Pharmacodynamics and Bactericidal Activity of Combination Regimens in Pulmonary Tuberculosis: Application to Bedaquiline-Pretomanid-Pyrazinamide

Abstract

A critical barrier to codevelopment of tuberculosis (TB) regimens is a limited ability to identify optimal drug and dose combinations in early-phase clinical testing. While pharmacokinetic-pharmacodynamic (PKPD) target attainment is the primary tool for exposure-response optimization of TB drugs, the PD target is a static index that does not distinguish individual drug contributions to the efficacy of a multidrug combination. A PKPD model of bedaquiline-pretomanid-pyrazinamide (BPaZ) for the treatment of pulmonary TB was developed as part of a dynamic exposure-response approach to regimen development. The model describes a time course relationship between the drug concentrations in plasma and their individual as well as their combined effect on sputum bacillary load assessed by solid culture CFU counts and liquid culture time to positivity (TTP). The model parameters were estimated using data from the phase 2A studies NC-001-(J-M-Pa-Z) and NC-003-(C-J-Pa-Z). The results included a characterization of BPaZ activity as the most and least sensitive to changes in pyrazinamide and bedaquiline exposures, respectively, with antagonistic activity of BPa compensated by synergistic activity of BZ and PaZ. Simulations of the NC-003 study population with once-daily bedaquiline at 200 mg, pretomanid at 200 mg, and pyrazinamide at 1,500 mg showed BPaZ would require 3 months to attain liquid culture negativity in 90% of participants. These results for BPaZ were intended to be an example application with the general approach aimed at entirely novel drug combinations from a growing pipeline of new and repurposed TB drugs.

Keywords: clinical trial; combination chemotherapy; dose selection; killing kinetics; pharmacometrics; tuberculosis regimen.

FIG 1

NC001 drug pairs. Visual predictive check for population data and PKPD model simulations. Day 14 plasma concentrations for bedaquiline (BDQ), pretomanid (Pa), and pyrazinamide (PZA). Days −1 to 0 (pretreatment) and days 1 to 14 sputum CFU and time to positivity (TTP). (A) Bedaquiline-pretomanid, (B) bedaquiline-pyrazinamide, and (C) pretomanid-pyrazinamide. Observed data (points); median (square point), 5th and 95th percentiles (error bars). Model predictions are shown as Monte Carlo (MC) distribution summaries (sample size equal to 10,000), median (solid line), and 5th and 95th percentiles (dashed lines).

FIG 2

NC003 BPaZ combination. Visual predictive check for population data and PKPD model simulations. Day 14 plasma concentrations for bedaquiline (BDQ), pretomanid (Pa), and pyrazinamide (PZA). Days −1 to 0 (pretreatment) and days 1 to 14 sputum CFU and time to positivity (TTP). Observed data (points), median (square point), 5th and 95th percentiles (error bars) for the CFU and TTP mean (triangle) and SE (error bars). Model predictions are shown as Monte Carlo (MC) distribution summaries (sample size equal to 10,000), median (solid line), and 5th and 95th percentiles (dashed lines), and for the mean CFU and TTP (solid line).

FIG 3

NC003 BPaZ combination. Visual predictive check for individual data and PKPD model simulations. Day 1 to 14 plasma concentrations for bedaquiline (BDQ), pretomanid (Pa), and pyrazinamide (PZA). Days −1 to 0 (pretreatment) and days 1 to 14 sputum culture CFU and time to positivity (TTP). Observed data (points) and model-predicted mean profiles (lines). The day 9 and day 11 observed TTP values for the fifth row (from the top) participant are not shown but were equal to 31.6 days and 36.2 days, respectively.

FIG 4

Single-drug dose ranging for bedaquiline (B_XPaZ), pretomanid (BPa_XZ), and pyrazinamide (BPaZ_X), where X denotes the varied drug. Monte Carlo (MC) simulations of the early bactericidal activity (EBA), calculated for log₁₀(CFU) and time to positivity (TTP) with 14 days of once-daily BPaZ dosing. The solid and dashed curves are E_max model fits to the MC distribution mean (sample size equal to 10,000). The horizontal axis for the dose is shown with logarithm scale increments.

FIG 5

PKPD model simulations of CFU and time to positivity (TTP) versus time for 8 weeks of the NC005 BPaZ combinations, and the individual components. B_loadPaZ and B₂₀₀PaZ denote bedaquiline 400 mg once daily for 2 weeks (loading dose) then 200 mg three times per week, and bedaquiline 200 mg once daily, respectively, together with once daily pretomanid (Pa) at 200 mg and pyrazinamide (Z) at 1,500 mg.

FIG 6

PKPD model simulations of CFU and time to positivity (TTP) versus time for 8 weeks of treatment with once-daily dosing at 200 mg bedaquiline (B), 200 mg pretomanid (Pa), and 1,500 mg pyrazinamide (Z). (A) Single drugs were combined into pairs: BPa, BZ, and PaZ. (B) Drug pairs combined with the remaining single drug.

FIG 7

Time to positivity (TTP) versus time for the 8-week NC005 BPaZ regimens. Data are the observed (OBS) mean (points) and SD (error bars) reported by Tweed et al. (21), and the NC003 PKPD model-forecasted data (lines). B_load PaZ and B₂₀₀PaZ denote bedaquiline 400 mg once daily for 2 weeks (loading dose) then 200 mg three times per week, and bedaquiline 200 mg once daily, respectively, together with once daily pretomanid at 200 mg and pyrazinamide at 1,500 mg.

FIG 8

NC003 PKPD model-forecasted probability of negative sputum culture (NC) versus days of treatment with once-daily BPaZ (bedaquiline 200 mg, pretomanid 200 mg, and pyrazinamide 1,500 mg or 3,000 mg), for solid culture CFU and liquid culture time to positivity (TTP). The dashed horizontal line denotes probability equal to 0.9, the observed data (OBS) are the day 56 NC005 BPaZ mean (points) and SD (error bars) results reported by Tweed et al. (21), and the solid and dashed curves are the probabilities calculated from Monte Carlo (MC) simulation of CFU and TTP outcomes for each dosage (sample size = 10,000).