Clinical Pharmacology

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https://scholar.sun.ac.za/handle/10019.1/164
This division was known as Pharmacology until 27 June 2013.

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Browsing Clinical Pharmacology by browse.metadata.advisor "Reuter, H."

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    Pharmacokinetic study of anti-tb drug para-aminosalicylic acid and its metabolites: a possible relationship with the development of toxicity
    (Stellenbosch : Stellenbosch University, 2019-04) Adams, Kim; Reuter, H.; Stander, M.; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine: Clinical Pharmacology.
    Background Para-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 its association with gastrointestinal (GI) intolerance. The intolerance was considered to be due to the dosing strategy, which therefore caused clinicians to opt for divided doses as opposed 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 could possibly be responsible for poor tolerability of the drug. Aims The aim of the study was to investigate the potential association between the plasma concentrations of the main metabolites, acetyl-PAS (APAS) and glycine-PAS (GPAS), and the occurrence of GI intolerance, after the administration of a granular slow release PAS (GSR-PAS) formulation. Study design and methodology A 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, South Africa. These patients were assigned to a 4g twice-daily GSR-PAS regimen for 1 week followed by another week given 8g once-daily GSR-PAS. Whole blood was collected in EDTA-containing tubes at 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose, at the end of each week. PAS plasma concentrations were determined using an ultra high performance liquid chromatography system coupled to a tandem mass spectrometer, (UHPLC-MS/MS) of which the assay was developed and partially validated according to the Food and Drug Administration (FDA) criteria. Thereafter, pharmacokinetic analysis was performed for the metabolites and parent drug of which pharmacokinetic parameters Cmax, AUC0-24 and Tmax were determined by non-compartmental analysis, using Winnonlin 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 left indicating no symptoms and the most right indicating severe symptoms. The patients completed the evaluation on a daily basis after dosing. The AE’s evaluated included nausea, bloating, diarrhoea, vomiting, and abdominal pain and cramps. A correlation analysis using STATA software version 15.1 was used to measure the association between each AE and the median Cmax of PAS, APAS and GPAS using the Spearman’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 a single run of 4 minutes. A large inter-individual variability was observed in the Cmax ranging from 40.42 to 102.41 mg/L for PAS, and 10.00 to 22.36 mg/L and 3.90 to 9.45 mg/L for APAS and GPAS, respectively. The VAS data reported that 26 patients had evidence 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 4g twice-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 found for GPAS concentrations and diarrhoea (rho= -0.412; p= 0.041). Conclusions: Plasma concentrations of metabolites APAS and GPAS did not correlate with the occurrence of AE’s. On the contrary, the data showed that higher plasma concentrations of APAS and GPAS were associated with lower scores of AE’s, which were statistically significant relationships but considered clinically negligible. Further work with a larger population size may be needed to determine the true effect of metabolite formation on the presence of GI discomfort when treated with PAS.