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

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. A systematic search was p...

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Vydáno v:Journal of antimicrobial chemotherapy Ročník 73; číslo 9; s. 2305
Hlavní autoři: Stott, K E, Pertinez, H, Sturkenboom, M G G, Boeree, M J, Aarnoutse, R, Ramachandran, G, Requena-Méndez, A, Peloquin, C, Koegelenberg, C F N, Alffenaar, J W C, Ruslami, R, Tostmann, A, Swaminathan, S, McIlleron, H, Davies, G
Médium: Journal Article
Jazyk:angličtina
Vydáno: England 01.09.2018
Témata:
Administration, Oral
Adult
Antibiotics, Antitubercular - administration & dosage
Antibiotics, Antitubercular - pharmacokinetics
Female
Healthy Volunteers
Humans
Male
Rifampin - administration & dosage
Rifampin - pharmacokinetics
Tuberculosis - drug therapy
ISSN:1460-2091, 1460-2091
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Shrnutí: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. 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. 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. 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.
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ISSN:1460-2091
1460-2091
DOI:10.1093/jac/dky152