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Yasvanth Ashokraj

Publications and source records attributed to Yasvanth Ashokraj.

5 recordsLinked to original sources
PubMed2006

Statistical evaluation of physiological variability of rifampicin in fixed dose combinations.

Tuberculosis is one of the microbial diseases having a long history of its occurrence and yet to be eradicated from the world. Due to the development of bacterial resistance, treatment has changed from monotherapy to combotherapy to fixed dose combinations (FDCs). Rifampicin has been found one of the most important anti-tubercular drugs, however variable bioavailability of rifampicin in some FDCs as well as separate formulations has been reported in the literature, and led to the development of WHO model protocol for evaluation of FDCs for bioequivalence trials. In present investigation, role of physiological variability in rifampicin bioequivalence was studied. Influence of subject's body weight, inter/intra-individual variability of elimination rate and impact of outliers on the decision of bioequivalence were investigated. Normalization of pharmacokinetic measures for bioequivalence (AUC and C(max)) were carried out as per body weights and elimination rate constants of subjects, then different statistical tests like two-way ANOVA, hauschke analysis, normal and log-transformed confidence interval were applied to check for the change in bioequivalence decision. It was found that normalization as per body weights did not play a significant role in the outcome of bioequivalence endpoint. Similarly, elimination rate variability and outliers have been found insignificant regarding final outcome of bioequivalence study. Hence, it has been concluded that physiological variability did not play a significant role in bioequivalence of rifampicin in FDCs.

Analysis of Variance↗
PubMed2004

Solid-state characterization of rifampicin samples and its biopharmaceutic relevance.

Polymorphism of rifampicin has been postulated to be responsible for its variable bioavailability from solid oral dosage forms. In this regard, it was believed that form II is the preferred form and the content of amorphous needs to be critically monitored. However, there was no study in literature that determines solubility advantage associated with rifampicin polymorphs and further the desired raw material characteristics for the consistent bioavailability. Hence, this investigation was undertaken with an objective to determine biopharmaceutic relevance of rifampicin physical forms and to propose critical raw material specifications for rifampicin bulk material. For this purpose, solid-state properties of standard form I, form II, amorphous and commercial samples acquired from rifampicin manufacturers were characterized by differential scanning calorimetry (DSC), Fourier transformed infrared spectroscopy (FTIR), hot stage microscopy (HSM), thermogravimetric analysis (TGA), powder X-ray diffraction (p-XRD), solid-state nuclear magnetic resonance (NMR) and molecular modelling. In addition, intrinsic dissolution of standard samples, powder dissolution as well as particle size distribution of all the samples and powder dissolution of various sieve fraction of commercial samples were done in order to study the influence of polymorphism and other factors on rate and extent of dissolution. It was found that rifampicin in commercial bulk samples exist as various combinations of form I, form II and amorphous. As physical forms show comparable intrinsic dissolution rate (IDR) at all the pH values, solubility advantage associated with rifampicin polymorphs is negligible. Nevertheless, powder dissolution of commercial samples was influenced by particle size. In powder dissolution of different sieve fractions of commercial samples, fine particles below 100 microm have shown high rate and extent of dissolution irrespective of polymorphic content, whereas particles above 100 microm exhibited reduced dissolution. In intrinsic dissolution, thermodynamically unstable form II exhibited lower IDR than stable form I. Further, this difference is evident only at pH 2.0 and at all other pH values there was no difference in IDR of these two forms. For this unexpected finding, two hypotheses based on differences in H-bonding of the polymorph have been proposed.

Biological Availability↗
PubMed2004

Biopharmaceutic classification system: a scientific framework for pharmacokinetic optimization in drug research.

The tenets of biopharmaceutics, solubility and permeability, are of pivotal importance in new drug discovery and lead optimization due to the dependence of drug absorption and pharmacokinetics on these two properties. A classification system for drugs based on these two fundamental parameters, Biopharmaceutic Classification System (BCS), provides drug designer an opportunity to manipulate structure or physicochemical properties of lead candidates so as to achieve better "deliverability". Considering the facts for failure of NCEs, drug research, once concentrating on optimizing the efficacy and safety of the leads, dramatically transformed in the past two decades. With the enormous number of molecules being synthesized using combinatorial and parallel synthesis, high throughput methodologies for screening solubility and permeability has gained significant interest in pharmaceutical industry. Ultimate aim of the drug discovery scientist in pharmacokinetic optimization is to tailor the molecules so that they show the features of BCS class I without compromising on pharmacodynamics. Considerations to optimize drug delivery and pharmacokinetics right from the initial stages of drug design propelled need for "High Throughput Pharmaceutics" (HTP). In silico predictions and development of theoretical profiles for solubility and lipophilicity provides structure based biopharmaceutical optimization, while in vitro experimental models (microtitre plate assays and cell cultures) validate the predictions. Thus, biopharmaceutical characterization during drug design and early development helps in early withdrawal of molecules with insurmountable developmental problems associated with pharmacokinetic optimization.

Animals↗
PubMed2003

P-glycoprotein inhibitors and their screening: a perspective from bioavailability enhancement.

Drug efflux pumps like P-glycoprotein (P-gp) and multidrug resistance (MDR) proteins were recognized to possess functional role in determining the pharmacokinetics of drugs administered by peroral as well as parenteral route. Advancements in molecular biology, to some extent, had revealed the structure, localization and functional role of P-glycoprotein and its mechanism of drug efflux. Broad substrate recognition by this protein and clinical implications of its inhibition has revolutionized cancer chemotherapy leading to design and development of novel P-glycoprotein inhibitors. In the recent times, the application of these inhibitors in improving peroral drug delivery has gained special interest. Inhibition of P-glycoprotein improves intestinal absorption and tissue distribution while reducing the substrate metabolism and its elimination. Eventually, various screening methodologies have been developed for determining the activity of P-glycoprotein, kinetics of drug transport and identification of substrates and inhibitors. In the present review, techniques used for screening P-glycoprotein inhibitors and the scope of these inhibitors in optimizing peroral drug absorption and pharmacokinetics are discussed along with a brief introduction to P-glycoprotein, its physiological function and active role in extrusion of drugs.

ATP Binding Cassette Transporter, Subfamily B, Mem↗