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

Abstract

ObjectivesThe 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. MethodsA 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.ResultsSubstantial 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.ConclusionsVast 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.

Pharmacokinetics and Pharmacodynamics of Intensive Antituberculosis Treatment of Tuberculous Meningitis

“…28 Of note, we did not find that HIV coinfection influenced exposures of any of the antituberculosis drugs, contrary to some previous reports. [29][30][31] Our study has several limitations. First, we were unable to sample the entire trial population, which may have reduced our power to define exposure-response relationships.…”

Current research toward optimizing dosing of first-line antituberculosis treatment

“…A recent metanalysis found that rifampin's area under the concentration-time curve (AUC) varied 3-to 4-fold between different studies [30]. While between-laboratory differences, and genetic, environmental and pathophysiological differences between the study populations may play a role, evidence from multiple studies suggests that differences in bioavailability between formulations and batches could be responsible for large bioavailability deviations.…”

“…The extent to which genetic variation governs the large differences in rifampin exposures observed between patients and between studies, is not well understood [30]. Organic-anion -transporting polypeptide1B1 (encoded by SLCO1B1) mediates transfer of rifampin into the hepatocyte, from where it is excreted via the bile.…”

Early antituberculosis drug exposure in hospitalized patients with human immunodeficiency virus‐associated tuberculosis

“…HIV infection has a variable effect on anti‐TB drug concentrations across studies, with some studies showing lower concentrations than in HIV‐negative patients . There are few pharmacokinetic studies in HIV‐TB that assess relationships between drug exposure and clinical outcomes …”

“…Rifampicin is a potent inducer of drug metabolizing liver enzymes and also undergoes auto‐induction . The majority of rifampicin pharmacokinetic studies have been performed after administration of multiple doses when autoinduction is advanced, yet mortality in hospitalized HIV‐TB patients occurs early. In the parent cohort of this pharmacokinetic (PK) study 37% of deaths occurred within 7 days of enrolment .…”