Pharmacokinetic study of anti-tb drug para-aminosalicylic acid and its metabolites: a possible relationship with the development of toxicity

[摘要] BackgroundPara-aminosalicylic acid (PAS) is a bacteriostatic anti-tuberculosis (anti-TB) drug,used in the treatment of multi-drug resistant (MDR) and extensively drug-resistant(XDR) tuberculosis (TB). While PAS has shown great efficacy, it is notorious for itsassociation with gastrointestinal (GI) intolerance. The intolerance was considered to bedue to the dosing strategy, which therefore caused clinicians to opt for divided doses asopposed to a single large dose daily, but no evidence of improvement has been reported.It has thus been proposed that the rate of absorption and/or metabolism of PAS couldpossibly be responsible for poor tolerability of the drug.AimsThe aim of the study was to investigate the potential association between the plasmaconcentrations of the main metabolites, acetyl-PAS (APAS) and glycine-PAS (GPAS),and the occurrence of GI intolerance, after the administration of a granular slow releasePAS (GSR-PAS) formulation.Study design and methodologyA two-period study of PAS and its metabolites was conducted in 29 adult patients (≥18 years old) MDR- and XDR-TB, at the Brooklyn Chest Hospital, Cape Town, SouthAfrica. These patients were assigned to a 4g twice-daily GSR-PAS regimen for 1 weekfollowed by another week given 8g once-daily GSR-PAS. Whole blood was collectedin EDTA-containing tubes at 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose, at the end ofeach week.PAS plasma concentrations were determined using an ultra high performance liquidchromatography system coupled to a tandem mass spectrometer, (UHPLC-MS/MS) ofwhich the assay was developed and partially validated according to the Foodand Drug Administration (FDA) criteria. Thereafter, pharmacokinetic analysis wasperformed for the metabolites and parent drug of which pharmacokinetic parametersCmax, AUC0-24 and Tmax were determined by non-compartmental analysis, usingWinnonlin software version 8.0.The tolerability of PAS was evaluated using a 10-point visual analogue scale (VAS)rating the severity of the adverse effects (AE's) experienced, with the most leftindicating no symptoms and the most right indicating severe symptoms. The patientscompleted the evaluation on a daily basis after dosing. The AE's evaluated includednausea, bloating, diarrhoea, vomiting, and abdominal pain and cramps.A correlation analysis using STATA software version 15.1 was used to measure theassociation between each AE and the median Cmax of PAS, APAS and GPAS using theSpearman's rank correlation. Statistical significant was set at a P value less than 0.05.Results:The developed method proved successful in the assay of APAS, GPAS and PAS in asingle run of 4 minutes. A large inter-individual variability was observed in the Cmaxranging from 40.42 to 102.41 mg/L for PAS, and 10.00 to 22.36 mg/L and 3.90 to 9.45mg/L for APAS and GPAS, respectively. The VAS data reported that 26 patients hadevidence of GI intolerance, but the majority of these scores were clustered around zero.Abdominal pain and cramps were found to be statistically more frequent in the 4gtwice-daily than 8g once-daily regime [0.14(0 – 0.59) versus 0(0 – 0.08); median (IQR);p= 0.018]. Statistically significant inverse associations were observed between APAS concentrations and bloating (rho= -0.448; p= 0.025) and diarrhoea (rho= -0.407; p=0.044), respectively, for the twice-daily dose. The same inverse association was foundfor GPAS concentrations and diarrhoea (rho= -0.412; p= 0.041).Conclusions:Plasma concentrations of metabolites APAS and GPAS did not correlate with theoccurrence of AE's. On the contrary, the data showed that higher plasma concentrationsof APAS and GPAS were associated with lower scores of AE's, which were statisticallysignificant relationships but considered clinically negligible. Further work with a largerpopulation size may be needed to determine the true effect of metabolite formation onthe presence of GI discomfort when treated with PAS.

[发布机构] Stellenbosch University