Studies on Blood Serum Levels of Rifampicin in Patients with Normal and Impaired Liver Function

Abstract

Patients with normal liver function present a dose-related change in the kinetics of rifampicin. The drug interferes with serum bilirubin levels. Interference with serum bilirubin levels practically disappears during repeated administration. This fact is paralleled by a change in the slope of the excretory part of rifampicin blood serum level curve. Patients with liver cirrhosis or with other type of severe liver impairment present higher blood serum levels of the antibiotic. The slope of the curve is flat and remains practically constant during repeated administration. The interference with blood serum bilirubin remains unchanged throughout the treatment period. In such patients, a dose of 6–8 mg/kg b.w. of rifampicin should not be exceeded.

Development and Evaluation of Physiologically Based Pharmacokinetic Drug–Disease Models for Predicting Rifampicin Exposure in Tuberculosis and Cirrhosis Populations

“…The model predictions in cirrhosis population showed an increase in rifampicin exposure that was consistent with the reported clinical data [73]. In cirrhosis (CP-A) population, the observed and predicted AUC 0–∞ after administration of 10 mg/kg dose of rifampicin was 68.8 and 86.2 µg/mL·h, respectively [53]. Moreover, in comparison with the healthy adults, the mean observed and predicted CL/F values were lower in cirrhotic patients.…”

“…All of these pathophysiological changes have been incorporated within Simcyp ® cirrhosis populations (CP, A-C) [38]. Since the clinical PK data were only available in CP-A population, the developed rifampicin-cirrhosis model was evaluated only in CP-A population [53]. The model predictions in cirrhosis population showed an increase in rifampicin exposure that was consistent with the reported clinical data [73].…”

“…Observed and predicted plasma concentration-time profiles of rifampicin in cirrhosis patients after oral administration. Cirrhosis patients after oral administration ( A ) 4 mg/kg, ( B ) 6 mg/kg, ( C ) 8 mg/kg and ( D ) 10 mg/kg [53]. The observed data are shown as filled colored circles.…”

Relevance of liver failure for anti-infective agents: from pharmacokinetic alterations to dosage adjustments

“…Based on comparing multiple-dose studies, examining rifampicin PK in normal hepatic function at 8, 12, and 16 mg/kg biweekly, or in cirrhosis and other chronic liver diseases at 4, 6, 8, and 10 mg/kg biweekly, Curci and colleagues recommend no more than 6 to 8 mg/kg biweekly for those with severe liver impairment [Curci et al , 1973]. In a 7-day study of 13 patients with cirrhosis and 5 healthy volunteers given 600 mg rifampicin daily, total pretreatment bilirubin was a predictor of rifampicin accumulation.…”

A practical approach to tuberculosis diagnosis and treatment in liver transplant recipients in a low-prevalence area

“…Therapeutic drug monitoring of isoniazid, pyrazinamide, and rifamycins should be performed, at least initially, to ensure achievement of target exposure. Therapeutic drug monitoring should be repeated every week or every other week for rifamycins during the induction phase because of potentially decreased concentrations due to auto-induction [38,47,48]; (vii) fluoroquinolones, ethambutol, cycloserine, or aminoglycosides may be used in case of hepatotoxicity with first-line agents; (viii) maintenance tuberculosis therapy should include isoniazid and a rifamycin as long as tolerability permits; (ix) the optimal duration is not determined and should be considered on a case-by-case basis. An initial induction/intensive 13 phase of two months is advisable with at least three active antituberculosis drugs [8,9,36].…”