Karina R. Vega-Villa

Clinical toxicities of nanocarrier systems.

Toxicity of nanocarrier systems involves physiological, physicochemical, and molecular considerations. Nanoparticle exposures through the skin, the respiratory tract, the gastrointestinal tract and the lymphatics have been described. Nanocarrier systems may induce cytotoxicity and/or genotoxicity, whereas their antigenicity is still not well understood. Nanocarrier may alter the physicochemical properties of xenobiotics resulting in pharmaceutical changes in stability, solubility, and pharmacokinetic disposition. In particular, nanocarriers may reduce toxicity of hydrophobic cancer drugs that are solubilized. Nano regulation is still undergoing major changes to encompass environmental, health, and safety issues. The rapid commercialization of nanotechnology requires thoughtful environmental, health and safety research, meaningful, and an open discussion of broader societal impacts, and urgent toxicological oversight action.

Clinical pharmacokinetic and pharmacodynamic profile of etoricoxib.

The NSAID etoricoxib is a selective inhibitor of cyclo-oxygenase 2 (COX-2), approved for treatment of patients with chronic arthropathies and musculoskeletal and dental pain. The rate of absorption of etoricoxib is moderate when given orally (the maximum plasma drug concentration occurs after ∼1 hour), and the extent of absorption is similar with oral and intravenous doses. Etoricoxib is extensively protein bound, primarily to plasma albumin, and has an apparent volume of distribution of 120 L in humans. The area under the plasma concentration-time curve (AUC) of etoricoxib increases in proportion to increasing oral doses between 5 and 120 mg. The elimination half-life of ∼20 hours in healthy subjects enables once-daily dosing. Etoricoxib is eliminated following biotransformation to carboxylic acid and glucuronide metabolites that are excreted in urine and faeces, with little of the drug (<1%) being eliminated unchanged in the urine. Etoricoxib is metabolized primarily by the cytochrome P450 (CYP) 3A4 isoenzyme. Plasma concentrations (AUC) of etoricoxib appear not to be different in patients with chronic renal insufficiency compared with individuals who have normal renal function. Compared with healthy subjects, it has been reported that the AUC is increased by approximately 40% in patients with moderate hepatic impairment. No inhibitory effects on CYP2C9, 2C19, 2D6, 2E1 or 3A4 are expected to occur with etoricoxib. Coadministration of etoricoxib with other drugs has been examined only to a limited extent, thus further assessment is necessary. Etoricoxib has been assessed for the management of several specific disease states, including pain, osteoarthritis, and rheumatoid arthritis, and has shown similar efficacy in comparison with traditional NSAIDs (including naproxen, diclofenac and ibuprofen) in these conditions. Etoricoxib has demonstrated a significant reduction in gastrointestinal toxicity compared with many traditional NSAIDs. The renal adverse effects of etoricoxib appear to be similar to those of other NSAIDs, and the cardiovascular adverse effects of this selective COX-2 inhibitor require further clinical scrutiny. Further study is necessary to delineate the relevance of the pharmacokinetic disposition in terms of the clinical benefits and risks of etoricoxib compared with other options in the clinical arsenal.

Minimizing risks of NSAIDs: cardiovascular, gastrointestinal and renal

Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in treating inflammation, pain and fever, but their cardiovascular, renal and gastrointestinal toxicity can result in significant morbidity and mortality to patients. Techniques for minimizing the adverse risks of NSAIDs include avoiding use of NSAIDs where possible, particularly in high-risk patients; keeping NSAID dosages low; prescribing modified-release and enteric-coated NSAIDs; prescribing cyclooxygenase-2-selective inhibitors where appropriate; monitoring for early signs of side effects; prescribing treatments designed to minimize NSAID side effects; and developing new therapeutic strategies beyond the inhibition of cyclooxygenase. All of the above strategies can be useful in reducing the risk of NSAID complications. The optimal use and management of NSAIDs involves an individualized paradigm approach to establish efficacy with optimal tolerability given the patient risk factors for adverse events.

High-performance liquid chromatographic analysis: applications to nutraceutical content and urinary disposition of oxyresveratrol in rats

A high-performance liquid chromatographic (HPLC) method was developed for the analysis of the stilbene, oxyresveratrol. This method involves the use of a Luna C(18) column with ultraviolet detection at 320 nm. The mobile phase consisted of acetonitrile, water and formic acid (30 : 70 : 0.04 v/v) with a flow rate of 0.6 mL/min. The calibration curves were linear over the range of 0.5-100.0 microg/mL. The mean extraction efficiency was between 98.9 and 109%. The precision of the assay was 0.069-18.4% (RSD%), and within 20% at the limit of quantitation (0.5 microg/mL). The bias of the assay was <15% and within 15% at the limit of quantitation. This assay was successfully applied to pre-clinical pharmacokinetic samples from rat urine and to nutraceutical product analysis.

Stereospecific analysis of sakuranetin by high-performance liquid chromatography : Pharmacokinetic and botanical applications

A stereospecific method for analysis of sakuranetin was developed. Separation was accomplished using a Chiralpak AD-RH column with UV (ultraviolet) detection at 288 nm. The stereospecific linear calibration curves ranged from 0.5 to 100 microg/mL. The mean extraction efficiency was >98%. Precision of the assay was <12% (relative standard deviation (R.S.D.)%), and within 10% at the limit of quantitation (0.5 microg/mL). Bias of the assay was lower than 10%, and within 5% at the limit of quantitation. The assay was applied successfully to pharmacokinetic quantification in rats, and the stereospecific quantification in oranges, grapefruit juice, and matico (Piper aduncum L.).

Stereospecific pharmacokinetics of racemic homoeriodictyol, isosakuranetin, and taxifolin in rats and their disposition in fruit

The chirality of flavonoids has been overlooked in the majority of pharmacokinetic studies of homoeriodictyol, isosakuranetin, and taxifolin. The stereospecific pharmacokinetic disposition of these xenobiotics in male Sprague-Dawley rats is described for the first time. Validated HPLC methods were used to analyze serum and urine samples of rats following intravenous administration of each flavonoid via jugular vein cannulation and to determine their content in selected fruits. The characterization and interpretation of the pharmacokinetic disposition profiles of homoeriodictyol, isosakuranetin, and taxifolin are described. A discrepancy exists between half-lives in serum and urine which may be attributed to low assay sensitivity in serum for the three compounds; thus, a more accurate estimation of the pharmacokinetic parameters was obtained from urine. The pharmacokinetics of homoeriodictyol, isosakuranetin, and taxifolin revealed distribution, metabolism, and elimination that were dependent on the stereochemistry of the stereoisomers. The (-)-(S)-enantiomers of homoeriodictyol and isosakuranetin and the (+)-(2S; 3R)-stereoisomer of taxifolin were predominant in lemon, grapefruit, and tomato. These findings were achieved using chiral methods of analysis; the utility and necessity of developing chiral methods of analysis for chiral xenobiotics are discussed.

Abstract 2065: Development of a general framework for effective translation of in vitro synergistic combination into in vivo synergy using a systemic modeling approach.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Purpose: Failure of identifying optimal dosing regimen is often responsible for failed or inconclusive clinical evaluation of combination cancer therapy, and selecting synergistic combination doses remains a great challenge. The information from well-designed in vitro and preclinical animal drug combination studies - which include dose, pharmacokinetics (PK), efficacy, synergism/antagonism, and schedule dependence - can significantly contribute to the success of drug combination clinical trials. However, general methodologies for translating in vitro combination effects into preclinical and clinical in vivo doses are lacking. This study aims to develop a systemic approach for effective in vitro-in vivo translation by the combined efforts of experimental data and computational modeling. Methods: Erlotinib and CLEFMA, a novel curcuminoid, against erlotinib-resistant NSCLC (H441) was used as a proof-of-concept drug combination for this study. The key components of the framework include a) evaluation of in vitro combination effects of two drugs and estimation of the interaction parameter (ψ) that defines the nature of drug interaction; b) in vivo PK information of two drugs in plasma and tumor that was obtained from the literature and characterized by compartmental PK models; and c) in vivo inhibitory effects of each drug alone on tumor growth in xenograft mice, which were described by a modified Simeoni model. The final integrated model was then used to describe combined in vivo effects by incorporating the interaction parameter, thereby predicting optimal combination doses. Results: In vitro combined effects of two drugs were fitted to 3-dimensional response surface model and suggested to be synergistic (ψ = 0.68). Erlotinib PK in tumor-bearing mice following oral administration was described using a two-compartment model and CLEFMA PK following intravenous administration was simulated. Plasma-to-tumor distribution ratio was 0.6 for erlotinib and 0.36 for CLEFMA and tumor drug concentrations were used as a driving force for the observed inhibitory effects on tumor growth in vivo to closely mimic in vitro effective concentrations. The tumor progression in non-treated mice was depicted by an exponential growth followed by a linear growth. In treated mice, the combined inhibitory effect was described as a function of the tumor drug concentrations and the interaction parameter ψ. Conclusion: The present study lays out the strategy and tactics for translating in vitro synergy into maximal in vivo synergy. The developed approach can be used to better design preclinical experiments in xenograft model in a rational manner after in vitro combination studies, and to select the most advantageous in vivo combination doses and schedules for maximal synergy, thereby facilitating early anticancer drug development. Citation Format: Karina Vega-Villa, Michael Ihnat, Sukyung Woo. Development of a general framework for effective translation of in vitro synergistic combination into in vivo synergy using a systemic modeling approach. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2065. doi:10.1158/1538-7445.AM2013-2065