Drug-Drug Interaction Studies on First-Line Anti-tuberculosis Drugs

Abstract

The purpose of this study was to carry out drug-drug compatibility studies on pure first line anti-tuberculosis drugs, viz., rifampicin (R), isoniazid (H), pyrazinamide (Z), and ethambutol hydrochloride (E). Various possible binary, ternary, and quaternary combinations of the four drugs were subjected to accelerated stability test conditions of 40 degrees C and 75% relative humidity (RH) for 3 months. For comparison, parallel studies were also conducted on single drugs. Changes were looked for in the samples drawn after 15, 30, 60, and 90 days of storage. Analyses for R, H, and Z were carried out using a validated HPLC method. The E was analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), as it does not absorb in ultraviolet (UV). All single pure drugs were relatively stable and showed only 3%-5% degradation under accelerated conditions for 3 months. However, significant interactions were observed in case of the drug mixtures. In particular, ternary and quaternary drug combinations containing R and H along with Z and/or E were very unstable, showing 90%-95% and 70%-75% loss of R and H, respectively. In all these cases, isonicotinyl hydrazone (HYD) of 3-formylrifamycin and H was found to be the major degradation product. In case of RE and RZE mixtures, where H was absent, 3-formylrifamycin was instead the key degradation product. Another unidentified peak was observed in the mixture containing RZE. Apart from these chemical changes, considerable physical changes were also observed in pure E and the mixtures containing E, viz., RE, ZE, RHE, RZE, and RHZE. In addition, significant physical changes associated with noteworthy loss of H and E were also observed in mixtures containing HE and HZE. The present study thus amply shows that the four primary anti-tuberculosis drugs, when present together, interact with each other in a multiple and complex manner.

Halloysite nanotubes as tools to improve the actual challenge of fixed doses combinations in tuberculosis treatment

“…). In line with previous studies, isonicotinylhydrazone could be stated as the major degradation product of INH, which is formed by the interaction of the imino group of 3‐formyl rifampicin of RIF with the hydrazine group of INH under acidic conditions provided by the presence of ETB . In the presence of the nanohybrid, compatibility of quaternary mixtures was enhanced, achieving residual INH contents from 5 to 10 times higher than that found in absence of HLNTs at the same time.…”

“…The WHO Model List of Essential Drugs includes fixed‐dose‐combinations (FDCs) of the first‐line tuberculostatic drugs (INH, Rifampicin [RIF], Pyrazinamide [PYR], and Ethambutol dihydrochloride [ETB]) with numerous advantages, as the minor risk of acquisition of drug resistance due to monotherapy and the improved patient adherence derived from the smaller number of solid dosage forms to ingest. However, the commercialized 4‐FDC dosage forms exhibit severe technological problems including extensive physical changes (color fading, red bleeding) and, particularly important for therapy efficacy, significant decomposition of RIF and INH in presence of the other drug molecules …”

LC and LC-MS study of stress decomposition behaviour of isoniazid and establishment of validated stability-indicating assay method

“…In our laboratory, we are carrying out extensive investigations on the stability behaviour of first-line anti-tuberculosis (TB) agents (viz., rifampicin, isoniazid, pyrazinamide and ethambutol HCl), both when they are present alone or in fixeddose combinations (FDCs) [1][2][3]. As a part of the same, we * Corresponding author.…”

Entrapment of multiple anti‐Tb drugs in microemulsion system: Quantitative analysis, stability, and in vitro release studies

“…Hence, these microemulsion formulations have proved to be efficient in controlling the drug‐drug interactions to certain extend by showing no change in physical or chemical stability. However, Bhutani et al34 have emphasized on the strong interaction of these ATDs with each other in a multiple and complex manner. The stability of the chosen combinations in the present case has also been supported by their studies on different marketed products.…”