ICH S7B In Vitro Assays Do Not Address Mechanisms of QTC Prolongation for Peptides and Proteins - Data in Support of Not Needing Dedicated QTC Studies.

Current cardiac safety testing focuses on detecting drug-induced QTC prolongation as a surrogate for risk of Torsade de Pointes. The nonclinical strategy, described in International Conference on Harmonization (ICH) S7B, includes in vitro assessment of hERG block or ventricular repolarization delay and in vivo QT prolongation. Several studies have reported predictive values of ICH S7B results for clinical QTC outcomes for small molecules; none has examined peptides and proteins other than monoclonal antibodies. To address this knowledge gap, information for peptides and proteins submitted to the US Food and Drug Administration (FDA) was collected. Results of hERG assays, ventricular repolarization assays, and in vivo QT assessment were compared with clinical QTC study outcomes. The results show that 14% clinical QTC studies for approved and investigational products failed to exclude 10-ms QTC prolongation. Clinical QTC prolongation for these molecules lacked concentration-dependence which is expected for hERG block-mediated mechanism or QTC prolongation could not be excluded due to characterization in the clinical study. The hERG and ventricular repolarization assays do not identify clinical QTC prolongation potential for peptides and proteins. Lack of alignment between hERG and ventricular repolarization assay results and clinical QTC outcomes suggests that the mechanisms of QTC prolongation by some peptides and proteins are unrelated to direct cardiac ion channel block. Similar to large targeted proteins and monoclonal antibodies, peptides and proteins regardless of size have a low likelihood of direct cardiac ion channel interactions. This characteristic supports waiving the requirement for thorough QT assessment for products comprised of naturally occurring amino acids unless proarrhythmia potential is suggested by nonclinical or clinical data.

Human radiolabeled mass balance studies supporting the FDA approval of new drugs.

Human radiolabeled mass balance studies are an important component of the clinical pharmacology programs supporting the development of new investigational drugs. These studies allow for understanding of the absorption, distribution, metabolism, and excretion of the parent drug and metabolite(s) in the human body. Understanding the drug's disposition as well as metabolite profiling and abundance via mass balance studies can help inform the overall drug development program. A survey of the US Food and Drug Administration (FDA)-approved new drug applications (NDAs) indicated that about 66% of the drugs had relied on findings from the mass balance studies to help understand the pharmacokinetic characteristics of the drug and to inform the overall drug development program. When such studies were not available in the original NDA, adequate justifications were routinely provided. Of the 104 mass balance studies included in this survey, most of the studies were conducted in healthy volunteers (90%) who were mostly men (>86%). The studies had at least six evaluable participants (66%) and were performed using the final route(s) of administration (98%). Eighty-five percent of the studies utilized a dose within the pharmacokinetic linearity range with 54% of the studies using a dose the same as the approved dose. Nearly all studies were performed as a single-dose (97%) study using a fit-for-purpose radiolabeled formulation. In this analysis, we summarized the current practices for conducting mass balance studies and highlighted the importance of conducting appropriately designed human radiolabeled mass balance studies and the challenges associated with inadequately designed or untimely studies.

Relative bioavailability of diclofenac potassium from softgel capsule versus powder for oral solution and immediate-release tablet formulation.

The oral bioavailability of diclofenac potassium 50 mg administered as a soft gelatin capsule (softgel capsule), powder for oral solution (oral solution), and tablet was evaluated in a randomized, open-label, 3-period, 6-sequence crossover study in healthy adults. Plasma diclofenac concentrations were measured using a validated liquid chromatography-mass spectrometry/mass spectrometry method, and pharmacokinetic analysis was performed by noncompartmental methods. The median time to achieve peak plasma concentrations of diclofenac was 0.5, 0.25, and 0.75 hours with the softgel capsule, oral solution, and tablet formulations, respectively. The geometric mean ratio and associated 90%CI for AUCinf, and Cmax of the softgel capsule formulation relative to the oral solution formulation were 0.97 (0.95-1.00) and 0.85 (0.76-0.95), respectively. The geometric mean ratio and associated 90%CI for AUCinf and Cmax of the softgel capsule formulation relative to the tablet formulation were 1.04 (1.00-1.08) and 1.67 (1.43-1.96), respectively. In conclusion, the exposure (AUC) of diclofenac with the new diclofenac potassium softgel capsule formulation was comparable to that of the existing oral solution and tablet formulations. The peak plasma concentration of diclofenac from the new softgel capsule was 67% higher than the existing tablet formulation, whereas it was 15% lower in comparison with the oral solution formulation.

Bioavailability of valsartan oral dosage forms.

The oral bioavailability of valsartan from extemporaneous suspension and solution formulations were evaluated relative to tablet formulation in two separate open-label, randomized crossover studies in healthy adults. In both studies, the plasma concentrations of valsartan after oral administration were analyzed using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods, and the corresponding pharmacokinetic parameters were estimated using noncompartmental analysis. The peak plasma concentration (Cmax ) and area under the concentration time-curves (AUC(0-∞) ) of valsartan from the extemporaneous suspension were higher by 1.93- and 1.56-fold, respectively, relative to the tablet formulation (P < .001). The Cmax and AUC(0-∞) of valsartan from the oral solution were higher by 2.21- and 1.74-fold, respectively, relative to the tablet formulation (P < .001). These results indicate that both rate and extent of absorption of valsartan are higher in the two liquid dosage forms (extemporaneous suspension and solution formulations) relative to the solid oral dosage form (tablet formulation).

Nanoparticulate drug delivery systems for cancer chemotherapy.

Nanoparticles (NPs) are, in general, colloidal particles, less than 1000 nm, that can be used for better drug delivery and prepared either by encapsulating the drug within a vesicle and or by dispersing the drug molecules within a matrix. Nanoparticulate drug delivery systems have been extensively studied in recent years for spatial and temporal delivery, especially in tumour and brain targeting. NPs have great promise for better drug delivery as found in both pharmaceutical and clinical research. As a drug carrier, NPs have significant advantages like better bioavailability, systemic stability, high drug loading, long blood circulation time and selective distribution in the organs/tissues with longer half life. The selective targeting of NPs can be achieved by the enhanced permeability and retention effect (EPR-effect), attaching specific ligands, or by making selective distribution due to change of the physiological conditions of specific systems like nature, pH, temperature, etc. It has been observed that drug-loaded NPs can have selective distribution to organs/tissues using different types of and proportions of polymers. The current aim of researchers is to prepare NPs that are long-lived with and that demonstrate the appropriate selective distribution for better therapy and thus improved clinical outcomes. Nanoparticulate drug delivery systems have the potential to deliver a drug to the target site with specificity and to maintain the desired concentration at the site for the intended time without untoward effects. In this review article, the methods for the preparation of NPs, their characterization, biodistribution, and pharmacokinetic characteristics are discussed.

Application of rotatable central composite design in the preparation and optimization of poly(lactic-co-glycolic acid) nanoparticles for controlled delivery of paclitaxel.

CONTEXT: Polymeric carrier systems of paclitaxel (PCT) offer advantages over only available formulation Taxol® in terms of enhancing therapeutic efficacy and eliminating adverse effects. OBJECTIVE: The objective of the present study was to prepare poly (lactic-co-glycolic acid) nanoparticles containing PCT using emulsion solvent evaporation technique. METHODS: Critical factors involved in the processing method were identified and optimized by scientific, efficient rotatable central composite design aiming at low mean particle size and high entrapment efficiency. Twenty different experiments were designed and each formulation was evaluated for mean particle size and entrapment efficiency. The optimized formulation was evaluated for in vitro drug release, and absorption characteristics were studied using in situ rat intestinal permeability study. RESULTS: Amount of polymer and duration of ultrasonication were found to have significant effect on mean particle size and entrapment efficiency. First-order interactions of amount of miglyol with amount of polymer were significant in case of mean particle size, whereas second-order interactions of polymer were significant in mean particle size and entrapment efficiency. The developed quadratic model showed high correlation (R(2) > 0.85) between predicted response and studied factors. The optimized formulation had low mean particle size (231.68 nm) and high entrapment efficiency (95.18%) with 4.88% drug content. The optimized formulation showed controlled release of PCT for more than 72 hours. In situ absorption study showed faster and enhanced extent of absorption of PCT from nanoparticles compared to pure drug. CONCLUSION: The poly (lactic-co-glycolic acid) nanoparticles containing PCT may be of clinical importance in enhancing its oral bioavailability.

Validation of an HPLC method for determination of imatinib mesylate in rat serum and its application in a pharmacokinetic study.

A simple, selective, and sensitive liquid chromatographic method has been developed and validated for quantitative determination of Imatinib mesylate in rat serum. Efficient chromatographic separation has been performed on a Zorbax Extend (5 microm, 4.6 x 250 mm) double end-capped C(18) column using a mobile phase consisting of methanol and aqueous triethyl amine (pH 10.5; 1%, v/v) (60:40, v/v) in an isocratic mode at a flow rate of 1 mL/min. Simple and effective liquid-liquid extraction technique has resulted in consistent and high recoveries (90.32-95.86%) at all concentrations studied. The method has demonstrated linearity from 25 to 1600 ng/mL with a regression coefficient of 0.9995. Accuracy of the method is acceptable with intra-batch %bias between -2.34 to 3.42 and inter-batch %bias between -2.17 to 3.45. The method has demonstrated high sensitivity with lower limit of quantification of 25 ng/mL and excellent stability of Imatinib mesylate in serum. The method is found to be rapid, reliable, and suitable for in vivo pharmacokinetic study.

Development and validation of an ion-pairing RP-HPLC method for the estimation of gatifloxacin in bulk and formulations.

A new, simple, and sensitive ion-pair reverse-phase liquid chromatographic method is developed and validated for the estimation of 1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methylpiperazin-1-yl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (gatifloxacin) in bulk and formulations using a UV detector under isocratic conditions. The selected mobile phase consists of the aqueous phase (a 25 mM citrate buffer comprising of 10mM cationic and anionic pairing agents, pH adjusted to 3.5) and acetonitrile (52:48%, v/v). The selected wavelength is 292 nm. Retention time of gatifloxacin is 5.2 min. The linearity range is found to be 50 to 1000 ng/mL (the regression equation is area = 105.5 x concentration in ng/mL--695.8), and the regression coefficient is 0.9996. Validation results demonstrate accuracy, precision, and reproducibility (relative standard deviation < 3%) of the method. The detection and quantitation limits are found to be 6.50 and 17.38 ng/mL, respectively. The method is successfully used for the estimation of gatifloxacin in a variety of dosage forms, and the results are in good agreement with the label claims.