Subtherapeutic Rifampicin Concentration Is Associated With Unfavorable Tuberculosis Treatment Outcomes

Abstract

Background The relationships between first-line drug concentrations and clinically important outcomes among patients with tuberculosis (TB) remain poorly understood. Methods We enrolled a prospective cohort of patients with new pulmonary TB receiving thrice-weekly treatment in India. The maximum plasma concentration of each drug was determined at months 1 and 5 using blood samples drawn 2 hours postdose. Subtherapeutic cutoffs were: rifampicin <8 µg/mL, isoniazid <3 µg/mL, and pyrazinamide <20 µg/mL. Factors associated with lower log-transformed drug concentrations, unfavorable outcomes (composite of treatment failure, all-cause mortality, and recurrence), and individual outcomes were examined using Poisson regression models. Results Among 404 participants, rifampicin, isoniazid, and pyrazinamide concentrations were subtherapeutic in 85%, 29%, and 13%, respectively, at month 1 (with similar results for rifampicin and isoniazid at month 5). Rifampicin concentrations were lower with human immunodeficiency virus coinfection (median, 1.6 vs 4.6 µg/mL; P = .015). Unfavorable outcome was observed in 19%; a 1-μg/mL decrease in rifampicin concentration was independently associated with unfavorable outcome (adjusted incidence rate ratio [aIRR], 1.21 [95% confidence interval {CI}, 1.01–1.47]) and treatment failure (aIRR, 1.16 [95% CI, 1.05–1.28]). A 1-μg/mL decrease in pyrazinamide concentration was associated with recurrence (aIRR, 1.05 [95% CI, 1.01–1.11]). Conclusions Rifampicin concentrations were subtherapeutic in most Indian patients taking a thrice-weekly TB regimen, and low rifampicin and pyrazinamide concentrations were associated with poor outcomes. Higher or more frequent dosing is needed to improve TB treatment outcomes in India.

Individualized Dosing With High Inter-Occasion Variability Is Correctly Handled With Model-Informed Precision Dosing—Using Rifampicin as an Example

“…Individualized dosing is crucial to ensure optimal rifampicin exposure, since treatment failure, resistance development, and relapse of TB disease have been linked to suboptimal rifampicin plasma concentrations (Pasipanodya et al, 2013;Alsultan and Peloquin, 2014;Ramachandran et al, 2019). To prevent prolonged treatment, which increases the patient's risk for adverse events and treatment costs, it is critical to use approaches ensuring that adequate drug exposure is achieved in every patient, which can be accomplished through MIPD.…”

“…Rifampicin is one of the core-drugs in the first-line treatment of drug-susceptible tuberculosis (TB) (WHO, 2017). With the currently recommended dosage of 10 mg/kg once daily (WHO, 2017), a substantial amount of patients do not reach sufficient drug exposure, which has been shown to result in treatment failure, development of drug resistance, and disease relapse (Pasipanodya et al, 2013;Alsultan and Peloquin, 2014;Ramachandran et al, 2019). Therefore, higher doses of rifampicin have been studied and were shown to lead to higher efficacy than the current recommended dosage (Svensson et al, 2018b), while still being safe (Boeree et al, 2015).…”

The Impact of First-Line Anti-Tubercular Drugs’ Pharmacokinetics on Treatment Outcome: A Systematic Review

“…The geographic location of the included studies was; six from Africa, [25][26][27][28][29][30] one from Europe, 31 two from Latin America, 32,33 and the remaining three from Asia. [34][35][36] The majority of the studies were observational prospective in design. Only two of the studies included in this review were randomized clinical trials as shown in Table 2.…”

“…In all studies, some participants had comorbid conditions; either HIV or diabetes mellitus. 29,[33][34][35][36] The PRISMA Flow diagram is shown in Figure 1.…”

“…Among the twelve studies evaluating PK parameters with treatment outcome, four assessed RMP only, 26,27,30,32 one INH only, 33 five three drugs (RMP, INH, and PZA) 25,29,[34][35][36] and two all drugs (RMP, INH, PZA, EMB). 28,31 All studies reported clinical outcomes and their association with some kind of pharmacokinetics parameters.…”