Systematic Review and Meta-analysis of the Pharmacokinetics of Benznidazole in the Treatment of Chagas Disease

Abstract

Chagas disease is a neglected parasitic illness affecting approximately 8 million people, predominantly in Latin America. Benznidazole is the drug of choice for treatment, although its availability has been limited. A paucity of knowledge of the pharmacokinetic properties of this drug has contributed to its limited availability in several jurisdictions. The objective of this study was to conduct a systematic literature review and a Bayesian meta-analysis of pharmacokinetic studies to improve estimates of the basic pharmacokinetic properties of benznidazole. A systematic search of the Embase, Medline, LILACS, and SciELO (Scientific Electronic Library Online) databases was conducted. Eligible studies reported patient-level data from single-100-mg-dose pharmacokinetic evaluations of benznidazole in adults or otherwise provided data relevant to the estimation of pharmacokinetic parameters which could be derived from such studies. A Bayesian hierarchical model was used for analysis. Secondary data (i.e., data from studies that did not include patient-level, single-100-mg-dose data) were used for the generation of empirical priors for the Bayesian analysis. The systematic search identified nine studies for inclusion. Nine pharmacokinetic parameters were estimated, including the area under the concentration-time curve (AUC), the maximum concentration of drug in plasma (C_max), the time to C_max, the elimination rate constant (k_el), the absorption rate constant (K_a), the absorption and elimination half-lives, the apparent oral clearance, and the apparent oral volume of distribution. The results showed consistency across studies. AUC and C_max were 51.31 mg · h/liter (95% credible interval [CrI], 45.01, 60.28 mg · h/liter) and 2.19 mg/liter (95% CrI, 2.06, 2.33 mg/liter), respectively. K_a and k_el were 1.16 h^-1 (95% CrI, 0.59, 1.76 h^-1) and 0.052 h^-1 (95% CrI, 0.045, 0.059 h^-1), respectively, with the corresponding absorption and elimination half-lives being 0.60 h (95% CrI, 0.38, 1.11 h) and 13.27 h (95% CrI, 11.79, 15.42 h), respectively. The oral clearance and volume of distribution were 2.04 liters/h (95% CrI, 1.77, 2.32 liters/h) and 39.19 liters (95% CrI, 36.58, 42.17 liters), respectively. A Bayesian meta-analysis was used to improve the estimates of the standard pharmacokinetic parameters of benznidazole. These data can inform clinicians and policy makers as access to this drug increases.

FIG 1

PRISMA (preferred reporting items for systematic reviews and meta-analyses) flow diagram of systematic literature search.

FIG 2

Study-level Forest plot for AUC (in milligram · hours per liter, as indicated on the x axis). The midline of each estimate (row) represents the point estimate for the individual study (light blue) and the pooled estimate (dark blue). Each estimate extends to include the lower (left) and upper (right) bounds of the 95% credible interval. The small arrow at the end indicates that the credible interval extends slightly beyond the scale of the x axis. Bronn, Lucano, and Raaflaub, the studies of Bronn (17), Pergrina Lucano (20), and Raaflaub and Ziegler (22), respectively.

FIG 3

Study-level Forest plot for C_max (in milligrams per liter, as indicated on the x axis). The midline of each estimate (row) represents the point estimate for the individual study (light blue) and the pooled estimate (dark blue). Each estimate extends to include the lower (left) and upper (right) bounds of the 95% credible interval.

FIG 4

Study-level Forest plot for T_max (in hours, as indicated on the x axis). The midline of each estimate (row) represents the point estimate for the individual study (light blue) and the pooled estimate (dark blue). Each estimate extends to include the lower (left) and upper (right) bounds of the 95% credible interval.

FIG 5

Study-level Forest plot for k_el (in hours⁻¹, as indicated on the x axis). The midline of each estimate (row) represents the point estimate for the individual study (light blue) and the pooled estimate (dark blue). Each estimate extends to include the lower (left) and upper (right) bounds of the 95% credible interval. The small arrow at the end indicates that the credible interval extends slightly beyond the scale of the x axis.

FIG 6

Study-level Forest plot for K_a (in hours⁻¹, as indicated on the x axis). The midline of each estimate (row) represents the point estimate for the individual study (light blue) and the pooled estimate (dark blue). Each estimate extends to include the lower (left) and upper (right) bounds of the 95% credible interval.

FIG 7

Study-level Forest plot for V/F (in liters, as indicated on the x axis). The midline of each estimate (row) represents the point estimate for the individual study (light blue) and the pooled estimate (dark blue). Each estimate extends to include the lower (left) and upper (right) bounds of the 95% credible interval. The small arrows at the ends of the estimates indicate that the credible interval extends slightly beyond the scale of the x axis.

FIG 8

Study-level Forest plot for CL/F (in liters per hour, as indicated on the x axis). The midline of each estimate (row) represents the point estimate for the individual study (light blue) and the pooled estimate (dark blue). Each estimate extends to include the lower (left) and upper (right) bounds of the 95% credible interval. The small arrow at the end indicates that the credible interval extends slightly beyond the scale of the x axis.