Pharmacokinetics of rifampicin in adult TB patients and healthy volunteers: a systematic review and meta-analysis

Abstract

Objectives: The objectives of this study were to explore inter-study heterogeneity in the pharmacokinetics (PK) of orally administered rifampicin, to derive summary estimates of rifampicin PK parameters at standard dosages and to compare these with summary estimates for higher dosages.

Methods: A systematic search was performed for studies of rifampicin PK published in the English language up to May 2017. Data describing the Cmax and AUC were extracted. Meta-analysis provided summary estimates for PK parameter estimates at standard rifampicin dosages. Heterogeneity was assessed by estimation of the I2 statistic and visual inspection of forest plots. Summary AUC estimates at standard and higher dosages were compared graphically and contextualized using preclinical pharmacodynamic (PD) data.

Results: Substantial heterogeneity in PK parameters was evident and upheld in meta-regression. Treatment duration had a significant impact on the summary estimates for rifampicin PK parameters, with Cmax 8.98 mg/L (SEM 2.19) after a single dose and 5.79 mg/L (SEM 2.14) at steady-state dosing, and AUC 72.56 mg·h/L (SEM 2.60) and 38.73 mg·h/L (SEM 4.33) after single and steady-state dosing, respectively. Rifampicin dosages of at least 25 mg/kg are required to achieve plasma PK/PD targets defined in preclinical studies.

Conclusions: Vast inter-study heterogeneity exists in rifampicin PK parameter estimates. This is not explained by the available modifying variables. The recommended dosage of rifampicin should be increased to improve efficacy. This study provides an important point of reference for understanding rifampicin PK at standard dosages as efforts to explore higher dosing strategies continue in this field.

Figure 1.

Forest plot displaying estimated rifampicin AUC after univariate analysis according to dosing duration. In univariate analysis, the effect of steady-state dosing was to approximately halve the estimated rifampicin AUC (P < 0.0001).

Figure 2.

(a) Forest plot displaying estimated rifampicin AUC after univariate analysis according to HIV status; data are limited to steady-state dosing. Once data were limited to steady-state dosing, HIV status no longer had a significant impact on rifampicin AUC estimate. P values for comparison were >0.05. (b) Forest plot displaying estimated rifampicin AUC after univariate analysis according to TB status; data are limited to steady-state dosing. Once data were limited to steady-state dosing, TB status no longer had a significant impact on the rifampicin AUC estimate. P value for comparison was >0.05.

Figure 3.

(a) Impact of increasing dose on rifampicin AUC. With increasing dose, there appears to be a greater than proportional increase in AUC. Error bars show SEM. Data are displayed in Table 3. (b) Impact of increasing dose on rifampicin AUC/MIC. Taking the ECOFF MIC of 0.5 mg/L, available data indicate that a rifampicin dose of ≥25 mg/kg is required to attain the PK/PD target associated with a 1 log cfu reduction (an AUC/MIC of 271).