT (p=0.041) were independently associated with plasma nivolumab Cmin at day 42. The present ELISA method for quantification of nivolumab in plasma from NSCLC patients is sensitive and accurate enough to be used for further PK/PD investigations.

Dose optimisation of voriconazole with therapeutic drug monitoring in children: a single-centre experience in China

The pharmacokinetic profile of voriconazole is highly variable, rendering inconsistent and/or inadequate dosing, especially in children <2 years old. A retrospective analysis was performed in children receiving voriconazole with at least one plasma trough level (Ctrough) monitored. Statistical analyses were performed to examine the dose–exposure relationship as well as other factors potentially affecting voriconazole Ctrough in children of different ages. A total of 107 paediatric patients were included, of whom 75 were <2 years old. The voriconazole Ctrough was highly variable in patients aged <2 years and those aged 2–12 years. Only 47.7% of children reached the therapeutic target of 1.0–5.5 mg/L at initial dosing, whereas 48.6% of Ctrough values were subtherapeutic and 3.7% were supratherapeutic. The mean maintenance dose to reach an adequate Ctrough was 5.9 mg/kg compared with 5.1 mg/kg, resulting in insufficient levels (P = 0.005) in children aged <2 years. In this age group, the 5 to <7 mg/kg dose range significantly increased the chance of reaching the therapeutic target compared with the 3 to <5 mg/kg dose range (56.7% vs. 25.8%; P = 0.014). Overall, factors such as sex, age, liver function, renal function and co-administered medications explained only 15.9% of variability in voriconazole exposure. Co-administration of omeprazole significantly increased the voriconazole level (P = 0.032), likely through CYP2C19 inhibition. This is the largest series to date describing voriconazole dose–exposure relationships in children aged <2 years. A starting maintenance dose of 5 to <7 mg/kg intravenously twice daily may be required for most children of Asian origin to reach the therapeutic target.