| 1. |
- Litjens, Carlijn H. C., et al.
(författare)
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Protein binding of rifampicin is not saturated when using high-dose rifampicin
- 2019
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Ingår i: Journal of Antimicrobial Chemotherapy. - : OXFORD UNIV PRESS. - 0305-7453 .- 1460-2091. ; 74:4, s. 986-990
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Tidskriftsartikel (refereegranskat)abstract
- 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 from a clinical trial on high-dose rifampicin. Methods Protein-unbound rifampicin concentrations were measured in human serum spiked with increasing total concentrations (up to 64mg/L) of rifampicin and in samples obtained by intensive pharmacokinetic sampling of patients who used standard (10mg/kg daily) or high-dose (35mg/kg) rifampicin up to steady-state. The performance of total AUC(0-24) to predict unbound AUC(0-24) was evaluated. Results The in vitro free fraction of rifampicin remained unaltered (approximate to 9%) up to 21mg/L and increased up to 13% at 41mg/L and 17% at 64mg/L rifampicin. The highest (peak) concentration in vivo was 39.1mg/L (high-dose group). The arithmetic mean percentage unbound to total AUC(0-24)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 AUC(0-24) based on total AUC(0-24) resulted in a bias of -0.05% and an imprecision of 13.2%. Conclusions Plasma protein binding of rifampicin can become saturated, 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.
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| 2. |
- Stemkens, Ralf, et al.
(författare)
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Drug interaction potential of high-dose rifampicin in patients with pulmonary tuberculosis
- 2023
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Ingår i: Antimicrobial Agents and Chemotherapy. - : American Society for Microbiology. - 0066-4804 .- 1098-6596. ; 67:10
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Tidskriftsartikel (refereegranskat)abstract
- Accumulating evidence supports the use of higher doses of rifampicin for tuberculosis (TB) treatment. Rifampicin is a potent inducer of metabolic enzymes and drug transporters, resulting in clinically relevant drug interactions. To assess the drug interaction potential of higher doses of rifampicin, we compared the effect of high-dose rifampicin (40 mg/kg daily, RIF40) and standard-dose rifampicin (10 mg/kg daily, RIF10) on the activities of major cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp). In this open-label, single-arm, two-period, fixed-order phenotyping cocktail study, adult participants with pulmonary TB received RIF10 (days 1–15), followed by RIF40 (days 16–30). A single dose of selective substrates (probe drugs) was administered orally on days 15 and 30: caffeine (CYP1A2), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), midazolam (CYP3A), and digoxin (P-gp). Intensive pharmacokinetic blood sampling was performed over 24 hours after probe drug intake. In all, 25 participants completed the study. Geometric mean ratios (90% confidence interval) of the total exposure (area under the concentration versus time curve, RIF40 versus RIF10) for each of the probe drugs were as follows: caffeine, 105% (96%–115%); tolbutamide, 80% (74%–86%); omeprazole, 55% (47%–65%); dextromethorphan, 77% (68%–86%); midazolam, 62% (49%–78%), and 117% (105%–130%) for digoxin. In summary, high-dose rifampicin resulted in no additional effect on CYP1A2, mild additional induction of CYP2C9, CYP2C19, CYP2D6, and CYP3A, and marginal inhibition of P-gp. Existing recommendations on managing drug interactions with rifampicin can remain unchanged for the majority of co-administered drugs when using high-dose rifampicin. Clinical Trials registration number NCT04525235.
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| 3. |
- te Brake, Lindsey H. M., et al.
(författare)
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Increased bactericidal activity but dose-limiting intolerability at 50 mg.kg(-1) rifampicin
- 2021
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Ingår i: European Respiratory Journal. - : European Respiratory Society. - 0903-1936 .- 1399-3003. ; 58:1
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Tidskriftsartikel (refereegranskat)abstract
- Accumulating data have indicated that higher rifampicin doses are more effective and shorten tuberculosis treatment duration. This study evaluated the safety, tolerability, pharmacokinetics, and 7 and 14-day early bactericidal activity (EBA) of increasing doses of rifampicin. Here we report the results of the final cohorts of PanACEA HIGHRIF1, a dose-escalation study in treatment-naive adult smear-positive patients with tuberculosis. Patients received, in consecutive cohorts, 40 or 50mg/kg rifampicin once daily in monotherapy (day 1-7), supplemented with standard dose isoniazid, pyrazinamide and ethambutol between day 8-14. In the 40mg/kg cohort (n=15), 13 patients experienced a total of 36 adverse events (AEs) during monotherapy, resulting in one treatment discontinuation. In the 50mg/kg group (n=17), all patients experienced AEs during monotherapy, 93 in total; 11 patients withdrew or stopped study medication. AEs were mostly mild/moderate and tolerability-rather than safety-related, i.e. gastrointestinal disorders, pruritis, hyperbilirubinemia and jaundice. There was a more than proportional increase in the rifampicin geometric mean AUC(0-24h) for 50mg/kg compared to 40mg/kg; 571 mg/L*h (range 320-995) versus 387 mg/L*h (201-847), while peak exposures saw proportional increases. Protein-unbound exposure after 50mg/kg (11%, 8-17%) was comparable with lower rifampicin doses. Rifampicin exposures and bilirubin concentrations were correlated (day-3 Spearman's rho 0.670, p<0.001). EBA increased considerably with dose, with the highest seen after 50mg/kg; 14-day EBA -0.427 logCFU/mL/day (95%CI -0.500, -0.355). In conclusion, although associated with an increased bactericidal effect, the 50mg/kg dose was not well tolerated. Rifampicin at 40mg/kg was well tolerated and therefore selected for evaluation in a phase IIC treatment shortening trial.
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