Yasvanth Ashokraj

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.

In Vivo Dissolution: Predominant Factor Affecting the Bioavailability of Rifampicin in its Solid Oral Dosage Forms

The current recommended treatment for tuberculosis (TB) is a cocktail of anti-TB drugs, preferably in fixed dose combinations (FDC). Rifampicin, one of the important anti-TB drugs, was reported to exhibit variable bioavailability and is classified as a class II drug in the Biopharmaceutic Classification System, (less soluble and highly permeable), thus, factors affecting rate and extent of dissolution would determine its bioavailability. The objective of this investigation was to characterize the role of in vivo dissolution and effect of biopharmaceutic factors on absorption of rifampicin. A 3-way bioequivalence study was conducted comparing a solution formulation of FDC (sachet) and tablets with the same drugs and dose levels. Results indicated that solution formulation is bioequivalent to one FDC I and exhibited a higher bioavailability of rifampicin when compared to FDC II. The difference in absorption was attributed to cohort effect of gastric emptying time (15–20 min in a fasting state) and pH dependent solubility of rifampicin (less soluble when pH > 3). Therefore, a rapid and complete absorption of rifampicin from the solution formulation compared to tablets provided evidence that in vivo dissolution is the major factor affecting absorption of rifampicin. In addition, the present study also demonstrated the feasibility of interchangeability of tablets and powder formulation that is dissolved and immediately administered for the child patient population. The study indicated in vivo dissolution is a key factor in BA of rifampicin.

A decision tree for rapid quality assurance and control of rifampicin-containing oral dosage forms for global distribution for tuberculosis treatment

For centuries tuberculosis remained as a complex socioeconomic problem impeding human development. Directly observed treatment short-course and fixed dose combinations were implemented in tuberculosis therapy for maximum success of treatment. However, drug shortages primarily hindered the expansion of directly observed treatment short-course, which lead to development of the global tuberculosis drug facility. Since large geographical area is covered by the global tuberculosis drug facility for global drug supply for tuberculosis eradication programs, a rapid quality control and assurance has become necessary to ensure the quality and performance of supplied antituberculosis drugs. In this manuscript a decision tree is proposed for facilitating rapid quality control (in vitro and in vivo) of antituberculosis formulations procured by the global tuberculosis drug facility. This decision tree also predicted to be applicable at every stages of anti tuberculosis drug product development, especially in identification of poor quality products and monitoring batch-to-batch variability. Further, it provides opportunity for effective quality control in resource poor settings and the gained knowledge is anticipated to be applicable for development and evaluation of antimalarial and antiAIDS fixed dose combinations.

Feasibility studies on division of fixed dose combinations of anti-tubercular drugs: an improvement in the tuberculosis therapy.

Currently available anti-tubercular drugs for adults come in the following strengths and dosage regimens: 150 mg rifampicin, 75 mg isoniazid, 400 mg pyrazinamide and 275 mg ethambutol hydrochloride during the initial phase and 150 mg rifampicin with 75 mg isoniazid during the continuation phase. The number of dosage units to be administered depends on the body weight. For children, the doses are 60 mg rifampicin, 30 mg isoniazid and 150 mg pyrazinamide during the initial intensive phase and 60 mg rifampicin with 30 mg (or 60) isoniazid during the continuation phase. When the individual strengths are available as fixed-dose combinations (FDCs), the majority of tuberculosis patients would be treated with only four sets of combinations. As one of the major advantages of FDCs is to simplify drug supply and management, it would facilitate stock maintenance if the dosage unit for adults could be divided and administered to children. Furthermore, the feasibility of dividing the adult unit dosage form would also make possible more precise dosing. We therefore studied whether dividing FDC tablets allowed body-weight-based dosage adjustment. Four formulations (two four-drug FDC tablets and two two-drug FDC tablets) available in the international market were sourced for the study through the World Health Organization. Tablets were removed from their original packs and broken into twohalves aswell as twopieces of oneand twothird. Broken tablets were then packed separately in plastic pouches, sealed and stored in the desiccators over activated silica until required for testing. Weights, hardness, friability, disintegration, drug content (1, 2) and dissolution (3, 4) were measured using the intact as well as the fractional units. All the formulations in their original form passed the weight variation (± 5%), friability (<1%) and disintegration tests (<30 min) as predefined in the compendial specifications. Even the divided units passed the friability test (<1%) in spite of exposure of broken surface. The drug content was found to be within acceptable limits of label claim (90–110%) for all formulations tested (Table 1). When the formulations divided into either halves or thirds were tested, the distribution of drug content was found to be in the same ratio predicted by the breaks (Table 1). There was no significant difference between intact and broken units in dissolution rate for any of the formulations (United States Pharmacopoeia (USP); see Refs. 3, 4 for details). Despite the good performance of the tablets in the tests, certain improvements are proposed. The smaller tablets (two FDCs) were found to be difficult to hold and break into halves, although the scored tablets resulted in equal units. As two-third of the tablet was wasted when only one-third of a round tablet was required, we would suggest that when thirds are required, caplets with one break line on one side and two break lines on the other would be preferable (Fig. 1). In conclusion, this study has demonstrated the feasibility of dividing FDCs to provide reliable body-weightbased dosage adjustments. This helps improve drug supply and stock maintenance, while