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

Litjens, Carlijn H C; Aarnoutse, R.E.; Kolmer, E.W.J. van Ewijk-Beneken; Svensson, Elin M; Colbers, Angela; Burger, David M.; Boeree, Martin J.; Brake, Lindsey H.M. te

doi:10.1093/jac/dky527

Cited by 14 publications

(9 citation statements)

References 18 publications

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“…The extent of plasma protein binding for safranal varied from 87 to 92% in the experimental concentration range of 5–20 μM (Figure ). Plasma protein binding of rifampicin as standard is found to be 91%, which matches with the reported results (82–92%). , Plasma protein binding can be classified as very high protein binding (>98%), high protein binding (85–98%), and medium-to-low protein binding (<85%) . Therefore, results indicate that plasma protein binding is high and concentration-independent.…”

Section: Resultssupporting

confidence: 88%

Description of Druglike Properties of Safranal and Its Chemistry behind Low Oral Exposure

et al. 2020

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Safranal, a plant secondary metabolite isolated from saffron, has been reported for several promising pharmacological properties toward the management of Alzheimer's disease. In the present study, we observe and report for the first time about several druglike attributes of safranal, such as adherence to Lipinski's rule of five; optimum lipophilicity; high permeability; low blood-to-plasma ratio; less to moderate propensity to interact with P-glycoprotein (P-gp) or breast cancer-resistant protein (BCRP) transporters; and high plasma protein binding as common to most of the marketed drugs using in vitro and ex vivo models. In spite of the above attributes, in vivo oral absorption was found to be very poor, which is linked to the structural integrity of safranal in simulated gastric fluid, simulated intestinal fluid, plasma, and liver microsomes. Moreover, the presence of unsaturated aldehyde moiety in safranal remains in equilibrium with its hydroxylated acetal form. Further research work is required to find out the stable oral absorbable form of safranal by derivatization of its aldehyde group without losing its potency.

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Section: Resultssupporting

confidence: 88%

Description of Druglike Properties of Safranal and Its Chemistry behind Low Oral Exposure

et al. 2020

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“…Of note, large interindividual variability in AUC 0-24 h and C max was observed, with exposures between groups overlapping considerably (table 3 and supplementary figure E2). Protein-unbound rifampicin exposure, or free fraction, was comparable to other (lower) doses of rifampicin [14]. For rifampicin pharmacokinetic profiles and pharmacokinetic parameters of other study drugs, see supplementary figure E3 and supplementary table E1, respectively.…”

Section: Pharmacokineticsmentioning

confidence: 81%

Increased bactericidal activity but dose-limiting intolerability at 50 mg·kg⁻¹ rifampicin

Brake¹,

Jager

Narunsky

et al. 2021

Eur Respir J

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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 50 mg·kg−1 rifampicin once daily in monotherapy (day 1–7), supplemented with standard dose isoniazid, pyrazinamide and ethambutol between day 8–14. In the 40 mg·kg−1 cohort (n=15), 13 patients experienced a total of 36 adverse events (AEs) during monotherapy, resulting in one treatment discontinuation. In the 50 mg·kg−1 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 AUC0–24h for 50 mg·kg−1 compared to 40 mg·kg; 571 mg·L*h−1 (range 320–995) versus 387 mg·L*h−1 (201–847), while peak exposures saw proportional increases. Protein-unbound exposure after 50 mg·kg−1 (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 50 mg·kg−1; 14-day EBA −0.427 logCFU·mL−1·day−1 (95%CI −0.500, −0.355). In conclusion, although associated with an increased bactericidal effect, the 50 mg·kg−1 dose was not well tolerated. Rifampicin at 40 mg·kg−1 was well tolerated and therefore selected for evaluation in a phase IIC treatment shortening trial.

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“…This dogma could be questioned in meningitis patients where protein levels in CSF can be substantially increased [ 4 ]. In plasma, rifampicin is around 80% protein-bound [ 37 , 38 ]. Albumin accounts for 30%–40% of the binding in serum, which leaves a possible important role for γ-globulin binding proteins [ 37 , 39 ].…”

Section: Discussionmentioning

confidence: 99%

“…Total rifampicin concentrations were measured and modeled while only unbound concentrations are generally considered to exhibit pharmacological effects. However, it has recently been shown that the free fraction remains constant over a wide range of rifampicin concentrations [ 38 ], mitigating the risk of bias when evaluating total concentrations as done here. The exposure-safety analysis performed is rather simplistic, evaluating all type of adverse events jointly.…”

Section: Discussionmentioning

confidence: 99%

Model-Based Meta-analysis of Rifampicin Exposure and Mortality in Indonesian Tuberculous Meningitis Trials

Svensson

Dian

Brake³

et al. 2019

Clinical Infectious Diseases

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Background Intensified antimicrobial treatment with higher rifampicin doses may improve outcome of tuberculous meningitis, but the desirable exposure and necessary dose are unknown. Our objective was to characterize the relationship between rifampicin exposures and mortality in order to identify optimal dosing for tuberculous meningitis. Methods An individual patient meta-analysis was performed on data from three Indonesian randomized controlled phase II trials comparing oral rifampicin 450mg (~10mg/kg) to intensified regimens including 750-1350mg orally, or a 600mg intravenous infusion. Pharmacokinetic data from plasma and CSF was analyzed with nonlinear mixed-effects modeling. Six-month survival was described with parametric time-to-event models. Results Pharmacokinetic analyses included 133 individuals (1150 concentration measurements, 170 from CSF). The final model featured two disposition-compartments, saturable clearance and autoinduction. Rifampicin CSF concentrations were described by a partition coefficient (5.5% [95%CI 4.4-6.4]) and half-life for distribution plasma to CSF (2.1 h [1.3-2.9]). Higher CSF protein concentration increased the partition coefficient. Survival of 148 individuals (58 died, 15 drop-outs) was well described by an exponentially declining hazard, with lower age, higher baseline Glasgow Coma Scale score and higher individual rifampicin plasma exposure reducing the hazard. Simulations predicted an increase in 6-month survival from ~50% to ~70% upon increasing the oral rifampicin dose from 10 to 30mg/kg, and that higher doses would further increase survival. Conclusions Higher rifampicin exposure substantially decreased the risk of death, and the maximal effect was not reached within the studied range. We suggest a rifampicin dose of at least 30mg/kg to be investigated in phase III clinical trials.

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

Cited by 14 publications

References 18 publications

Description of Druglike Properties of Safranal and Its Chemistry behind Low Oral Exposure

Description of Druglike Properties of Safranal and Its Chemistry behind Low Oral Exposure

Increased bactericidal activity but dose-limiting intolerability at 50 mg·kg⁻¹ rifampicin

Model-Based Meta-analysis of Rifampicin Exposure and Mortality in Indonesian Tuberculous Meningitis Trials

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

Cited by 14 publications

References 18 publications

Description of Druglike Properties of Safranal and Its Chemistry behind Low Oral Exposure

Description of Druglike Properties of Safranal and Its Chemistry behind Low Oral Exposure

Increased bactericidal activity but dose-limiting intolerability at 50 mg·kg−1 rifampicin

Model-Based Meta-analysis of Rifampicin Exposure and Mortality in Indonesian Tuberculous Meningitis Trials

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Increased bactericidal activity but dose-limiting intolerability at 50 mg·kg⁻¹ rifampicin