Nephrogenic systemic fibrosis risk after liver magnetic resonance imaging with gadoxetate disodium in patients with moderate to severe renal impairment: results of a prospective, open-label, multicenter study.
ABSTRACT: The objective of this study was to assess the risk of gadoxetate disodium in liver imaging for the development of nephrogenic systemic fibrosis (NSF) in patients with moderate to severe renal impairment.We performed a prospective, multicenter, nonrandomized, open-label phase 4 study in 35 centers from May 2009 to July 2013. The study population consisted of patients with moderate to severe renal impairment scheduled for liver imaging with gadoxetate disodium. All patients received a single intravenous bolus injection of 0.025-mmol/kg body weight of liver-specific gadoxetate disodium. The primary target variable was the number of patients who develop NSF within a 2-year follow-up period.A total of 357 patients were included, with 85 patients with severe and 193 patients with moderate renal impairment, which were the clinically most relevant groups. The mean time period from diagnosis of renal disease to liver magnetic resonance imaging (MRI) was 1.53 and 5.46 years in the moderate and severe renal impairment cohort, respectively. Overall, 101 patients (28%) underwent additional contrast-enhanced MRI with other gadolinium-based MRI contrast agents within 12 months before the start of the study or in the follow-up. No patient developed symptoms conclusive of NSF within the 2-year follow-up.Gadoxetate disodium in patients with moderate to severe renal impairment did not raise any clinically significant safety concern. No NSF cases were observed.
Project description:The aim of this study was to assess the potential risk of gadobutrol-enhanced magnetic resonance imaging (MRI) in patients with moderate to severe renal impairment for the development of nephrogenic systemic fibrosis (NSF).We performed a prospective, international, multicenter, open-label study in 55 centers. Patients with moderate to severe renal impairment scheduled for any gadobutrol-enhanced MRI were included. All patients received a single intravenous bolus injection of gadobutrol at a dose of 0.1 mmol/kg body weight. The primary target variable was the number of patients who develop NSF within a 2-year follow-up period.A total of 908 patients were enrolled, including 586 with moderate and 284 with severe renal impairment who are at highest risk for developing NSF. The mean time since renal disease diagnosis was 1.83 and 5.49 years in the moderate and severe renal impairment cohort, respectively. Overall, 184 patients (20.3%) underwent further contrast-enhanced MRI with other gadolinium-based contrast agents within the 2-year follow-up. No patient developed symptoms conclusive of NSF.No safety concerns with gadobutrol in patients with moderate to severe renal impairment were identified. There were no NSF cases.
Project description:PURPOSE:Evaluate Gadoxetate Disodium enhanced dual-energy CT for visualization of perihilar cholangiocarcinoma by exploiting the hepatobiliary uptake of Gadoxetate Disodium and viewing images at the k-edge of gadolinium on the spectrum of simulated monoenergetic energies available with Dual Energy CT. MATERIAL AND METHODS:In this prospective, IRB-approved study in patients with suspected cholangiocarcinoma, subjects who underwent a clinically indicated Gadoxetate Disodium liver MRI were immediately scanned without further IV contrast administration using rapid kVp-switching dual energy CT (rsDECT). Initial Gadoxetate Disodium dose was the FDA approved clinical dose, 0.025 mmol/kg; after additional IRB/FDA approval, 10 subjects were scanned with 0.05 mmol/kg. Both 50 keV and 70 keV simulated monoenergetic images as well as gadolinium(-water) material density images were viewed qualitatively and measured quantitatively for gadolinium uptake in the hepatic parenchyma and any focal lesions identified. RESULTS:Of 18 subjects (mean age 55 years, 10M, 8F, weight 84 kg), eight were scanned with 0.025 mmol/kg (Group 1) and 10 with 0.05 mmol/kg Gadoxetate Disodium (Group 2). Five patients had cholangiocarcinoma (all in Group 1). On synthetic monoenergetic images using standard and double Gadoxetate Disodium dose, the liver parenchyma did not appear enhanced qualitatively. Comparison of mean hepatic parenchymal HU at 50 and 70 keV showed a measurable increase in attenuation at the lower viewing energy, which corresponded to the k-edge of gadolinium. No statistically significant difference was observed on quantitative gadolinium measurement of hepatic parenchyma for single versus double Gadoxetate Disodium dose using rsDECT gadolinium material density images. Of the five cholangiocarcinomas, the tumor to nontumoral hepatic tissue HU differences were 51.1 (32.2) (mean and std dev) and 49.0(26.5) at 50 and 70 keV, respectively. CONCLUSION:In this small pilot population, evaluation of potential hilar/perihilar cholangiocarcinoma using dual energy CT at both the single FDA-approved dose and double dose of gadolinium demonstrated observed differences in attenuation between the hepatic parenchyma and lesions. However, small sample size and heterogeneity of lesions warrants further investigation.
Project description:OATP1B3 is expressed de novo in primary prostate cancer tissue and to a greater degree in prostate cancer metastases. Gadoxetate disodium is a substrate of OATP1B3, and its uptake has been shown to correlate with OATP1B3 expression in other cancers. We aimed to evaluate use of gadoxetate disodium to image prostate cancer and to track its utility as a biomarker. A single center open-label non-randomized pilot study recruited men with (1) localized, and (2) metastatic castration resistant prostate cancer (mCRPC). Gadoxetate disodium-enhanced MRI was performed at four timepoints post-injection. The Wilcoxon signed rank test was used to compare MRI contrast enhancement ratio (CER) pre-injection and post-injection. OATP1B3 expression was evaluated via immunohistochemistry (IHC) and a pharmacogenomic analysis of OATP1B3, NCTP and OATP1B1 was conducted. The mCRPC subgroup (n?=?9) demonstrated significant enhancement compared to pre-contrast images at 20-, 40- and 60-min timepoints (p?<?0.0078). The localized cancer subgroup (n?=?11) demonstrated earlier enhancement compared to the mCRPC group, but no retention over time (p?>?0.05). OATP1B3 expression on IHC trended higher contrast enhancement between 20-40 min (p???0.064) and was associated with contrast enhancement at 60 min (p?=?0.0422). OATP1B1 haplotype, with N130D and V174A substitutions, impacted enhancement at 40-60 min (p???0.038). mCRPC lesions demonstrate enhancement after injection of gadoxetate disodium on MRI and retention over 60 min. As inter-individual variability in OATP1B3 expression and function has both predictive and prognostic significance, gadoxetate disodium has potential as a biomarker in prostate cancer.
Project description:The objective of this study was to use noninvasive dynamic contrast-enhanced magnetic resonance imaging (MRI) techniques to study, in vivo, the distribution and elimination of the hepatobiliary contrast agent gadoxetate in the human body and characterize the transport mechanisms involved in its uptake into hepatocytes and subsequent efflux into the bile using a novel tracer kinetic model in a group of healthy volunteers.Ten healthy volunteers (age range, 18-29 years), with no history of renal or hepatic impairment, were recruited via advertisement. Participants attended 2 MRI visits (at least a week apart) with gadoxetate as the contrast agent. Dynamic contrast-enhanced MRI data were acquired for approximately 50 minutes with a 3-dimensional gradient-echo sequence in the axial plane, at a temporal resolution of 6.2 seconds. Data from regions of interest drawn in the liver were analyzed using the proposed 2-compartment uptake and efflux model to provide estimates for the uptake rate of gadoxetate in hepatocytes and its efflux rate into the bile. Reproducibility statistics for the 2 visits were obtained to examine the robustness of the technique and its dependence in acquisition time.Eight participants attended the study twice and were included into the analysis. The resulting images provided the ability to simultaneously monitor the distribution of gadoxetate in multiple organs including the liver, spleen, and kidneys as well as its elimination through the common bile duct, accumulation in the gallbladder, and excretion in the duodenum. The mean uptake (ki) and efflux (kef) rates in hepatocytes, for the 2 visits using the 50-minute acquisition, were 0.22 ± 0.05 and 0.017 ± 0.006/min, respectively. The hepatic extraction fraction was estimated to be 0.19 ± 0.04/min. The variability between the 2 visits within the group level (95% confidence interval; ki: ±0.02/min, kef: ±0.004/min) was lower compared with the individual variability (repeatability; ki: ±0.06/min, kef: ±0.012/min). Data truncation demonstrated that the uptake rate estimates retained their precision as well as their group and individual reproducibility down to approximately 10 minutes of acquisition. Efflux rate estimates were underestimated (compared with the 50-minute acquisition) as the duration of the acquisition decreased, although these effects were more pronounced for acquisition times shorter than approximately 30 minutes.This is the first study that reports estimates for the hepatic uptake and efflux transport process of gadoxetate in healthy volunteers in vivo. The results highlight that dynamic contrast-enhanced MRI with gadoxetate can provide novel quantitative insights into liver function and may therefore prove useful in studies that aim to monitor liver pathology, as well as being an alternative approach for studying hepatic drug-drug interactions.
Project description:PURPOSE:To investigate the safety of gadoterate meglumine and identify the incidence of nephrogenic systemic fibrosis (NSF). MATERIALS AND METHODS:An international prospective observational study was conducted from November 2008 to June 2013. A total of 35,499 adults and children who were scheduled to undergo contrast-enhanced MRI using gadoterate meglumine were analyzed (female, 53.1%; mean age: 49.5 years; range: 0-98 years). At least 3-month follow-up was planned for patients with an estimated creatinine clearance or glomerular filtration rate <60 mL/min (/1.73 m2) to detect any suspicion or occurrence of NSF. Adverse events (AEs) were prospectively recorded. Demographic data, risk factors, indications for MRI examinations, characteristics of gadoterate meglumine administration, and efficacy were documented. RESULTS:MRI examinations were mainly for central nervous system (61%). The most frequent risk factor was renal insufficiency (14.7%). Seventy AEs were observed in 44 patients (0.12%). Among the 70 AEs, 38 in 32 patients (0.09% of all patients) were considered related to gadoterate meglumine and classified as adverse drug reaction (ADR).The most frequent ADRs were urticaria (9 patients, 0.03%), nausea (7 patients, 0.02%), and vomiting (4 patients, 0.01%). Within the pediatric population (1,629 patients), only one AE (vomiting) was observed. Nine adult patients (0.03%) experienced serious AEs. Moderate to severe renal insufficiency at inclusion was reported in 514 patients (1.5%). Among them, 476 (92.6%) were followed-up. No patients were suspected of having NSF and no cases of NSF were observed. CONCLUSION:Our study confirms the excellent safety profile of gadoterate meglumine in routine practice. LEVEL OF EVIDENCE:1 J. Magn. Reson. Imaging 2017;45:988-997.
Project description:To date there are potential chronology-based but not conclusive reasons to believe that at least some of the gadolinium complexes play a causative role in the pathophysiology of nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD). Still, the exact pathogenesis and the risk for patients is unclear beside the obvious connection to moderate to severe renal insufficiency. So far, MR imaging with Gd-enhancement was regarded as the safest imaging modality in these patients--the recent development creates tremendous uncertainty in the MR-community. Nevertheless, one should remember that, despite the over 200 cases of NSF and about 100 with proven involvement of Gd(3+), the vast majority of over 200 million patients exposed to gadolinium since the 1980s have tolerated these agents well. Importantly, NSF is a rare disease and does not appear to occur in patients without renal impairment. Many patients and researchers have undergone MR investigations with Gd exposure in the past. For those, it is essential to know about the safety of the agents at normal renal function. We can hope that pharmacoepidemiological and preclinical studies will allow us to better understand the pathophysiology and role of the various MR contrast agents in the near future.
Project description:Estimation of liver function is important to monitor progression of chronic liver disease (CLD). A promising method is magnetic resonance imaging (MRI) combined with gadoxetate, a liver-specific contrast agent. For this method, we have previously developed a model for an average healthy human. Herein, we extended this model, by combining it with a patient-specific non-linear mixed-effects modeling framework. We validated the model by recruiting 100 patients with CLD of varying severity and etiologies. The model explained all MRI data and adequately predicted both timepoints saved for validation and gadoxetate concentrations in both plasma and biopsies. The validated model provides a new and deeper look into how the mechanisms of liver function vary across a wide variety of liver diseases. The basic mechanisms remain the same, but increasing fibrosis reduces uptake and increases excretion of gadoxetate. These mechanisms are shared across many liver functions and can now be estimated from standard clinical images.
Project description:<h4>Aim(s)</h4>This study assessed the effect of differences in renal function on the pharmacokinetics and pharmacodynamics of dapagliflozin, a renal sodium glucose co-transporter-2 (SGLT2) inhibitor for the treatment of type 2 diabetes mellitus (T2DM).<h4>Methods</h4>A single 50 mg dose of dapagliflozin was used to assess pharmacokinetics and pharmacodynamics in five groups: healthy non-diabetic subjects; patients with T2DM and normal kidney function and patients with T2DM and mild, moderate or severe renal impairment based on estimated creatinine clearance. Subsequently, 20 mg once daily multiple doses of dapagliflozin were evaluated in the patients with T2DM. Formation rates of dapagliflozin 3-O-glucuronide (D3OG), an inactive metabolite, were evaluated using human isolated kidney and liver microsomes.<h4>Results</h4>Plasma concentrations of dapagliflozin and D3OG were incrementally increased with declining kidney function. Steady-state Cmax for dapagliflozin were 4%, 6% and 9% higher and for D3OG were 20%, 37% and 52% higher in patients with mild, moderate and severe renal impairment, respectively, compared with normal function. AUC(0,?) was likewise higher. D3OG formation in kidney microsomes was three-fold higher than in liver microsomes and 109-fold higher than in intestine microsomes. Compared with patients with normal renal function, pharmacodynamic effects were attenuated with renal impairment. Steady-state renal glucose clearance was reduced by 42%, 83% and 84% in patients with mild, moderate or severe renal impairment, respectively.<h4>Conclusions</h4>These results indicate that both kidney and liver significantly contribute to dapagliflozin metabolism, resulting in higher systemic exposure with declining kidney function. Dapagliflozin pharmacodynamics in diabetic subjects with moderate to severe renal impairment are consistent with the observation of reduced efficacy in this patient population.
Project description:Diabetes is associated with hepatic metabolic dysfunction predisposing patients to drug-induced liver injury. Mouse models of type 2 diabetes (T2D) have dramatically reduced expression of organic anion transporting polypeptide (OATP)1A1, a transporter expressed in hepatocytes and in the kidneys. The effects of diabetes on OATP1B2 expression are less studied and less consistent. OATP1A1 and OATP1B2 both transport endogenous substrates such as bile acids and hormone conjugates as well as numerous drugs including gadoxetate disodium (Gd-EOB-DTPA). As master pharmacokinetic regulators, the altered expression of OATPs in diabetes could have a profound and clinically significant influence on drug therapies. Here, we report a method to noninvasively measure OATP activity in T2D mice by quantifying the transport of hepatobiliary-specific gadolinium-based contrast agents (GBCAs) within the liver and kidneys using dynamic contrast-enhanced MRI (DCE-MRI). By comparing GBCA uptake in control and OATP knockout mice, we confirmed liver clearance of the hepatobiliary-specific GBCAs, Gd-EOB-DTPA, and gadobenate dimeglumine, primarily though OATP transporters. Then, we measured a reduction in the hepatic uptake of these hepatobiliary GBCAs in T2D <i>ob</i>/<i>ob</i> mice, which mirrored significant reductions in the mRNA and protein expression of OATP1A1 and OATP1B2. As these GBCAs are U.S. Food and Drug Administration-approved agents and DCE-MRI is a standard clinical protocol, studies to determine OATP1B1/1B3 deficiencies in human individuals with diabetes can be easily envisioned.
Project description:Drug-induced liver injury (DILI) is a leading cause of acute liver failure and transplantation. DILI can be the result of impaired hepatobiliary transporters, with altered bile formation, flow, and subsequent cholestasis. We used gadoxetate dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), combined with pharmacokinetic modelling, to measure hepatobiliary transporter function in vivo in rats. The sensitivity and robustness of the method was tested by evaluating the effect of a clinical dose of the antibiotic rifampicin in four different preclinical imaging centers. The mean gadoxetate uptake rate constant for the vehicle groups at all centers was 39.3 +/- 3.4 s-1 (n = 23) and 11.7 +/- 1.3 s-1 (n = 20) for the rifampicin groups. The mean gadoxetate efflux rate constant for the vehicle groups was 1.53 +/- 0.08 s-1 (n = 23) and for the rifampicin treated groups was 0.94 +/- 0.08 s-1 (n = 20). Both the uptake and excretion transporters of gadoxetate were statistically significantly inhibited by the clinical dose of rifampicin at all centers and the size of this treatment group effect was consistent across the centers. Gadoxetate is a clinically approved MRI contrast agent, so this method is readily transferable to the clinic. CONCLUSION:Rate constants of gadoxetate uptake and excretion are sensitive and robust biomarkers to detect early changes in hepatobiliary transporter function in vivo in rats prior to established biomarkers of liver toxicity.