Recent evidence for pharmacological treatment of idiopathic pulmonary fibrosis.

OBJECTIVE: To describe emerging evidence for the pharmacological treatment of idiopathic pulmonary fibrosis (IPF). DATA SOURCES: A search of PubMed (1966 to July 2014) was performed using the terms idiopathic pulmonary fibrosis and treatment. STUDY SELECTION AND DATA EXTRACTION: Review of articles was restricted to articles in English and relating to placebo-controlled or comparative clinical trial data of recent significance. Evidence statements from the most recent international guidelines and some historical trial data were also included for context. DATA SYNTHESIS: Numerous treatment options have been evaluated for IPF. Therapies evaluated in large trials have either resulted in increased mortality (anticoagulation, triple-therapy with N-acetylcysteine [NAC], azathioprine, and prednisone) or demonstrated a lack of efficacy (endothelin receptor antagonists, single-agent NAC). Pirfenidone, a novel antifibrotic and anti-inflammatory agent, has demonstrated efficacy in several recent analyses and is the only approved medication for the treatment of IPF in more than 30 countries outside of the United States, with resubmission to the Food and Drug Administration (FDA) recently made. Nintedanib, a tyrosine kinase inhibitor, has demonstrated encouraging results in phase III studies and has also recently been submitted for FDA approval. CONCLUSIONS: Limited options have existed for the treatment of IPF. New evidence suggests that safe and efficacious treatment options for IPF are on the horizon in the form of pirfenidone and nintedanib, although both agents await FDA decisions.

Tolerability and safety of enteral nutrition in critically ill patients receiving intravenous vasopressor therapy.

BACKGROUND: Enteral nutrition (EN) is recommended within the first 24-48 hours following admission to an intensive care unit (ICU) once resuscitation and hemodynamic stability have been achieved; however, hemodynamic stability is not well defined. OBJECTIVE: To evaluate the tolerability and safety of EN in critically ill patients receiving intravenous (IV) vasopressor therapy. METHODS: A retrospective medical record review was conducted in an urban academic medical center and included adult ICU patients from 2011 who received concomitant EN and IV vasopressor therapy for ≥1 hour. EN tolerance was defined as an absence of gastric residuals ≥300 mL, emesis, positive finding on abdominal imaging, and evidence of bowel ischemia/perforation. RESULTS: Two hundred fifty-nine patients received 346 episodes of concomitant EN and IV vasopressor therapy. Overall EN tolerability was 74.9%. Adverse events included rising serum lactate (30.6%), elevated gastric residuals (14.5%), emesis (9.0%), positive finding on kidney/ureter/bladder radiograph (4.3%), and bowel ischemia/perforation (0.9%). An inverse relationship was found between maximum norepinephrine equivalent dose and EN tolerability (12.5 mcg/min for patients who tolerated EN vs 19.4 mcg/min, P = .0009). This relationship remained statistically significant after controlling for other variables (P = .019). Patients who tolerated EN were less likely to have received dopamine (63.8% vs 77.6%, P = .018) or vasopressin (58.9% vs 77.9%, P = .0027). These patients received concomitant therapy for less time and received more nutrition. CONCLUSIONS: Most patients receiving IV vasopressor therapy tolerate EN. Tolerability was related to the maximum cumulative vasopressor dose and may be related to the specific vasopressor administered.

Contemporary Anticoagulation Reversal Focus on Direct Thrombin Inhibitors and Factor Xa Inhibitors.

Several oral direct thrombin inhibitors (DTIs) and factor Xa (FXa) inhibitors have recent Food and Drug Administration approval or are under investigation in late-stage clinical trials for the prevention and treatment of thromboembolic events. Rapid reversal of anticoagulation is typically recommended in patients with severe or life-threatening bleeding and in patients requiring surgery or invasive procedures. However, no antidote exists for DTIs or FXa inhibitors though replacement of coagulation factors using clotting factor concentrates is routinely considered in some clinical scenarios. Clotting factor concentrates available in the United States include prothrombin complex concentrate, activated prothrombin complex concentrate, and recombinant factor VII, activated. Coagulation tests to confirm adequate reversal of anticoagulation should be considered and commonly include activated partial thromboplastin time and thrombin time (TT) for DTIs, and chromogenic FXa assay and TT for FXa inhibitors. Monitoring of coagulation tests should continue for 1 to 2 days after achievement of hemostasis, since the duration of the clotting factor concentrate may be shorter than the oral anticoagulant, especially in patients with organ dysfunction. Utilization of decision-support tools and use of standardized reversal protocols are recommended to prevent errors in prescribing and dispensing for clotting factor concentrates.

Ipilimumab: a novel treatment for metastatic melanoma.

OBJECTIVE: To review the mechanism of action, pharmacokinetics, efficacy, safety, drug interactions, dosing, and economic considerations of ipilimumab. DATA SOURCES: A literature search using MEDLINE (1966-November 2010) was performed using the terms ipilimumab, metastatic melanoma, MDX-010, and MDX-101. Additional data were obtained from meeting abstracts, bibliographies, and media releases. STUDY SELECTION AND DATA EXTRACTION: English-language articles identified from the data sources were reviewed. Selected studies evaluated the pharmacology, pharmacokinetics, efficacy, and safety of ipilimumab for the treatment of metastatic melanoma. DATA SYNTHESIS: The incidence of melanoma in the US is increasing faster than any other type of cancer in men and more than any other type of cancer, except lung cancer, in women. For patients with metastatic melanoma, systemic therapies are limited by low response rates, short durations of response, and a 5-year survival rate <10%. Ipilimumab, a novel CTLA-4 inhibitor, is under investigation for the treatment of metastatic melanoma. Results of a randomized, controlled Phase 3 trial showed a first-ever overall survival benefit for patients with previously treated metastatic melanoma who received ipilimumab compared with the controls. The majority of adverse events reported with ipilimumab administration are considered to be low-grade immune-related events involving the skin and intestine and can be managed medically. Nonetheless, 10-17% of patients have immune-related adverse events of grade 3 or higher severity, with 2-3% of these events resulting in death. CONCLUSIONS: Ipilimumab is a novel CTLA-4 inhibitor that has been evaluated for the treatment of metastatic melanoma. On March 25, 2011, the Food and Drug Administration approved ipilimumab, making it the first agent indicated for unresectable or metastatic melanoma in more than a decade.

Clinical and economic value of screening for Kras mutations as predictors of response to epidermal growth factor receptor inhibitors.

PURPOSE: The clinical and economic value of screening for Kras mutations as predictors of response to cetuximab and panitumumab are reviewed. SUMMARY: Epidermal growth factor receptor (EGFR) inhibitors cetuximab and panitumumab are agents currently used in the treatment of metastatic colorectal cancer. Cetuximab is approved in combination with irinotecan for second-line therapy or as a single agent in the third-line setting, and panitumumab is approved as a single agent for third-line therapy. Historically, response rates to EGFR inhibitors have been low; therefore, predictors of response or lack of response have been highly sought after. Mutations in the Kras oncogene, which encodes for the RAS protein located downstream from EGFR, have been associated with poor response to EGFR inhibitor therapy. Numerous studies have confirmed a Kras mutation frequency in approximately 40% of all metastatic colorectal cancers, as well as an associated lack of response to EGFR inhibitor therapy. Screening for Kras mutations before selecting a therapy may be clinically beneficial by avoiding the cost and toxicity of ineffective therapy. A simple breakeven analysis using a group of 100 hypothetical patients with metastatic colorectal cancer revealed that cost savings will be achieved if screening can be conducted for less than $3460 per patient, regardless of which EGFR inhibitor is used. CONCLUSION: Mutations in the Kras oncogene are associated with a poor response to EGFR inhibitor therapy in metastatic colorectal cancer. Implementing routine Kras screening and limiting the use of EGFR inhibitors to patients with wild-type (not mutated) Kras may have the potential for cost savings.

The effect of carbapenem antibiotics on plasma concentrations of valproic acid.

OBJECTIVE: To critically evaluate the mechanisms of the interaction between valproic acid and carbapenem antibiotics. DATA SOURCES: A PubMed search (January 1971-June 2009) was performed to identify literature on the interaction between valproic acid and carbapenem antibiotics. Additional references were identified through review of bibliographies of identified articles. STUDY SELECTION AND DATA EXTRACTION: Data on the mechanisms of the interaction between valproic acid and carbapenem antibiotics were extracted from identified references that were published in English. DATA SYNTHESIS: Valproic acid plasma concentrations fall markedly during concomitant administration with carbapenem antibiotics due to a combination of absorption, distribution, and metabolism mechanisms. Carbapenems appear to inhibit the intestinal transporter of valproic acid, thereby reducing absorption of orally administered valproic acid. In vivo experiments in rats demonstrate a 57% reduction in absorption of orally administered valproic acid in the presence of imipenem. Follow-up studies in Caco-2 cells suggest that the inhibition probably occurs at the basolateral membrane. In addition, enterohepatic recycling of valproic acid may be diminished due to carbapenem activity against gut flora producing beta-glucuronidase. When rabbits and rats were given intravenous valproic acid-glucuronide, the glucuronide metabolite of valproic acid, 50-90% of the conversion back into valproic acid was inhibited in the presence of a carbapenem. An increase in erythrocyte distribution of valproic acid has also been observed in the presence of carbapenems. After intravenous administration of a carbapenem and valproic acid, valproic acid plasma concentrations fell in the presence of a carbapenem, yet whole blood concentrations of valproic acid did not change significantly. Follow-up studies suggest that the mechanism of this distribution shift is that multidrug resistance proteins on adenosine triphosphate-binding cassette transporters on erythrocyte membranes are inhibited by carbapenems. Thus, valproic acid is not effluxed out of the erythrocytes. Finally, carbapenems may enhance glucuronidation of valproic acid by increasing UDP-glucuronic acid levels. In rats, UDP-glucuronic acid levels increased by 1.7-fold in the presence of panipenem, which was proportionate to the increase in valproic acid-glucuronide formation. CONCLUSIONS: Published data demonstrate a serious and complex interaction between valproic acid and carbapenem antibiotics. Coadministration should be avoided, but if no other antibiotic therapies exist, it is imperative to monitor valproic acid concentrations more frequently. Clinicians should anticipate higher doses of valproic acid to maintain therapeutic serum concentrations during coadministration and subsequent dose reductions upon discontinuation of the carbapenem antibiotic.