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Pharmacokinetics, pharmacodynamics and toxicology of theranostic nanoparticles.

ABSTRACT: Nanoparticles (NPs) are considered a promising tool in both diagnosis and therapeutics. Theranostic NPs possess the combined properties of targeted imaging and drug delivery within a single entity. While the categorization of theranostic NPs is based on their structure and composition, the pharmacokinetics of NPs are significantly influenced by the physicochemical properties of theranostic NPs as well as the routes of administration. Consequently, altered pharmacokinetics modify the pharmacodynamic efficacy and toxicity of NPs. Although theranostic NPs hold great promise in nanomedicine and biomedical applications, a lack of understanding persists on the mechanisms of the biodistribution and adverse effects of NPs. To better understand the diagnostic and therapeutic functions of NPs, this review discusses the factors that influence the pharmacokinetics, pharmacodynamics and toxicology of theranostic NPs, along with several strategies for developing novel diagnostic and therapeutic modalities.

SUBMITTER: Kang H

PROVIDER: S-EPMC4648690 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Pharmacokinetics, pharmacodynamics and toxicology of theranostic nanoparticles.

Kang Homan H Mintri Shrutika S Menon Archita Venugopal AV Lee Hea Yeon HY Choi Hak Soo HS Kim Jonghan J

Nanoscale 20151103 45

Nanoparticles (NPs) are considered a promising tool in both diagnosis and therapeutics. Theranostic NPs possess the combined properties of targeted imaging and drug delivery within a single entity. While the categorization of theranostic NPs is based on their structure and composition, the pharmacokinetics of NPs are significantly influenced by the physicochemical properties of theranostic NPs as well as the routes of administration. Consequently, altered pharmacokinetics modify the pharmacodyna ...[more]

PMID: 26528835

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Project description:Introduction:Solid lipid nanoparticles (SLNs) are considered a promising system in enhancing the oral bioavailability of poorly water-soluble drugs; owing to their intrinsic ability to increase the solubility together with protecting the incorporated drugs from extensive metabolism. Objective:Exploiting such properties, SLNs loaded with gliclazide (GLZ) were developed in an attempt to improve the oral bioavailability and the anti-diabetic action of GLZ, together with prolonging its duration of action for better glycemic control. Methods:SLNs were prepared by ultra-sonication technique using glyceryl behenate (Compritol®888 ATO) as a lipid matrix and poloxamer 188 (PLX) as a stabilizer. A 2*3 asymmetrical factorial design was adopted to study the effect of different stabilizer concentrations at different sonication times on the shape, and size of the particles, PDI and drug loading. The selected optimum formulation was then freeze dried using trehalose di-hydrate as a cryo-protectant in different ratios with respect to glyceryl behenate concentration. After freeze drying, the formulation was tested for in-vitro drug release, pharmacokinetics, and pharmacodynamics. Safety of the selected formula was established after carrying out a subacute toxicity study. Results:The factorial design experiment resulted in an optimum formulation coded 10F2 (150 mg PLX/10 min sonication). Scanning electron micrographs showed spherical particles with smooth surface, whereas a ratio of 2:1 cryo-protectant:lipid was found to be optimum with particle size of 245.9 ± 26.2 nm, polydispersity index of 0.482 ± 0.026, and biphasic in-vitro release with an initial burst effect, followed by a prolonged release phase. On the other hand, the selected SLNs exhibited prolonged drug release when compared with the GLZ commercial immediate release (IR) tablets (Diamicron®). Pharmacokinetics study showed about 5-fold increase in GLZ oral bioavailability loaded in SLNs when compared with raw GLZ powder. Pharmacodynamics study on a diabetic rat model confirmed the better anti-diabetic action of GLZ loaded SLNs when compared to raw GLZ powder. Subacute toxicity study indicated the safety of SLNs upon repetitive oral administration.

Project description:Afatinib is an oral, irreversible ErbB family blocker that covalently binds to the kinase domains of epidermal growth factor receptor (EGFR), human EGFRs (HER) 2, and HER4, resulting in irreversible inhibition of tyrosine kinase autophosphorylation. Studies in healthy volunteers and patients with advanced solid tumours have shown that once-daily afatinib has time-independent pharmacokinetic characteristics. Maximum plasma concentrations of afatinib are reached approximately 2-5 h after oral administration and thereafter decline, at least bi-exponentially. Food reduces total exposure to afatinib. Over the clinical dose range of 20-50 mg, afatinib exposure increases slightly more than dose proportional. Afatinib metabolism is minimal, with unchanged drug predominantly excreted in the faeces and approximately 5 % in urine. Apart from the parent drug afatinib, the major circulation species in human plasma are the covalently bound adducts to plasma protein. The effective elimination half-life is approximately 37 h, consistent with an accumulation of drug exposure by 2.5- to 3.4-fold based on area under the plasma concentration-time curve (AUC) after multiple dosing. The pharmacokinetic profile of afatinib is consistent across a range of patient populations. Age, ethnicity, smoking status and hepatic function had no influence on afatinib pharmacokinetics, while females and patients with low body weight had increased exposure to afatinib. Renal function is correlated with afatinib exposure, but, as for sex and body weight, the effect size for patients with severe renal impairment (approximately 50 % increase in AUC) is only mildly relative to the extent of unexplained interpatient variability in afatinib exposure. Afatinib has a low potential as a victim or perpetrator of drug-drug interactions, especially with cytochrome P450-modulating agents. However, concomitant treatment with potent inhibitors or inducers of the P-glycoprotein transporter can affect the pharmacokinetics of afatinib. At a dose of 50 mg, afatinib does not have proarrhythmic potential.

Dataset Information

Pharmacokinetics, pharmacodynamics and toxicology of theranostic nanoparticles.

Publications

Pharmacokinetics, pharmacodynamics and toxicology of theranostic nanoparticles.

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