Abstract:

Objective To evaluate the pharmacokinetic performance and safety of high does of isoniazid and rifapentine in healthy Han population, to provide clinical evidence for preventive therapy of tuberculosis. Methods From October to December 2019, a pharmacokinetic clinical trial was carried out at the Shanghai Public Health Clinical Center. 36 healthy subjects were randomly allocated into a domestic drug group (T) and a reference drug group (R) at a ratio of 1:1. Subjects in Group T were given a single dose oral administration of 900 mg domestic isoniazid and 900 mg domestic rifapentine, Subjects in Group R were given 900 mg reference isoniazid and 900 mg reference rifapentine. Half of the patients in each group were randomly chosen to take those drugs before meals (T1, R1), and the other half would take drugs after meals (T2, R2). After taking the drug, venous blood samples were collected at specified time points and the plasma were separated. Liquid chromatography-tandem mass spectrometry (LC-MS) was used to determine the concentration of drugs and their metabolites in the plasma. Phoenix WinNonlin 8.1 was used to calculate the pharmacokinetic parameters and record all adverse events during the observation period for 72 hours. Results For T1 and R1 group, the peak concentration (C_max) of rifapentin were (21.2±7.3) μg/ml and (15.2±2.8) μg/ml, respectively (t=3.256,P=0.003); area under the plasma concentration curve from administration to last observed concentration at time t (AUC_0-t) were (624.3±327.4) μg·h/ml and (479.3±141.8) μg·h/ml (t=1.724,P=0.094); C_max of isoniazid were (29.9±4.5) μg/ml and (25.2±6.8) μg/ml (t=2.445,P=0.020); AUC_0-t were (80.7±21.4) μg·h/ml and (80.4±12.7) μg·h/ml (t=0.051,P=0.960). For T2 and R2 groups, the C_max of rifapentine were (25.4±6.8) μg/ml and (26.5±5.2) μg/ml (t=-0.545,P=0.589); AUC_0-t were (756.4±253.2) μg·h/ml and (779.7±175.5) μg· h/ml (t=-0.321,P=0.750); the C_max of isoniazid were (11.5±1.6) μg/ml and (10.9±1.5) μg/ml (t=1.161, P=0.253); AUC_0-t were (54.2±9.3) μg·h/ml and (55.8±8.9) μg·h/ml (t=-0.527,P=0.602). The 90% confidence intervals of the T1/R1 geometric mean ratio of C_max and AUC_0-t of rifapentin were 102.7%-158.9% and 87.4%-169.0%,the 90% confidence intervals of the T1/R1 geometric mean ratio of C_max and AUC_0-t of isoniazid were 100.0%-147.8% and 80.9%-120.4%. The 90% confidence intervals of the T2/R2 geometric mean ratio of C_max and AUC_0-t of rifapentin were 78.3%-113.6% and 74.3%-119.5%,the 90% confidence intervals of the T2/R2 geometric mean ratio of C_max and AUC_0-t of isoniazid were 91.8%-120.8% and 82.1%-114.6%.There were no reports of serious adverse events. Conclusion According to the 90% confidence intervals of C_max and AUC_0-t for the test/reference geometric mean ratio in T and R groups, the pharmacokinetics of domestic isoniazid and domestic rifapentine were similar to the reference drugs, but they were not equivalent exactly.Single dose of administration could be stood with good safety.

Key words: Isoniazid, Rifapentine, Pharmacokinetics, Clinical trial