Determination of pyrazinamide plasma concentrations using lc-ms and pharmacokinetics of pyrazinamide in patients with multidrug-resistant tuberculosis and in patients co-infected with multidrug-resistant tuberculosis and HIV
Botha, Carla Ilse
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Tuberculosis and HIV are arguably South Africa’s largest and most important health issues. With drug-resistant strains of tuberculosis on the increase and little research on new drugs, there is an urgent need for research around the drugs presently available to ensure their optimal use and to minimise their sometimes serious and significant side effects. Treatment of drug-resistant tuberculosis is expensive and lengthy, and is complicated by a limited choice of drugs with lower efficacies and higher toxicities. Treatment is further complicated in patients with HIV due to several factors including drug interactions. While some authors suggest that HIV and malabsorption might be associated with poor clinical outcomes, other researchers have found no link. Patients may benefit from Therapeutic Drug Monitoring in order to ensure that their doses of antituberculosis drugs are reaching the required minimum effective concentrations, without attaining toxic levels in the plasma which may cause unpleasant side effects. There is little research concerning drug levels in HIV patients with TB in South Africa, let alone in patients with drug-resistant forms of tuberculosis, and there are no studies in this country that use Liquid Chromatography-Mass Spectrometry to investigate the plasma levels of pyrazinamide in patients with MDR-TB. This study aimed to investigate whether or not there is a difference in the pharmacokinetics of PZA in MDR-TB patients with HIV, and those without HIV infection. It also aimed to establish whether LC-MS could be used to study the levels of pyrazinamide in the plasma of patients with multidrug-resistant tuberculosis with and without concurrent HIV infection. The plasma levels of pyrazinamide in 32 MDR-TB patients (23 HIV negative and 9 HIV positive), were successfully 2 analysed using LC-MS, and the pharmacokinetics of PZA in these 2 populations was described. It was established that the Tmax of pyrazinamide was significantly higher in HIV-negative patients than in HIV-positive patients. Although there was a difference between the Ka in the two populations, this difference did not quite reach statistical significance. There were no statistically significant differences between HIV-negative and HIV-positive patients with regards to the other pharmacokinetic parameters investigated. Our findings established that there was little evidence to suggest that there is a difference between the pharmacokinetics of the antimycobacterial drug pyrazinamide in HIV-positive patients and that in HIV-negative patients. We were also able to successfully develop and validate an assay for the analysis of PZA in plasma using LC-MS, and this finding could be very valuable for further studies. Although our study failed to prove this, the possibility still exists that HIV-positive patients could exhibit altered kinetics of antiTB drugs and this has not been fully investigated in South Africa. The clinical impact of low plasma levels of antimycobacterial drugs is still largely unexplored and further research with larger sample sizes should be done in order to establish which factors may contribute to low plasma levels of anti-tuberculosis drugs in MDR-TB patients, and whether or not these low levels are increasing the risk of treatment failure or other poor clinical outcomes.