Systemic Pharmacokinetics of Rifaximin in Volunteers with Shigellosis

Abstract

Rifaximin is an oral antibiotic indicated for treatment of traveler's diarrhea. Rifaximin pharmacokinetics were evaluated in individuals challenged with Shigella flexneri. Peak plasma rifaximin concentrations were low after nine consecutive doses, and no accumulation was observed. Rifaximin serum levels were minimal and similar to those previously reported in studies of healthy volunteers.

Rifaximin (Xifaxan; Salix Pharmaceuticals, Inc., Morrisville, NC) is an oral antibiotic with broad-spectrum antimicrobial activity that exerts its effect by inhibiting bacterial RNA synthesis (Xifaxan package insert; Salix Pharmaceuticals, Inc.). Rifaximin is currently approved in the United States for the treatment of traveler's diarrhea caused by noninvasive strains of Escherichia coli at a recommended dose of 200 mg three times daily for 3 days (Xifaxan package insert). Studies have indicated that <0.4% of rifaximin is systemically absorbed following oral administration (1, 6; Xifaxan package insert). An evaluation of the systemic pharmacokinetics of a single, oral 400-mg dose of [¹⁴C]rifaximin in three healthy male volunteers demonstrated that the majority of radiolabeled drug was recovered unchanged in the feces (97%) and that only a trace amount was excreted in the urine (0.32%) (Xifaxan package insert). Additional studies of patients with gastrointestinal conditions further support the lack of systemic absorption of rifaximin (3-5). The objective of the present study was to evaluate the pharmacokinetics of rifaximin in individuals challenged with the invasive bacterium Shigella flexneri and to determine whether gastrointestinal inflammation in the colon, in response to a microbial pathogen, would have an impact on the pharmacokinetic profile of rifaximin.

This phase 1, single-site, open-label, pharmacokinetic study enrolled healthy male and female volunteers aged 18 to 45 years with no significant medical conditions at the time of screening and no history of abnormal bowel habits or stool patterns. Eligible individuals were admitted to the General Clinical Research Center at Johns Hopkins Hospital on day 0. On day 1, volunteers were challenged with approximately 1,500 CFU of S. flexneri 2a strain 2457T, given orally in sodium bicarbonate buffer (2 g/dose in a total of 150 ml). S. flexneri was supplied from a master cell bank and fermented and placed in vials under Good Manufacturing Practice conditions by the Bioproduction Facility of the Walter Reed Army Institute of Research. The protocol for this study was approved by the Committee on Human Research at the Johns Hopkins Bloomberg School of Public Health and by Salix Pharmaceuticals of Morrisville, NC. The trial was carried out in full compliance with Good Clinical Practice guidelines.

At the onset of illness (i.e., diarrhea plus one or more enteric symptoms), 200 mg of oral rifaximin was administered every 8 h for 3 days for a total of nine doses. Volunteers remained in the inpatient research facility at least through day 7 to be monitored for signs and symptoms of shigellosis and other adverse events. During rifaximin treatment, volunteers were administered a 3-day course of 500 mg of oral ciprofloxacin twice daily to eradicate S. flexneri if they developed shigellosis and did not respond to three doses of rifaximin. Individuals who began ciprofloxacin therapy completed the full nine-dose course of rifaximin. Volunteers were discharged after ciprofloxacin treatment was initiated, clinical assessments were complete, and two negative stool cultures for S. flexneri were obtained.

Blood samples for evaluation of rifaximin pharmacokinetics were collected on day 1 (prechallenge); immediately before the third, fifth, seventh, and ninth rifaximin doses; serially at 0.5, 1, 1.5, 2, 4, 6, and 8 h after the third and ninth doses; and additionally at 12, 16, 20, and 24 h after the ninth dose. Plasma concentrations of rifaximin were measured by reverse-phase high-performance liquid chromatography with tandem quadrupole mass spectrometric detection, with a lower limit of quantitation of 0.5 ng/ml. Subjects were eligible for pharmacokinetic evaluation if they developed shigellosis, if they received nine consecutive doses of rifaximin, and if sufficient plasma concentration data were obtained to determine the maximum plasma concentration (C_max) and area under the concentration-time curve from zero to the last measurable time point (AUC_0-last).

Pharmacokinetic parameters were calculated by the model independent approach (noncompartmental analysis) (2) using the WinNonlin Pro version 4.0 software program (Pharsight Corporation, Mountain View, CA). Both the C_max and the time to maximum concentration of drug in plasma (T_max) were calculated, and the AUC_0-last was determined using a combination of linear and logarithmic trapezoidal rules. Data summaries and statistical models were generated using SAS version 8.2 for Windows (SAS Institute, Inc., Cary, NC). As the AUC_0-∞ and half-life could not be accurately determined for rifaximin (AUC_0-∞ extrapolated was >40%), they were not included as part of the statistical analyses.

Fifteen healthy volunteers were enrolled in the study and challenged with S. flexneri. Thirteen individuals met the criteria for rifaximin treatment (i.e., developed shigellosis), received at least one dose of study medication, and were included in the pharmacokinetic and safety populations: 12 received all nine doses of rifaximin and 1 received eight doses. Of the 13 volunteers who received rifaximin, 9 were male (69%) and 4 were female (31%). The mean age of volunteers was 32.5 years (range, 18 to 45 years). All 13 individuals developed one or more symptoms of shigellosis; the predominant symptoms were abdominal pain (100%), headache (85%), and diarrhea (77%). Eight volunteers received rescue therapy with ciprofloxacin.

Rifaximin administration did not result in any clinically relevant changes in pharmacokinetic parameters (Table 1 and Fig. 1). After repeated administration of 200 mg of oral rifaximin, the mean C_max values for rifaximin were 1.63 ± 0.86 ng/ml on day 1 (three doses) and 1.23 ± 0.52 ng/ml on day 3 (nine doses). Similarly, no differences were observed on day 1 and day 3 for the mean T_max values (2.77 ± 2.24 and 2.11 ± 1.58 h, respectively) or the mean AUC_0-last values (6.95 ± 5.15 and 7.83 ± 4.94 ng·h/ml, respectively), indicating no accumulation of rifaximin. The ranges of peak plasma rifaximin concentrations were comparable after three and nine consecutive rifaximin doses (0.81 to 3.40 ng/ml and 0.68 to 2.26 ng/ml, respectively), and there were no differences in the mean rifaximin plasma concentrations after repeated dosing (Fig. 1A and B).

TABLE 1.

Pharmacokinetics of rifaximin

Parameterb	Value for volunteers aftera:
	Dose 3 (n = 12)	Dose 9 (n = 13)
Cmax (ng/ml)
Mean ± SD	1.63 ± 0.86	1.23 ± 0.52
Range	0.81-3.40	0.68-2.26
Median	1.16	1.06
%CV	53.02	42.76
Tmax (h)
Mean ± SD	2.77 ± 2.24	2.11 ± 1.58
Range	0.50-8.33	0.55-6.00
Median	1.85	1.52
%CV	80.96	74.84
AUC0-last (ng·h/ml)
Mean ± SD	6.95 ± 5.15	7.83 ± 4.94
Range	1.58-17.15	1.09-19.76
Median	5.69	6.98
%CV	74.10	63.10

^an, number of volunteers tested. Rifaximin was administered in nine doses of 200 mg. Data for dose 3 exclude one individual for which the rifaximin concentrations were below the assay limit of quantitation.

^b%CV, percent coefficient of variation; SD, standard deviation.

FIG. 1.

Mean rifaximin concentration-time profiles for the third (A) and ninth (B) consecutive rifaximin doses in 13 healthy volunteers challenged with S. flexneri. Upon diagnosis of a case definition of diarrhea, patients were administered 200 mg of oral rifaximin every 8 h for three days for a total of nine doses.

Clinical pharmacokinetic studies conducted with healthy volunteers and patients with traveler's diarrhea caused by noninvasive E. coli indicate that rifaximin is poorly absorbed from the gastrointestinal tract and that most of the drug is excreted unchanged in the feces (1; Xifaxan package insert). The goal of the current study was to evaluate the potential impact of colonic inflammation caused by a microbial pathogen on the pharmacokinetics of rifaximin. Oral rifaximin that was administered with the same dosing regimen indicated for the treatment of traveler's diarrhea (200 mg three times daily) effectively prevented shigellosis (7). Plasma concentrations and systemic exposure of rifaximin were low during the study. The C_max and T_max values were comparable, indicating no substantial accumulation of the drug following repeated administration. Overall, results from the current study demonstrate a lack of systemic absorption of rifaximin in individuals with mucosal inflammation in the colon, findings that are consistent with published reports demonstrating minimal rifaximin plasma concentrations and a lack of drug accumulation (3, 4, 6). There was no apparent difference between data from rifaximin's pharmacokinetic profile in this study and data from other studies, which further supports a lack of systemic absorption of rifaximin.

(Data from this study were presented previously in abstract form at the Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, March 2005 [8]).