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1.
Br J Clin Pharmacol ; 85(3): 530-539, 2019 03.
Article in English | MEDLINE | ID: mdl-30428505

ABSTRACT

AIMS: Oprozomib is an oral, second-generation, irreversible proteasome inhibitor currently in clinical development for haematologic malignancies, including multiple myeloma and other malignancies. Oprozomib is a rare example of a small molecule drug that demonstrates cytochrome P450 (CYP) mRNA suppression. This unusual property elicits uncertainty regarding the optimal approach for predicting its drug-drug interaction (DDI) risk. The current study aims to understand DDI potential during early clinical development of oprozomib. METHODS: To support early development of oprozomib (e.g. inclusion/exclusion criteria, combination study design), we used human hepatocyte data and physiologically-based pharmacokinetic (PBPK) modelling to predict its CYP3A4-mediated DDI potential. Subsequently, a clinical DDI study using midazolam as the substrate was conducted in patients with advanced malignancies. RESULTS: The clinical DDI study enrolled a total of 21 patients, 18 with advanced solid tumours. No patient discontinued oprozomib due to a treatment-related adverse event. The PBPK model prospectively predicted oprozomib 300 mg would not cause a clinically relevant change in exposure to CYP3A4 substrates (≤30%), which was confirmed by the results of this clinical DDI study. CONCLUSIONS: These results indicate oprozomib has a low potential to inhibit the metabolism of CYP3A4 substrates in humans. The study shows that cultured human hepatocytes are a more reliable system for DDI prediction than human liver microsomes for studying this class of compounds. Developing a PBPK model prior to a clinical DDI study has been valuable in supporting clinical development of oprozomib.


Subject(s)
Cytochrome P-450 CYP3A Inhibitors/pharmacokinetics , Cytochrome P-450 CYP3A/metabolism , Neoplasms/drug therapy , Oligopeptides/pharmacokinetics , Proteasome Inhibitors/pharmacokinetics , Adult , Aged , Aged, 80 and over , Cells, Cultured , Cytochrome P-450 CYP3A Inhibitors/administration & dosage , Drug Development , Drug Interactions , Female , Hepatocytes , Humans , Male , Microsomes, Liver , Midazolam/administration & dosage , Midazolam/pharmacokinetics , Middle Aged , Models, Biological , Neoplasms/blood , Neoplasms/pathology , Oligopeptides/administration & dosage , Primary Cell Culture , Proteasome Inhibitors/administration & dosage , Young Adult
2.
Clin Lymphoma Myeloma Leuk ; 17(7): 433-437, 2017 07.
Article in English | MEDLINE | ID: mdl-28576443

ABSTRACT

INTRODUCTION: This phase 1b study evaluated the safety and efficacy of 3 dose levels of carfilzomib when provided with fixed dose oral cyclophosphamide and dexamethasone (KCyd) in patients with newly diagnosed multiple myeloma (MM). PATIENTS AND METHODS: CHAMPION-2 was a multicenter single-arm study. Patients with newly diagnosed secretory MM were enrolled and received KCyd treatment for up to 8 cycles. A 3 + 3 dose escalation scheme was used to evaluate twice-weekly carfilzomib at 36, 45, and 56 mg/m2 dose levels, followed by a dose expansion. RESULTS: No dose-limiting toxicities were observed in any of the dose evaluation cohorts. The KCyd regimen that included the maximum planned carfilzomib dose of 56 mg/m2 twice weekly was brought forward into dose expansion. A total of 16 patients were treated at this dose level. At 56 mg/m2 the overall response rate was 87.5% (95% confidence interval, 61.7-98.4), and the median time to response of 14 patients whose disease responded to therapy was 1 month. At this dose level, common adverse events of grade 3 or higher were anemia (25.0%), neutropenia (18.8%), acute kidney injury (12.5%), and decreased white blood cell count (12.5%). Ten of 16 patients who received carfilzomib at 56 mg/m2 completed all 8 cycles, 5 patients discontinued study therapy before cycle 8 as a result of adverse events, and 1 patient discontinued therapy as a result of progressive disease. CONCLUSION: Carfilzomib in combination with cyclophosphamide and dexamethasone is effective and has manageable toxicity for patients with newly diagnosed MM.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Multiple Myeloma/drug therapy , Proteasome Inhibitors/therapeutic use , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Female , Humans , Male , Middle Aged , Multiple Myeloma/pathology , Proteasome Inhibitors/administration & dosage , Proteasome Inhibitors/pharmacology
3.
J Pediatr Hematol Oncol ; 37(3): e178-81, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25089608

ABSTRACT

Systemic adenovirus infection in the immunocompromised host is often fatal and therapeutic options are limited. We report an infant with acute lymphoblastic leukemia who developed disseminated adenovirus infection while lymphopenic during maintenance chemotherapy 6 months following a bout of adenoviral diarrhea. His serum adenoviral load peaked at 35 million copies/mL and was associated with pancytopenia and hepatic injury. Treatment with cidofovir was effective although associated with mild renal injury. The patient recovered fully and completed chemotherapy for infant acute lymphoblastic leukemia.


Subject(s)
Adenovirus Infections, Human/drug therapy , Antiviral Agents/therapeutic use , Cytosine/analogs & derivatives , Organophosphonates/therapeutic use , Precursor Cell Lymphoblastic Leukemia-Lymphoma/virology , Adenovirus Infections, Human/pathology , Adenovirus Infections, Human/virology , Cidofovir , Cytosine/therapeutic use , Humans , Immunocompromised Host , Infant , Male , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Prognosis , Survival Rate
4.
J Cardiothorac Vasc Anesth ; 21(3): 388-92, 2007 Jun.
Article in English | MEDLINE | ID: mdl-17544892

ABSTRACT

OBJECTIVE: To delineate the incidence, outcome impact, and clinical predictors of atrial fibrillation (AF) after adult aortic arch repair requiring deep hypothermic circulatory arrest (AAR-DHCA) AIMS: To determine the incidence of AF after AAR-DHCA, to determine whether AF after AAR-DHCA affects mortality or stay in the intensive care unit (ICU), to determine multivariate predictors for AF after AAR-DHCA, and to determine whether aprotinin protects against AF after AAR-DHCA. STUDY DESIGN: Retrospective and observational. STUDY SETTING: Single large university hospital. PARTICIPANTS: All adults undergoing AAR-DHCA in 2000 and 2001. MAIN RESULTS: The cohort size was 144. Antifibrinolytic exposure was 100%, aprotinin 66% and aminocaproic acid 34%. The incidence of AF was 34.0%. AF was not significantly associated with increased mortality or prolonged ICU stay. Advanced age was a multivariate risk factor for AF. Lower temperature nadir during DHCA was protective against postoperative AF. Aprotinin had no demonstrable effect on AF after AAR-DHCA. CONCLUSIONS: AF after AAR-DHCA is common but does not independently increase mortality or ICU stay. The risk of AF after AAR-DHCA increases with age but decreases with the degree of hypothermia during DHCA. Aprotinin does not appear to affect the risk of AF after AAR-DHCA.


Subject(s)
Aorta, Thoracic/surgery , Atrial Fibrillation/etiology , Heart Arrest, Induced , Postoperative Complications/etiology , Adult , Age Factors , Aged , Atrial Fibrillation/prevention & control , Cardiopulmonary Bypass , Female , Humans , Incidence , Male , Middle Aged , Multivariate Analysis , Retrospective Studies , Risk Factors
5.
J Cardiothorac Vasc Anesth ; 20(5): 673-7, 2006 Oct.
Article in English | MEDLINE | ID: mdl-17023287

ABSTRACT

OBJECTIVE: The purpose of this study was to evaluate renal dysfunction (RD) after thoracic aortic surgery (TAS) requiring deep hypothermic circulatory arrest (DHCA), to determine the influence of definition on RD after TAS-DHCA, to determine univariate predictors of RD after TAS-DHCA, and to determine multivariate predictors for RD TAS-DHCA. RD was defined in 3 ways: (1) >25% reduction in creatinine clearance, (2) >50% increase in serum creatinine, and (3) >50% increase in serum creatinine with an abnormal peak serum creatinine (>1.3 mg/dL for men and >1.0 mg/dL for women). STUDY DESIGN: Retrospective and observational. STUDY SETTING: Single large university hospital. PARTICIPANTS: All adults requiring TAS-DHCA in 2000 and 2001. MAIN RESULTS: The cohort size was 144. Antifibrinolytic exposure was 100%: aprotinin 66% and aminocaproic acid 34%. The incidence of RD TAS-DHCA was 22.9% to 38.2%, depending on the definition. The incidence of renal replacement therapy was 2.8%. Multivariate predictors for RD after TAS-DHCA were sepsis, aprotinin exposure, preoperative hypertension, age, and donor exposures. CONCLUSIONS: Although RD after TAS-DHCA varies substantially because of definition, it is still very common. Its multivariate predictors merit further focused research to enhance perioperative protection of the kidney.


Subject(s)
Aortic Diseases/surgery , Blood Vessel Prosthesis Implantation/methods , Circulatory Arrest, Deep Hypothermia Induced/adverse effects , Kidney Diseases , Adult , Aged , Aorta, Thoracic , Female , Follow-Up Studies , Humans , Incidence , Kidney Diseases/diagnosis , Kidney Diseases/epidemiology , Kidney Diseases/etiology , Male , Middle Aged , Retrospective Studies , Severity of Illness Index , Treatment Outcome
6.
J Cardiothorac Vasc Anesth ; 20(1): 8-13, 2006 Feb.
Article in English | MEDLINE | ID: mdl-16458206

ABSTRACT

OBJECTIVE: The purpose of this study was to describe clinical predictors for prolonged length of stay in the intensive care unit (PLOS-ICU) after adult thoracic aortic surgery requiring standardized deep hypothermic circulatory arrest (DHCA); and to determine the incidence of PLOS-ICU after DHCA, univariate predictors for PLOS-ICU, and multivariate predictors for PLOS-ICU. STUDY DESIGN: A retrospective and observational study. PLOS-ICU was defined as longer than 5 days in the ICU. STUDY SETTING: Cardiothoracic operating rooms and the ICU. PARTICIPANTS: All adults requiring thoracic aortic repair with DHCA INTERVENTIONS: None. MAIN RESULTS: The cohort size was 144. The incidence of PLOS-ICU was 27.8%. The mortality rate was 11.1%. Univariate predictors for PLOS-ICU were age, stroke, DHCA duration, vasopressor dependence >72 hours, mediastinal re-exploration for bleeding, and renal dysfunction. Multivariate predictors for PLOS-ICU were stroke, vasopressor dependence >72 hours, and renal dysfunction. CONCLUSIONS: PLOS-ICU after DHCA is common. The identified multivariate predictors merit further hypothesis-driven research to enhance perioperative protection of the brain, kidney, and cardiovascular system.


Subject(s)
Aorta, Thoracic/surgery , Circulatory Arrest, Deep Hypothermia Induced , Intensive Care Units , Length of Stay , Adult , Aged , Cardiopulmonary Bypass , Female , Humans , Kidney Diseases/epidemiology , Kidney Diseases/therapy , Male , Middle Aged , Retrospective Studies , Stroke/epidemiology
7.
Ann Card Anaesth ; 9(2): 114-9, 2006 Jul.
Article in English | MEDLINE | ID: mdl-17699892

ABSTRACT

This retrospective, observational study was performed on adult patients undergoing thoracic aortic surgery (ATAS) requiring standardized deep hypothermic circulatory arrest (DHCA) with following aims. (1). To determine the mortality rate after ATAS-DHCA (2). To determine univariate predictors for mortality after ATAS-DHCA (3). To determine multivariate predictors for mortality after ATAS-DHCA A total of 144 patients operated during 2000/2001 were included. The mortality rate was 11.1%. Univariate predictors for mortality after ATAS-DHCA were preoperative ejection fraction less than 40%, stroke, packed red blood cell transfusion within first 24 hours, sepsis, mediastinal re-exploration for bleeding within first 24 hours, and renal dysfunction. Multivariate predictors for mortality after ATAS-DHCA were sepsis (odds ratio 21.3:1; confidence interval 3.8-12.1; p=0.001), postoperative stroke (odds ratio 7.4:1; confidence interval 1.9-28.7; p=0.004) and mediastinal re-exploration within first 24 hours (odds ratio 7.7:1; confidence interval 1.3-45.1; p = 0.02) We conclude that mortality after ATAS-DHCA remains high. The identified multivariate predictors merit further hypothesis-driven intervention.

8.
J Cardiothorac Vasc Anesth ; 19(3): 310-5, 2005 Jun.
Article in English | MEDLINE | ID: mdl-16130056

ABSTRACT

OBJECTIVE: The purpose of this study was to evaluate needle-guided ultrasound for internal jugular venous cannulation in a large university anesthesia department, to determine cumulative cannulation success by method, to determine first-pass cannulation success by method and operator, and to determine arterial puncture by method and operator. STUDY DESIGN: Prospective, observational, and randomized. Blinding was not possible. Cohort size was calculated for 80% power to detect a technique difference, with significance defined as p < 0.05. SETTING: Operating rooms of the Hospital of the University of Pennsylvania. PARTICIPANTS: Elective surgical patients requiring internal jugular venous cannulation. INTERVENTIONS: Cannulation of the internal jugular vein occurred by needle-guided ultrasound (NGU) or by ultrasound without a needle guide. MAIN RESULTS: Four hundred thirty-four procedures were studied in 429 patients. NGU significantly enhances cannulation success after first (68.9%-80.9%, p = 0.0054) and second (80.0%-93.1%, p = 0.0001) needle passes. Cumulative cannulation success by the seventh needle pass is 100%, regardless of technique. The needle-guide specifically improves first-pass success in the junior operator (65.6%-79.8%, p = 0.0144). Arterial puncture averages 4.2%, regardless of technique (p > 0.05) or operator (p > 0.05). CONCLUSIONS: Although the needle guide facilitates prompt cannulation with ultrasound in the novice operator, it offers no additional protection against arterial puncture. This may be because of a lack of control of needle depth rather than needle direction. A possible solution may be biplanar ultrasound for central venous cannulation.


Subject(s)
Anesthesia Department, Hospital , Catheterization, Central Venous/instrumentation , Hospitals, University , Jugular Veins/diagnostic imaging , Needles , Catheterization, Central Venous/adverse effects , Catheterization, Central Venous/methods , Cohort Studies , Humans , Intraoperative Complications/etiology , Prospective Studies , Ultrasonography
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