Protein binding of rifampicin is not saturated when using high-dose rifampicin

Carlijn H.C. Litjens*, Rob E. Aarnoutse, Eleonora W.J. Van Ewijk-Beneken Kolmer, Elin M. Svensson, Angela Colbers, David M. Burger, Martin J. Boeree, Lindsey H. M. te Brake, PanACEA-MAMS-TB-01 Team

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)


Background: Higher doses of rifampicin are being investigated as a means to optimize response to this pivotal TB drug. It is unknown whether high-dose rifampicin results in saturation of plasma protein binding and a relative increase in protein-unbound (active) drug concentrations. Objectives: To assess the free fraction of rifampicin based on an in vitro experiment and data froma clinical trial on high-dose rifampicin.
Methods: Protein-unbound rifampicin concentrations were measured in human serum spiked with increasing total concentrations (up to 64 mg/L) of rifampicin and in samples obtained by intensive pharmacokinetic sampling of patients who used standard (10 mg/kg daily) or high-dose (35 mg/kg) rifampicin up to steady-state. The performance of total AUC0-24 to predict unbound AUC0-24 was evaluated.
Results: The in vitro free fraction of rifampicin remained unaltered (~9%) up to 21 mg/L and increased up to 13% at 41 mg/L and 17% at 64 mg/L rifampicin. The highest (peak) concentration in vivo was 39.1 mg/L (highdose group). The arithmetic mean percentage unbound to total AUC0-24 in vivo was 13.3% (range=8.1%- 24.9%) and 11.1% (range=8.6%-13.6%) for the standard group and the high-dose group, respectively (P=0.214). Prediction of unbound AUC0-24 based on total AUC0-24 resulted in a bias of -0.05% and an imprecision of 13.2%.
Conclusions: Plasma protein binding of rifampicin can becomesaturated, but exposures after high-dose rifampicin are not high enough to increase the free fraction in TB patients with normal albumin values. Unbound rifampicin exposures can be predicted from total exposures, even in the higher dose range.
Original languageEnglish
Pages (from-to)986-990
Number of pages5
JournalJournal of Antimicrobial Chemotherapy
Issue number4
Early online date28 Dec 2018
Publication statusPublished - Apr 2019


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