US FDA 505(b)(2) NDA clinical, CMC and regulatory strategy concepts to expedite drug development.

The 505(b)(2) NDA pathway can reduce drug development costs and accelerate the time to market by leveraging existing public data using clinical bridging and regulatory strategies. Whether or not a drug qualifies for the 505(b)(2) pathway depends on the active ingredient, drug formulation, clinical indication and other factors. Clinical programs can be streamlined and accelerated, and confer unique marketing benefits, such as exclusivity, depending on the regulatory strategy and product.

A Unique Formulation of Cardioprotective Bio-Actives: An Overview of Their Safety Profile.

The burden of cardiovascular disease (CVD) remains high globally and in the United States despite the availability of pharmaceuticals aimed at its prevention and treatment. An invention by Summit Innovation Labs, which is a formula consisting of a unique blend of select polyphenols (i.e.

A randomized controlled laboratory study on the long-term effects of methylphenidate on cardiovascular function and structure in rhesus monkeys.

Background: Whether long-term methylphenidate (MPH) results in any changes in cardiovascular function or structure can only be properly addressed through a randomized trial using an animal model which permits elevated dosing over an extended period of time.

Methods: We studied 28 male rhesus monkeys (Macaca mulatta) approximately 7 years of age that had been randomly assigned to one of three MPH dosages: vehicle control (0 mg/kg, b.i.

Streamlining nonclinical drug development using the FDA 505(b)(2) new drug application regulatory pathway.

In the USA, drugs are approved by the FDA by three main regulatory pathways: (i) 505(b)(1) new drug applications (NDAs); (ii) 505(b)(2) NDAs; and (iii) 505(j) abbreviated NDAs (ANDAs). The appropriate pathway depends on the active ingredient, already approved drug products, drug formulation, clinical indication, route of exposure, among other factors. The 505(b)(2) NDA pathway is a regulatory approval pathway that allows sponsors to use existing public data in lieu of conducting studies; thus, potentially offering significant drug development and marketing advantages.

Effects of 31 FDA approved small-molecule kinase inhibitors on isolated rat liver mitochondria.

The FDA has approved 31 small-molecule kinase inhibitors (KIs) for human use as of November 2016, with six having black box warnings for hepatotoxicity (BBW-H) in product labeling. The precise mechanisms and risk factors for KI-induced hepatotoxicity are poorly understood. Here, the 31 KIs were tested in isolated rat liver mitochondria, an in vitro system recently proposed to be a useful tool to predict drug-induced hepatotoxicity in humans.

Proteomic analysis of acetaminophen-induced hepatotoxicity and identification of heme oxygenase 1 as a potential plasma biomarker of liver injury.

Purpose: Overdose of acetaminophen (APAP) is a major cause of acute liver failure. This study was aimed to identify pathways related to hepatotoxicity and potential biomarkers of liver injury.

Experimental Design: Rats were treated with low (100 mg/kg) and high (1250 mg/kg) doses of APAP, and liver tissues at 6 and 24 h post-treatment were analyzed using a proteomic approach of 16O/18O labeling and 2D-LC-MS/MS.

Potential of extracellular microRNAs as biomarkers of acetaminophen toxicity in children.

Unlabelled: Developing biomarkers for detecting acetaminophen (APAP) toxicity has been widely investigated. Recent studies of adults with APAP-induced liver injury have reported human serum microRNA-122 (miR-122) as a novel biomarker of APAP-induced liver injury. The goal of this study was to examine extracellular microRNAs (miRNAs) as potential biomarkers for APAP liver injury in children.

Identification of a metabolic biomarker panel in rats for prediction of acute and idiosyncratic hepatotoxicity.

It has been estimated that 10% of acute liver failure is due to "idiosyncratic hepatotoxicity". The inability to identify such compounds with classical preclinical markers of hepatotoxicity has driven the need to discover a mechanism-based biomarker panel for hepatotoxicity. Seven compounds were included in this study: two overt hepatotoxicants (acetaminophen and carbon tetrachloride), two idiosyncratic hepatotoxicants (felbamate and dantrolene), and three non-hepatotoxicants (meloxicam, penicillin and metformin).

Green tea epigallocatechin gallate binds to and inhibits respiratory complexes in swelling but not normal rat hepatic mitochondria.

Epigallocatechin gallate (EGCG), the major flavonoid in green tea, is consumed via tea products and dietary supplements, and has been tested in clinical trials. However, EGCG can cause hepatotoxicity in humans and animals by unknown mechanisms. Here EGCG effects on rat liver mitochondria were examined.

Metabolomics evaluation of the effects of green tea extract on acetaminophen-induced hepatotoxicity in mice.

Green tea has been purported to have beneficial health effects including protective effects against oxidative stress. Acetaminophen (APAP) is a widely used analgesic drug that can cause acute liver injury in overdose situations. These studies explored the effects of green tea extract (GTE) on APAP-induced hepatotoxicity in liver tissue extracts using ultra performance liquid chromatography/quadrupole time-of-flight mass spectrometry and nuclear magnetic resonance spectroscopy.

Evaluating effects of penicillin treatment on the metabolome of rats.

Penicillin (PEN) V, a well-known antibiotic widely used in the treatment of Gram-positive bacterial infections, was evaluated in this study. LC/MS- and NMR-based metabolic profiling were employed to examine the effects of PEN on the host's metabolic phenotype. Male Sprague Dawley rats were randomly divided into groups that were orally administered either 0.

Inhibition of cytochrome P450s enhances (+)-usnic acid cytotoxicity in primary cultured rat hepatocytes.

(+)-Usnic acid (UA) is consumed as a dietary supplement to promote weight loss; however, dietary supplements containing UA have been associated with clinical cases of severe liver injury. UA has been shown to be hepatotoxic in rats and is extensively metabolized by hepatic cytochrome P450s (CYPs); therefore, we examined if UA metabolism results in the formation of cytotoxic metabolites or if metabolism is a detoxification process in primary rat hepatocytes. When CYP activity was suppressed by the non-isoenzyme-selective inhibitor SKF-525A (20 μM), or the CYP1A inhibitor alpha-naphthoflavone (10 μM), or the CYP3A inhibitor ketoconazole (25 μM), the cytotoxicity of UA at 3~6 μM after 3~20 h of exposure was significantly increased as measured by lactate dehydrogenase (LDH) leakage.

Mouse liver protein sulfhydryl depletion after acetaminophen exposure.

Acetaminophen (APAP)-induced liver injury is the leading cause of acute liver failure in many countries. This study determined the extent of liver protein sulfhydryl depletion not only in whole liver homogenate but also in the zonal pattern of sulfhydryl depletion within the liver lobule. A single oral gavage dose of 150 or 300 mg/kg APAP in B6C3F1 mice produced increased serum alanine aminotransferase levels, liver necrosis, and glutathione depletion in a dose-dependent manner.

Mechanisms for epigallocatechin gallate induced inhibition of drug metabolizing enzymes in rat liver microsomes.

Epigallocatechin gallate (EGCG) inhibits drug metabolizing enzymes by unknown mechanisms. Here we examined if the inhibition is due to covalent-binding of EGCG to the enzymes or formation of protein aggregates. EGCG was incubated with rat liver microsomes at 1-100μM for 30min.

Green tea extract can potentiate acetaminophen-induced hepatotoxicity in mice.

Green tea extract (GTE) has been advocated as a hepatoprotective compound and a possible therapeutic agent for acetaminophen (APAP) overdose. This study was conducted to determine if GTE can provide protection against APAP-induced hepatotoxicity. Three different exposure scenarios were tested.

Identification of urinary microRNA profiles in rats that may diagnose hepatotoxicity.

Circulating microRNAs (miRNAs) have emerged as novel noninvasive biomarkers for several diseases and other types of tissue injury. This study tested the hypothesis that changes in the levels of urinary miRNAs correlate with liver injury induced by hepatotoxicants. Sprague-Dawley rats were administered acetaminophen (APAP) or carbon tetrachloride (CCl(4)) and one nonhepatotoxicant (penicillin/PCN).

Changes in mouse liver protein glutathionylation after acetaminophen exposure.

The role of protein glutathionylation in acetaminophen (APAP)-induced liver injury was investigated in this study. A single oral gavage dose of 150 or 300 mg/kg APAP in B6C3F1 mice produced increased serum alanine aminotransferase and aspartate aminotransferase levels and liver necrosis in a dose-dependent manner. The ratio of GSH to GSSG was decreased in a dose-dependent manner, suggesting that APAP produced a more oxidizing environment within the liver.

MicroRNA expression profiles distinguish the carcinogenic effects of riddelliine in rat liver.

Pyrrolizidine alkaloids (PAs) are the most common plant constituents that poison livestock, wildlife and humans. Riddelliine is a prototype genotoxic PA and has been nominated to be classified as a reasonably anticipated human carcinogen by the US National Toxicology Program (NTP) in the 12th Report on Carcinogens. Riddelliine's nomination is due to the high incidence of liver tumours that were observed in both mice and rats in the NTP tumourigenicity bioassay study.

Hepatic cytochrome P450s attenuate the cytotoxicity induced by leflunomide and its active metabolite A77 1726 in primary cultured rat hepatocytes.

The Black Box Warning section of the U.S. drug label for leflunomide was recently updated to include stronger warnings about potential hepatotoxicity from this novel anti-arthritis drug.

Kava extract, an herbal alternative for anxiety relief, potentiates acetaminophen-induced cytotoxicity in rat hepatic cells.

The widely used over-the-counter analgesic acetaminophen (APAP) is the leading cause of acute liver failure in the United States and due to this high incidence, a recent FDA Advisory Board recommended lowering the maximum dose of APAP. Kava herbal dietary supplements have been implicated in several human liver failure cases leading to the ban of kava-containing products in several Western countries. In the US, the FDA has issued warnings about the potential adverse effects of kava, but kava dietary supplements are still available to consumers.