Evaluation of a Novel TB Drug SQ109 to Shorten and Simplify the treatment of Experimental Tuberculosis (TB)

SQ109 (ethambutol analogue) is a novel drug undergoing development for treatment of drug-resistant tuberculosis.

1.1.1 Pharmacokinetic properties of SQ109

Pharmacokinetic characteristics of SQ109, received on preclinical trial show evidence of relatively high efficiency even on the onset of single daily dose. According to preclinical research on pharmacokinetic properties of SQ109, characteristic findings in all species of experimental animals showed intense distribution of the drug in extracellular environment and, consequently, low presence in plasma. So, the terminal half-life (t1/2) of SQ109 in experimental dogs (12-29 hours) was more prolonged than that in experimental rats (7-8 h), due to more extensive distribution of the drug in dogs (388-1440 l / m2) as compared to that in rats (81.6 l / m2). Clearance of SQ109 in dogs (47-49 l / h / m2) is approximately four times more intensive than in rats (10 l / hr / m2). Extremely low bioavailability (BA) of the drug with oral dosage forms is partly related to its ability to quickly penetrate into the peripheral tissue, as well as due to intensive metabolic transformations of its parent molecule by the liver microsomal enzyme system, a study to identify isoenzymes of cytochrome P450 involved in metabolic transformations of SQ109, suggested that only CYP2D6 and CYP2C19 were involved in the process , they catalyze the reactions of N-nitrotoluene, N-dealkylation, intermediate epoxidation and oxidation.

Score of risks and benefits

Based on the available data and the proposed measures of safety monitoring, the total score of risk-benefit ratio for clinical trial of SQ109 is considered acceptable for the following reasons:

SQ109 is a new anti-TB drug, selected among a plurality of compounds for having high activity against sensitive and resistant strains of M. Tuberculosis, and Synergies or,  at least, it does not interact with existing anti-TB drugs. Application of SQ109 in addition to standard antituberculosis therapy can improve efficiency and reduce the duration.

In addition, reducing the time of cessation of bacterial excretion in patients with Multi-drug-resistant pulmonary tuberculosis (MDR-TB) will significantly reduce the epidemic risk of such patients.

In order to reduce potential risks to patients participating in the study the following measures are proposed:

• Registration of clinical symptoms and laboratory indicators to identify specific toxicity; this process must be performed in accordance with the table of toxicity provided by the National Institute of Allergy and Infectious Diseases (DMD toxicity table, Appendix B)

 

CONFIDENTIAL

• Along the course of study it is suggested to conduct an interim analysis for early therapeutic evaluation of safety and tolerability of single and multiple oral doses of the studied drug. The analysis will be performed after 12 weeks of therapy with SQ109 in the first 30 patients. According to the results of interim analysis conclusions will be made regarding possible future safety monitoring of research participants.

• Any clinically significant abnormalities continuing at the moment of completion of the study must be observed by the researcher until their resolution or stabilization of condition. Patients with registered changes in laboratory parameters showing 3rd or 4th degree severity levels, should be carefully examined by the doctor researcher. Patients in this case may either continue receiving SQ109, or they will be excluded from the study if, and according to the study, these deviations represent a significant risk in case of continuation of treatment. Some long-term adverse events (undesirable phenomena) cannot be tracked until the moment we obtain permission during the study. In this case, the subsequent observation of the patient must be performed by his doctor, which must be specified in the statement.

• To gather information on the delayed toxicity in the study, an observation period of 24 weeks from the date of SQ109 therapy completion should be regarded.

 

 

 

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Verified by: Dr.Diab (January 7, 2017)

Citation: Dr.Diab. (January 7, 2017). Evaluation of a Novel TB Drug SQ109 to Shorten and Simplify the treatment of Experimental Tuberculosis. Medcoi Journal of Medicine, 6(2). urn:medcoi:article17269.