scholarly journals A Mechanistic Model of Drug-Induced Liver Injury Aids the Interpretation of Elevated Liver Transaminase Levels in a Phase I Clinical Trial

2014 ◽  
Vol 3 (2) ◽  
pp. 98 ◽  
Author(s):  
BA Howell ◽  
SQ Siler ◽  
LKM Shoda ◽  
Y Yang ◽  
JL Woodhead ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Liver Injury ◽  
Phase I ◽  
Mechanistic Model ◽  
Phase I Clinical Trial ◽  
Drug Induced ◽  
Liver Transaminase ◽  
Drug Induced Liver Injury ◽  
Elevated Liver Transaminase

Survivin-responsive conditionally replicating adenovirus for patients with advanced sarcoma demonstrated potent and long-term efficacy and high safety in a phase I clinical trial.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 11512-11512
Author(s):  
Satoshi Nagano ◽  
Toshitaka Futagawa ◽  
Eriko Sumi ◽  
Nobuhiro Ijichi ◽  
Munekazu Yamaguchi ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Phase I Clinical Trial ◽  
Oncolytic Viruses ◽  
High Dose ◽  
Liver Transaminase ◽  
Musculoskeletal Tumors ◽  
Choi Criteria

11512 Background: Whereas one of oncolytic viruses (OVs), inducing selective tumor killing and systemic anti-tumor immunity, was approved by FDA in 2015, the best OV that more safely and efficiently treats intractable cancers has not been successfully developed. By our platform technology to efficiently construct next-generation OVs, i.e., “conditionally replicating adenoviruses (CRAs) that target and/or treat tumor cells with multiple factors” (m-CRAs), we identified that among candidates, survivin-responsive m-CRAs (Surv.m-CRAs) exhibited the most potent antitumor efficacy and cancer selectivity ( i.e., safety) in preclinical studies ( Cancer Res, 2005 et al.). Here we present the data of First-In-Human phase I clinical trial of Surv.m-CRA-1 for musculoskeletal tumors (MST). Methods: This single-arm, open label study included 9 patients with unresectable and advanced MST. Patients underwent a single intratumoral injection of either 1×10^10 viral particle (vp) (low), 1×10^11 vp (mid) or 1×10^12 vp (high). The primary endpoints were safety and tolerability. The secondary endpoints included the local control of treated tumor at one month, defined by RECIST and Choi criteria, analysis of dissemination of Surv.m-CRA-1, serum cytokine and adenoviral antibody. Long-term follow-up was done in some patients. Results: Four patients (44.4%) had grade 3 or higher adverse events, including lymphopenia, leukocytopenia and mildly elevated liver transaminase in 2, 1 and 1 patient, respectively. Virus excretions, including second peak of viremia from viral replication in tumor, were observed in 1, 2 and 3 patients of low, mid and high dose, respectively. Out of 9 patients, 5 PR, 3 SD and 1 PD by Choi, and 8 SD and 1 PD by RECIST were observed. During follow-up, another 1 and 2 patients became PR by Choi and RECIST, respectively. Of note, long-term PR (over 2 years) after a single injection of Surv.m-CRA-1 was achieved in two chordoma cases in low dose. Conclusions: Surv.m-CRA-1 was well tolerated and showed antitumor activity for prolonged periods against advanced MST. We about to start Phase I/II study of multiple injections of Surv.m-CRA-1 for advanced solid tumors in two-arms for musculoskeletal tumors and pancreatic cancer. Clinical trial information: R000026464 .

Validation of Multivariate Outlier Detection Analyses Used to Identify Potential Drug-Induced Liver Injury in Clinical Trial Populations

Drug Safety ◽  
2012 ◽  
Vol 35 (10) ◽  
pp. 865-875 ◽  
Author(s):  
Xiwu Lin ◽  
Daniel Parks ◽  
Jeffery Painter ◽  
Christine M. Hunt ◽  
Heide A. Stirnadel-Farrant ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Liver Injury ◽  
Outlier Detection ◽  
Potential Drug ◽  
Drug Induced ◽  
Multivariate Outlier Detection ◽  
Drug Induced Liver Injury

Phase I Clinical Trial of Oral COL-3, a Matrix Metalloproteinase Inhibitor, in Patients With Refractory Metastatic Cancer

2001 ◽  
Vol 19 (2) ◽  
pp. 584-592 ◽  
Author(s):  
Michelle A. Rudek ◽  
William D. Figg ◽  
Valerie Dyer ◽  
William Dahut ◽  
Maria L. Turner ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Growth Factor ◽  
Matrix Metalloproteinase ◽  
Phase I ◽  
Metastatic Cancer ◽  
Phase I Clinical Trial ◽  
Pharmacokinetic Parameters ◽  
Phase Ii Trials ◽  
Drug Induced ◽  
Disease Stabilization

PURPOSE: This phase I clinical trial was designed to determine the maximum-tolerated dose and dose-limiting toxicities of the matrix metalloproteinase (MMP) inhibitor COL-3 in patients with refractory solid tumors. PATIENTS AND METHODS: Thirty-five patients with different cancer types were enrolled. COL-3 doses were escalated from 36 mg/m2/d in successive cohorts of at least three patients. Circulating levels of MMP-2, MMP-9, vascular endothelial growth factor, and basic fibroblast growth factor were assessed during treatment. Pharmacokinetic parameters were assessed for single and multiple doses of drug. RESULTS: Cutaneous phototoxicity was dose-limiting at 98 mg/m2/d. With the use of prophylactic sunblock, COL-3 was well tolerated at 70 mg/m2/d. The dose of 36 mg/m2/d was well tolerated without the use of sunblock. Other toxicities that did not seem to be related to dose or pharmacokinetics included anemia, anorexia, constipation, dizziness, elevated liver function test results, fever, headache, heartburn, nausea, vomiting, peripheral and central neurotoxicities, fatigue, and three cases of drug-induced lupus. Disease stabilization for periods of 26+ months, 8 months, and 6 months were seen in hemangioendothelioma, Sertoli-Leydig cell tumor, and fibrosarcoma, respectively. There was a potentially statistically significant relationship between changes in plasma MMP-2 levels and cumulative doses of drug when progressive disease patients were compared with those with stable disease or toxicity (P = .042). CONCLUSION: COL-3 induced disease stabilization in several patients who had a nonepithelial type of malignancy. Phototoxicity was dose-limiting. We recommend the dose of 36 mg/m2/d for phase II trials.

scholarly journals Exploring BSEP inhibition-mediated toxicity with a mechanistic model of drug-induced liver injury

2014 ◽  
Vol 5 ◽  
Author(s):  
Jeffrey L. Woodhead ◽  
Kyunghee Yang ◽  
Scott Q. Siler ◽  
Paul B. Watkins ◽  
Kim L. R. Brouwer ◽  
...  
Keyword(s):  
Liver Injury ◽  
Mechanistic Model ◽  
Drug Induced ◽  
Drug Induced Liver Injury

Validation of Multivariate Outlier Detection Analyses Used to Identify Potential Drug-Induced Liver Injury in Clinical Trial Populations

Drug Safety ◽  
2012 ◽  
Vol 35 (10) ◽  
pp. 865-875
Author(s):  
Xiwu Lin ◽  
Daniel Parks ◽  
Jeffery Painter ◽  
Christine M. Hunt ◽  
Heide A. Stirnadel-Farrant ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Liver Injury ◽  
Outlier Detection ◽  
Potential Drug ◽  
Drug Induced ◽  
Multivariate Outlier Detection ◽  
Drug Induced Liver Injury

scholarly journals Application of a Mechanistic Model to Evaluate Putative Mechanisms of Tolvaptan Drug-Induced Liver Injury and Identify Patient Susceptibility Factors

2016 ◽  
Vol 155 (1) ◽  
pp. 61-74 ◽  
Author(s):  
Jeffrey L. Woodhead ◽  
William J. Brock ◽  
Sharin E. Roth ◽  
Susan E. Shoaf ◽  
Kim L.R. Brouwer ◽  
...  
Keyword(s):  
Liver Injury ◽  
Mechanistic Model ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Susceptibility Factors

Leberschaden unter oraler Antikoagulation, Statin- und ACE-Hemmertherapie

Praxis ◽  
2010 ◽  
Vol 99 (21) ◽  
pp. 1259-1265 ◽  
Author(s):  
Bruggisser ◽  
Terraciano ◽  
Rätz Bravo ◽  
Haschke
Keyword(s):  
Liver Injury ◽  
Wird Eine ◽  
Drug Induced ◽  
Drug Induced Liver Injury

Ein 71-jähriger Patient stellt sich mit Epistaxis und ikterischen Skleren auf der Notfallstation vor. Der Patient steht unter einer Therapie mit Phenprocoumon, Atorvastatin und Perindopril. Anamnestisch besteht ein langjähriger Alkoholabusus. Laborchemisch werden massiv erhöhte Leberwerte (ALAT, Bilirubin) gesehen. Der INR ist unter oraler Antikoagulation und bei akuter Leberinsuffizienz >12. Die weiterführenden Abklärungen schliessen eine Virushepatitis und eine Autoimmunhepatitis aus. Nachdem eine Leberbiopsie durchgeführt werden kann, wird eine medikamentös-toxische Hepatitis, ausgelöst durch die Komedikation von Atorvastatin, Phenprocoumon und Perindopril bei durch Alkohol bereits vorgeschädigter Leber diagnostiziert. Epidemiologie, Pathophysiologie und Klink der medikamentös induzierten Leberschäden (drug induced liver injury, DILI), speziell von Coumarinen, Statinen und ACE-Hemmern werden im Anschluss an den Fallbericht diskutiert.

Sign in / Sign up

Export Citation Format

Share Document