Therapeutic Drug Monitoring in the Treatment of Tuberculosis

Abstract

Therapeutic drug monitoring (TDM) is a standard clinical technique used for many disease states, including many infectious diseases. As for these other conditions, the use of TDM in the setting of tuberculosis (TB) allows the clinician to make informed decisions regarding the timely adjustment of drug therapy. Such adjustments may not be required for otherwise healthy individuals who are responding to the standard, four-drug TB regimens. However, some patients are slow to respond to treatment, have drug-resistant TB, are at risk of drug-drug interactions or have concurrent disease states that significantly complicate the clinical situation. Such patients may benefit from TDM and early interventions may preclude the development of further drug resistance. It is not possible to collect multiple blood samples in the clinical setting for logistical and financial reasons. Therefore, one typically is limited to one or two time points. When only one sample can be obtained, the 2-hour post-dose concentrations of isoniazid, rifampin, pyrazinamide and ethambutol are usually most informative. Unfortunately, low 2-hour values do not distinguish between delayed absorption (late peak, close to normal range) and malabsorption (low concentrations at all time points). A second sample, often collected at 6-hour post-dose, can differentiate between these two scenarios. The second time point can also provide some information about clearance and half-life, assuming that drug absorption was nearly completed by 2 hours. TDM requires that samples are promptly centrifuged, and that the serum is promptly harvested and frozen. Isoniazid and ethionamide, in particular, are not stable in human serum at room temperature. Rifampin is stable for more than 6 hours under these conditions. During TB treatment, isoniazid causes the greatest early reduction in organisms and is considered to be one of the two most important TB drugs, along with rifampin. Although isoniazid is highly active against TB, low isoniazid concentrations were associated with poorer clinical and bacteriological outcomes in US Public Health Services (USPHS) TB Trial 22. Several earlier trials showed a clear dose-response for rifampin and pyrazinamide, so low concentrations for those two drugs also may correlate with poorer treatment outcomes. At least in USPHS TB Trial 22, the rifampin pharmacokinetic parameters were not predictive of the outcome variables. In contrast, low concentrations of unbound rifapentine may have been responsible, in part, for the worse-than-anticipated performance of this drug in clinical trials. The 'second-line' TB drugs, including p-aminosalicylic acid, cycloserine and ethionamide, are relatively weak TB drugs. Under the best conditions, treatment with these drugs takes over 2 years, as opposed to 6 to 9 months with isoniazid- and rifampin-containing regimens. Therefore, TB centres such as National Jewish Medical and Research Center in Denver, CO, USA, measure serum concentrations of the 'second-line' TB drugs early in the course of treatment. That ...

Quantification of isoniazid, pyrazinamide and ethambutol in serum using liquid chromatography-tandem mass spectrometry

“…The analytical range was based on clinical pharmacokinetic data and set at 0.2-8 mg/L for isoniazid and ethambutol and 2-80 mg/L for pyrazinamide [3,16]. As stable isotope-labelled internal standards are known to compensate for matrix effects [9,10], isoniazid-D4 and ethambutol-D4 were used as such.…”

“…Recently, Pasipanodya et al showed that risk on treatment failure was almost nine fold higher in patients with low drug exposure compared to patients with higher drug exposure [2]. Therefore, monitoring of drug exposure in patients at risk for low drug exposure is worthwhile to explore in a prospective manner [3]. To be able to evaluate drug exposure a fast, accurate and simple method for determination of isoniazid, rifampin, pyrazinamide and ethambutol in serum is valuable.…”

Current status and opportunities for therapeutic drug monitoring in the treatment of tuberculosis

“…Pharmacokinetic and pharmacodynamic markers of antituberculosis drugs for the use of therapeutic drug monitoring [7,10,[18][19][20].…”

“…WHO group [21] Drug Adult daily dose* [7,18,20] C max [7,18,20] T max (h) [7,18,20] PK/PD b [7,18,20] PK/PD target value [19,22] The adult dosage is based on the dosage that is given a day, while dosing multiple times a day is not performed very often anymore because of compliance.…”

“…[48] Other adverse effects of anti-TB drugs include ocular toxicity, which is more common with a daily dose of ethambutol above 30 mg/kg. [18] Another study found that ocular toxicity may be due to overdosing of ethambutol in obese patients. Overdosing occurred in relation to the calculation of the dosage on total body weight.…”