Longitudinal Pharmacokinetic-Pharmacodynamic Biomarkers Correlate With Treatment Outcome in Drug-Sensitive Pulmonary Tuberculosis: A Population Pharmacokinetic-Pharmacodynamic Analysis

Abstract

Background: This study aims to explore relationships between baseline demographic covariates, plasma antibiotic exposure, sputum bacillary load, and clinical outcome data to help improve future tuberculosis (TB) treatment response predictions.

Methods: Data were available from a longitudinal cohort study in Malawian drug-sensitive TB patients on standard therapy, including steady-state plasma antibiotic exposure (154 patients), sputum bacillary load (102 patients), final outcome (95 patients), and clinical details. Population pharmacokinetic and pharmacokinetic-pharmacodynamic models were developed in the software package NONMEM. Outcome data were analyzed using univariate logistic regression and Cox proportional hazard models in R, a free software for statistical computing.

Results: Higher isoniazid exposure correlated with increased bacillary killing in sputum (P < .01). Bacillary killing in sputum remained fast, with later progression to biphasic decline, in patients with higher rifampicin area under the curve (AUC)_0-24 (P < .01). Serial sputum colony counting negativity at month 2 (P < .05), isoniazid C _MAX (P < .05), isoniazid C _MAX/minimum inhibitory concentration ([MIC] P < .01), and isoniazid AUC_0-24/MIC (P < .01) correlated with treatment success but not with remaining free of TB. Slower bacillary killing (P < .05) and earlier progression to biphasic bacillary decline (P < .01) both correlate with treatment failure. Posttreatment recurrence only correlated with slower bacillary killing (P < .05).

Conclusions: Patterns of early bacillary clearance matter. Static measurements such as month 2 sputum conversion and pharmacokinetic parameters such as C _MAX/MIC and AUC_0-24/MIC were predictive of treatment failure, but modeling of quantitative longitudinal data was required to assess the risk of recurrence. Pooled individual patient data analyses from larger datasets are needed to confirm these findings.

Keywords: outcome; pharmacodynamics; pharmacokinetics; standard treatment; tuberculosis.

Figure 1.

Simulation based (n = 2000) visual predictive checks for isoniazid (top left), rifampicin (top right), pyrazinamide (bottom left), and ethambutol (bottom right). Open circles represent observations, solid and dashed black lines represent observed 2.5, 50th, and 97.5 percentiles. Shaded areas represent the 90% confidence intervals around the simulated 2.5, 50th, and 97.5 percentiles.

Figure 2.

Visualization of pharmacokinetic-pharmacodynamic model characteristics. The solid line (A) illustrates monophasic bacillary clearance from sputum with a clearance rate represented by LAM. The dashed (B) and dotted (C) lines illustrate biphasic bacillary clearance trajectories; LAM represents the initial clearance rate (faster in B than C line), BETA represents the magnitude of decreased bacillary clearance (larger in C than B), and t_1/2 represents the time it takes to switch from fast to slow killing (earlier in B than C). CFU, colony-forming units.

Figure 3.

Simulation-based (n = 2000) visual predictive checks for the pharmacokinetic-pharmacodynamic model. Open circles in the top panel represent observations, and solid and dashed black lines represent observed 50th and 97.5 percentiles, respectively. Shaded areas in the top panel represent the 90% confidence intervals around the simulated 2.5, 50th, and 97.5 percentiles. The dots and solid line in the bottom panel represent the observed proportion of samples below the limit of quantification, and the shaded area represents the corresponding 90% confidence interval of proportion samples below limit of quantification produced by the model. Bars at the bottom of the lower panel indicate the binning windows. CFU, colony-forming units; LLOQ, lower limit of quantification.

Figure 4.

Visualization pharmacokinetic-pharmacodynamic covariate effects (baseline bilirubin-LAM; isoniazid-LAM; rifampicin-t_1/2 and alcohol consumption-LAM]). High and low exposure refers to highest and lowest values in the study population: 1–32 μmol/L, 54.9–515 hrxμmol/L, and 19.9–145 hrxμmol/L for baseline bilirubin, isoniazid, and rifampicin, respectively. CFU, colony-forming units.