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Multicenter Study
, 67 (1), 34-41

The Potential for Treatment Shortening With Higher Rifampicin Doses: Relating Drug Exposure to Treatment Response in Patients With Pulmonary Tuberculosis

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Multicenter Study

The Potential for Treatment Shortening With Higher Rifampicin Doses: Relating Drug Exposure to Treatment Response in Patients With Pulmonary Tuberculosis

Elin M Svensson et al. Clin Infect Dis.

Abstract

Background: Tuberculosis remains a huge public health problem and the prolonged treatment duration obstructs effective tuberculosis control. Higher rifampicin doses have been associated with better bactericidal activity, but optimal dosing is uncertain. This analysis aimed to characterize the relationship between rifampicin plasma exposure and treatment response over 6 months in a recent study investigating the potential for treatment shortening with high-dose rifampicin.

Methods: Data were analyzed from 336 patients with pulmonary tuberculosis (97 with pharmacokinetic data) treated with rifampicin doses of 10, 20, or 35 mg/kg. The response measure was time to stable sputum culture conversion (TSCC). We derived individual exposure metrics with a previously developed population pharmacokinetic model of rifampicin. TSCC was modeled using a parametric time-to-event approach, and a sequential exposure-response analysis was performed.

Results: Higher rifampicin exposures increased the probability of early culture conversion. No maximal limit of the effect was detected within the observed range. The expected proportion of patients with stable culture conversion on liquid medium at week 8 was predicted to increase from 39% (95% confidence interval, 37%-41%) to 55% (49%-61%), with the rifampicin area under the curve increasing from 20 to 175 mg/L·h (representative for 10 and 35 mg/kg, respectively). Other predictors of TSCC were baseline bacterial load, proportion of culture results unavailable, and substitution of ethambutol for either moxifloxacin or SQ109.

Conclusions: Increasing rifampicin exposure shortened TSCC, and the effect did not plateau, indicating that doses >35 mg/kg could be yet more effective. Optimizing rifampicin dosage while preventing toxicity is a clinical priority.

Figures

Figure 1.
Figure 1.
Evaluation of the pharmacokinetic model. A, Comparison between individual rifampicin area under the concentrations curve from 0 to 24 hours after the dose (AUC0–24h) at day 28 derived by noncompartmental analysis (NCA) and by the model, per rifampicin dose level (circles represent 10 mg/kg; triangles, 20 mg/kg; squares, 35 mg/kg). B, Distribution of AUC0–24h values (box-and-whisker plots) simulated including interindividual variability for 9 representative patients (dose level 10 mg/kg for individuals 1–3, 20 mg/kg for individuals 4–6, and 35 mg/kg for individuals 7–9) with corresponding individual typical AUC0–24h, that is, expected value given the individual’s dose and fat-free mass (FFM), and “true” AUC0–24h, that is, expected value given the individual’s rifampicin dose, FFM and observed rifampicin plasma concentrations. The 9 patients were chosen to cover the 3 most common absolute rifampicin doses per dose level, simply selecting the first included patient per dose. Boxes represents the first, second, and third quartiles, and whiskers extend to the highest and lowest values within 1.5 times the interquartile range. Abbreviation: PK, pharmacokinetics.
Figure 2.
Figure 2.
Evaluation of the final time-to-event model describing time to sputum culture conversion (TSCC) based on liquid cultures, per study arm, in the form of a visual predictive check. Solid lines represent Kaplan-Meier curves based on the observed data. Vertical tick marks signify censored data, and shaded area outlines 95% prediction interval based on simulations using the model. Study arms include the control arms (R10HZE) and experimental arms 1–4 (R35HZE, R10HZQ, R20HZQ and, R20HZM). (Number in arm name represent rifampicin dose [in milligrams per kilogram] used in the first treatment period, 2 months for R10HZE and 3 months for all other arms). Abbreviation: SCC, sputum culture conversion.
Figure 3.
Figure 3.
Predicted proportion without sputum culture conversion (SCC) versus time after start of treatment for virtual populations of patients (n = 10000) having rifampicin area under the concentration versus time curve from 0 to 24 hours after the dose (AUC0-24h) of either 21, 62, or 173 mg/L·h (median observed exposure in dose groups 10, 20 and 35 mg/kg, respectively), and standard doses of isoniazid, pyrazinamide, and ethambutol. The distribution of baseline bacterial load and missing sputum samples in the simulation mimicked the results in the study used to build the models.
Figure 4.
Figure 4.
Expected proportion of patients with sputum culture conversion (SCC) at week 8 over varying rifampicin exposures for a virtual population of patients (distribution of baseline bacterial load and missing sputum samples mimicking that of the study) treated with standard doses of isoniazid, pyrazinamide, and ethambutol. Black dots represents simulation results (n = 10000 in each); dark gray line, a locally weighted smooth of the simulation results; and light gray shaded area, 95% confidence interval based on the uncertainty in the estimate of the parameter for rifampicin effect. Vertical lines represent median observed exposures in the dose groups 10 (red), 20 (green), and 35 (blue) mg/kg, respectively, and tick marks at the bottom of the graph are individual observed exposures. Abbreviation: AUC0–24h, area under the curve from 0 to 24 hours after dose.

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