Abstract Background Drug Clearance (CL) is a better pharmacokinetic (PK) metric compared to trough levels (TL) in associating with therapeutic outcome of infliximab, adalimumab and ustekinumab therapy in Crohn’s disease (CD). However, data regarding vedolizumab (VDZ) are limited. We compared the performances of VDZ CL and TL in associating with therapeutic outcomes in CD. Methods This retrospective analysis included a subset patients from the LOVE-CD trial at Amsterdam UMC. Blood samples were collected at trough during intravenous VDZ maintenance treatment and stored at -80ºC until analysis. VDZ TL were measured using homogenous mobility shift assay and CL was estimated using nonlinear mixed effect models. Therapeutic outcomes consisted of endoscopic remission (Simple Endoscopic Scoring for CD [SES-CD] <3) measured at one-year after starting treatment, and clinical and biochemical remission status (CRP <3 mg/L with CD activity index <150) at each maintenance cycle. Statistical analyses included receiver operating characteristics (ROC) curves, area under the curve (AUC) and logistic regression. Results A total of 50 patients (24 females, mean age 37 years) were evaluated in this analysis. At one year 39 patients had endoscopic data; 17/39 (44%) were in endoscopic remission. In the 50 patients, 38% of cycles (120/312, median 6 per patients) showed clinical and biochemical remission. Median TL and CL were 16.0 µg/mL (IQR: 9.5-23.8 µg/mL) and 0.154 L/day (IQR: 0.125-0.190 L/day) respectively. Anti-drug antibodies to VDZ were negligible in this cohort (2.5%, 8/323 specimens). ROC analysis yielded higher AUC with CL (AUC= 0.824 [95%CI: 0.683-0.964]) than with TL (AUC=0.606 [95%CI: 0.421- 0.790]) (difference= 0.218 95%CI: 0.074- 0.362; p=0.003) in distinguishing endoscopic remission from endoscopic active disease. Similar results were observed with the clinical and biochemical remission outcome (AUC [conc]=0.530 [95%CI: 0.466-0.595] compared to AUC[CL]=0.646 [95%CI: 0.584- 0.709]) (difference: 0.116 95%CI: 0.063- 0.169; p<0.001). Logistic regression revealed that TL were not significantly associated with either of the two outcomes (p>0.28) (Figure). In contrast, higher CL (>0.156 L/day) was associated with 9.0-fold (95%CI: 1.7,44.0) and 2.1-fold (95%CI: 1.3,3.4) lower likelihood of endoscopic and clinical & biochemical remission, respectively (p<0.01) (Table). Conclusion These data support the hypothesis that VDZ CL is better than TL in associating with outcomes of VDZ treatment in CD. Given that there was little immune response to VDZ in this study, the association between higher CL and poor outcome most likely reflects higher inflammatory burden that consumes the drug from the central compartment.
Supplementary Figure from Preclinical and Pilot Study of Type I FLT3 Tyrosine Kinase Inhibitor, Crenolanib, with Sorafenib in Acute Myeloid Leukemia and <i>FLT3</i>-Internal Tandem Duplication
2523 Background: Gefitinib is an orally active inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase. Neuroblastoma, rhabdomyosarcoma, osteosarcoma, and high-grade gliomas are known to express EGFR. Thus, three phase I studies evaluating gefitinib pharmacokinetics were conducted in children with recurrent/refractory solid tumors (COG ADVL0016 and SJZD1839) or brain tumors (PBTC007). Because of wide inter-individual variability in gefitinib disposition, the present study was conducted to describe the population PK of gefitinib and to assess the relationship between gefitinib disposition and patient covariates. Methods: Subjects received daily oral gefitinib ranging from 100 to 500 mg/m2 as single agent therapy for 8 to 10 days prior to PK evaluation. Multiple plasma samples were collected per subject and analyzed using a validated LC MS/MS assay. The data consisted of 73 subjects and 600 samples. Data were analyzed using NONMEM v5 to obtain gefitinib apparent oral clearance (CL/F), apparent volume of distribution (V/F), and the absorption rate constant (ka). Covariates investigated included demographic (age, body surface area [BSA]) and laboratory variables, concomitant drug therapy (dexamethasone, H2-receptor antagonist), and genetic polymorphisms in CYP3A4*1B, CYP3A5*3C, CYP3A5*6, ABCB1 (exon 21 and 26), and ABCG2 (exons 2 and 5). Results: Gefitinib pharmacokinetics were described by a one-compartment model with first-order absorption. BSA was a significant covariate (p<0.05). The mean population estimates were CL/F 17.8 L/h/m2, V/F 348 L/h/m2, ka 0.519 h-1. A significant relationship was found between CL/F and ABCB1 exon 21 (p<0.05) and ABCB1 exon 26 (p<0.05) polymorphisms. Specifically, CL/F was decreased in patients homozygous for exons 21 and 26 (36% and 20%, respectively) relative to wild-type and heterozygous. Conclusions: The results obtained are consistent with published data in adults. The relationship between gefitinib CL/F and ABCB1 genetic polymorphisms explained a significant amount of the interindividual variability in CL/F. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration AstraZeneca
Although cure rate of childhood acute lymphoblastic leukemia (ALL) has surpassed 80%, drug resistance remains a major cause of treatment failure. We previously identified a panel of 33 genes differentially expressed in prednisolone sensitive versus resistant ALL cells from newly diagnosed children. Here we used bioinformatics to identify resistance genes most likely to contain single nucleotide polymorphisms (SNPs) in their promoter region. The highest priority gene was SMARCB1, a core member of the SWI/SNF complex which promotes glucocorticoid effects through nucleosome remodeling. We identified several SNPs in the SMARCB1 promoter in lymphoblastoid cells from 90 individuals in the Centre d'Etude du Polymorphisme Humain (CEPH) panel. Among these SNPs, the −228G>T SNP (allele frequency 9.4%) was the only one that significantly increased reporter activity in human ALL cell lines. Furthermore, we identified nuclear protein poly (ADP-ribose) polymerase family, member 1 (PARP1) as a nuclear protein binding to the SMARCB1 promoter and showed that the −228 SNP significantly altered PARP1 binding affinity. The −228G>T SNP altered SMARCB1 mRNA and protein levels and a positive association was found between the SMARCB1 mRNA level and both the −228 genotype and prednisolone sensitivity in CEPH cell lines. Finally, knockdown experiments performed in human ALL cell lines confirmed that lower SMARCB1 expression increased prednisolone resistance. In summary, we provide functional evidence that SMARCB1 is involved in prednisolone resistance and identified a promoter SNP that alters the level of SMARCB1 mRNA and protein expression and the binding of PARP1 to the SMARCB1 promoter.
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