Isoniazid, Rifampin, Ethambutol, and Pyrazinamide Pharmacokinetics and Treatment Outcomes among a Predominantly HIV‐Infected Cohort of Adults with Tuberculosis from Botswana

Abstract

Background We explored the association between anti-tuberculosis drug pharmacokinetics and treatment outcomes among pulmonary tuberculosis (TB) patients in Botswana. Methods Consenting TB outpatients had blood collected 1, 2, and 6 hours after simultaneous isoniazid, rifampin, ethambutol, and pyrazinamide ingestion. Maximum serum concentrations (Cmax) and areas under the serum concentration-time curve (AUC0-6 h) were determined. Clinical status was monitored throughout treatment. Results Of 225 participants, 36 (16%) experienced a poor treatment outcome (treatment failure or death); 155 (69%) were HIV-infected. Compared with published standards, low isoniazid Cmax occurred in 84 (37%); rifampin in 188 (84%); ethambutol in 87 (39%); and pyrazinamide in 11 (5%) patients. Median rifampin and pyrazinamide levels differed significantly by HIV status and CD4 cell count (HIV-CD4) categories. Only pyrazinamide pharmacokinetics were significantly associated with treatment outcome; low pyrazinamide Cmax was associated with a higher risk of documented poor treatment outcome than normal Cmax (50% vs. 16%; p<0.01). HIV-infected patients with CD4 <200 cells/μL had higher risk of poor treatment outcome (27%) than HIV-uninfected patients (11%) or HIV-infected patients with CD4 ≥ 200 cells/μL (12%); p=0.01. Adjusting for HIV infection and CD4, patients with low pyrazinamide Cmax were thrice more likely to have poor outcomes than patients with normal pyrazinamide Cmax [adjusted risk ratio = 3.38, 95% confidence interval (1.84 – 6.22)]. Conclusions Lower-than-expected anti-tuberculosis drug Cmax occurred frequently and low pyrazinamide Cmax was associated with poor treatment outcome. Exploring the global prevalence and significance of these findings may suggest modifications in treatment regimens that could improve TB cure rates.

Suboptimal Exposure to Anti‐TB Drugs in a TBM/HIV+ Population Is Not Related to Antiretroviral Therapy

“…Bhatt et al 9 found that antiretroviral drugs did not influence exposure to RIF or INH when concomittantly administered in HIV-infected TB patients. Other studies, however, have found that HIV-infected TB patients receiving ART often have a lower exposure to RIF and INH 10 , 11 compared to HIV-negative individuals.…”

“…A debate also exists on the interaction between anti-retroviral drugs and Rifampicin in particular with the literature providing mixed messages on whether anti-retroviral therapy decreases Rifampicin exposure or doesn't affect it at all 9 , 10,11 .…”

Rifamycin action on RNA polymerase in antibiotic-tolerant Mycobacterium tuberculosis results in differentially detectable populations

“…Doses of RIF, INH, pyrazinamide (PZA), and ETH were selected based on mean peak drug concentrations (Cmax) achieved in patients' serum (36)(37)(38). For these studies, Mtb was starved in PBS for 4 wk, then exposed to the four drugs simultaneously for 5 d, with two different doses of RIF-one based on Cmax data (3 μg/mL), and one already shown to create DD Mtb (10 μM; 8.2 μg/mL).…”

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

“…[4,6] PK variability is a well-known problem affecting drug exposure and thereby TB treatment. [7,8] For example, Pranger et al observed a nine-fold variability in the area under the time concentration curve between 0 and 24 h (area under the curve [AUC 0-24 h ]) of moxifloxacin, possibly due to variation in protein binding.…”

“…[7] Furthermore, Chideya et al found that pyrazinamide plasma concentrations below 35 µg/ml were a predictor of poor treatment outcome, which can function as a reference value in TDM. [6] However, more studies are needed to elucidate PK/PD indices in 'real life' treatment, because the PK/PD index (Table 1) of a drug in a combination regimen may differ from the index of that particular drug given as monotherapy in an EBA study.…”