Xifaxan (Rifaximin) - Clinical Pharmacology

CLINICAL PHARMACOLOGY

Pharmacokinetics

Absorption:

The mean pharmacokinetic parameters of rifaximin in 14 healthy subjects after a single oral 400-mg dose given as 2 x 200 mg doses under fed and fasting conditions are summarized in Table 1.

Table 1. Effect of Food on the Mean ± S.D. Pharmacokinetic Parameters Following a Single 400-mg Dose of Rifaximin (N = 14)

Parameter	Fasting	Fed
Cmax (ng/mL)	3.80 ± 1.32	9.63 ± 5.93
Tmax (h)	1.21 ± 0.47	1.90 ± 1.52
Half-Life (h)	5.85 ± 4.34	5.95 ± 1.88
AUC (ng•h/mL)	18.35 ± 9.48	34.70 ± 9.23
% Excreted in Urine	0.023 ± 0.009	0.051 ± 0.017

Rifaximin can be administered with or without food. Systemic absorption of rifaximin was low in both the fasting state and when administered within 30 minutes of a high-fat breakfast.

¹⁴C-Rifaximin was administered as a single dose to 4 healthy male subjects. The mean overall recovery of radioactivity in the urine and feces of 3 subjects during the 168 hours after admin istration was 96.94 ± 5.64% of the dose. Radioactivity was excreted almost exclusively in the feces (96.62 ± 5.67% of the dose), with only a small proportion of the dose (mean 0.32% of the dose) excreted in urine. Analysis of fecal extracts indicated that rifaximin was being excreted as unchanged drug. The amount of radioactivity in urine (<0.4% of the dose) suggests that rifaximin is poorly absorbed from the gastrointestinal tract and is almost exclusively and completely excreted in feces as unchanged drug. Mean rifaximin pharmacokinetic parameters were C_max 4.3 ± 2.8 ng/mL and AUC_t 19.5 ± 16.5 ng•h/mL with a median T_max of 1.25 hours.

Systemic absorption of rifaximin (200 mg three times daily) was also evaluated in 13 subjects with shigellosis on Days 1 and 3 of a three-day course of treatment. Rifaximin concentrations and exposures were low and variable. There was no evidence of accumulation of rifaximin following repeated administration for 3 days (9 doses). Peak plasma rifaximin concentrations after 3 and 9 consecutive doses ranged from 0.81 to 3.4 ng/mL on Day 1 and 0.68 to 2.26 ng/mL on Day 3. Similarly, AUC_0-last estimates were 6.95 ± 5.15 ng•h/mL on Day 1 and 7.83 ± 4.94 ng•h/mL on Day 3. Rifaximin is not suitable for treating systemic bacterial infections because less than 0.4% of the drug is absorbed after oral administration (see WARNINGS).

Distribution:

Animal pharmacokinetic studies have demonstrated that 80% to 90% of orally administered rifaximin is concentrated in the gut with less than 0.2% in the liver and kidney, and less than 0.01% in other tissues. In adults with infectious diarrhea treated with rifaximin 800 mg daily for three days, concentrations of rifaximin in stools averaged ~8000 µg/g the day after treatment ended.

Metabolism:

In vitro drug interactions studies have shown that rifaximin, at concentrations ranging from 2 to 200 ng/mL, did not inhibit human hepatic cytochrome P450 isoenzymes: 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4. In an in vitro hepatocyte induction model, rifaximin was shown to induce cytochrome P450 3A4 (CYP3A4), an isoenzyme which rifampin  is known to induce. Two clinical drug-drug interaction studies using midazolam and an oral contraceptive containing ethinyl estradiol and norgestimate demonstrated that rifaximin did not alter the pharmacokinetics of these drugs (see Drug-Drug Interactions).

Excretion:

Rifaximin is excreted primarily in the feces. After oral administration of 400 mg ¹⁴C-rifaximin to healthy volunteers, approximately 97% of the dose was recovered in feces, almost entirely as unchanged drug, and 0.32% was recovered in the urine.

Special Populations

Geriatric:

The pharmacokinetics of rifaximin in patients ≥65 years of age has not been studied.

Pediatric:

The pharmacokinetics of rifaximin has not been studied in pediatric patients of any age.

Gender:

The effect of gender on the pharmacokinetics of rifaximin has not been studied.

Renal Insufficiency:

The pharmacokinetics of rifaximin in patients with impaired renal function has not been studied.

Hepatic Insufficiency:

Mean peak rifaximin plasma concentrations of 13.5 ng/mL were detected in hepatic encephalopathy patients administered rifaximin 800 mg three times daily for 7days. Less than 0.1% of the administered dose was recovered after 7 days. Because of the limited systemic absorption of rifaximin, no specific dosing adjustments are recommended for patients with hepatic insufficiency.

Drug-Drug Interactions

In an in vitro hepatocyte induction model, rifaximin was shown to induce cytochrome P450 3A4 (CYP3A4), an isoenzyme which rifampin is known to induce. Two clinical drug-drug interaction studies were conducted using midazolam and an oral contraceptive containing ethinyl estradiol and norgestimate to assess the effect of rifaximin on the pharmacokinetics of these drugs.

The midazolam study was an open-label, randomized, crossover, drug-interaction trial designed to assess the effect of rifaximin 200 mg administered orally (PO) every 8 hours (Q8H) for 3 days and every 8 hours for 7 days, on the pharmacokinetics of a single dose of either midazolam 2 mg intravenous (IV) or midazolam 6 mg PO. No significant difference was observed in the metrics of systemic exposure or elimination of IV or PO midazolam or its major metabolite, 1'-hydroxymidazolam, between midazolam alone or together with rifaximin. Therefore, rifaximin was not shown to significantly affect intestinal or hepatic CYP3A4 activity.

The oral contraceptive study utilized an open-label, crossover design in 28 healthy female subjects to determine if rifaximin 200 mg PO administered Q8H for 3 days altered the pharmacokinetics of a single dose of an oral contraceptive containing 0.07 mg ethinyl estradiol and 0.50 mg norgestimate. Results showed that the pharmacokinetics of single doses of ethinyl estradiol and norgestimate were not altered by rifaximin.

Microbiology

Rifaximin acts by binding to the beta-subunit of bacterial DNA dependent RNA polymerase resulting in inhibition of bacterial RNA synthesis.

Escherichia coli has been shown to develop resistance to rifaximin in vitro. However, the clinical significance of such an effect has not been studied.

Rifaximin is a structural analog of rifampin. Organisms with high rifaximin minimum inhibitory concentration (MIC) values also have elevated MIC values against rifampin. Cross-resistance between rifaximin and other classes of antimicrobials has not been studied.

Rifaximin has been shown to be active against the following pathogen in clinical studies of infectious diarrhea as described in the INDICATIONS AND USAGE section: Escherichia coli (enterotoxigenic and enteroaggregative strains).

Susceptibility Tests

In vitro susceptibility testing was performed according to the National Committee for Clinical Laboratory Standards (NCCLS) agar dilution method M7-A6¹. However, the correlation between susceptibility testing and clinical outcome has not been determined.

CLINICAL STUDIES

The efficacy of rifaximin (200 mg orally taken three times a day for 3 days) was evaluated in two-randomized, multi-center, double-blind, placebo controlled studies in adult subjects with travelers' diarrhea. One study was conducted at clinical sites in Mexico, Guatemala, and Kenya (Study 1). The other study was conducted in Mexico, Guatemala, Peru, and India (Study 2). Stool specimens were collected before treatment and 1 to 3 days following the end of treatment to identify enteric pathogens. The predominant pathogen in both studies was Escherichia coli.

The clinical efficacy of rifaximin was assessed by the time to return to normal, formed stools and resolution of symptoms. The primary efficacy endpoint was time to last unformed stool(TLUS) which is defined as the time to the last unformed stool passed, after which clinical cure was declared. Table 3 displays the median TLUS and the number of patients who achieved clinical cure for the intent to treat population (ITT) of Study 1. The duration of diarrhea was significantly shorter in patients treated with rifaximin than in the placebo group. More rifaximin-treated patients were classified as clinical cures than were those in the placebo group.

Table 3. Clinical Response in Study 1 (ITT population) 

	Rifaximin (n=125)	Placebo (n=129)	Estimate (97.5% CI)	P-Value
a Hazard Ratio b Difference in rates
Median TLUS    (hours)	32.5	58.6	1.78a (1.26, 2.50)	0.0002
Clinical cure, n (%)	99 (79.2)	78 (60.5)	18.7b (5.3, 32.1)	0.001

Microbiological eradication (defined as the absence of a baseline pathogen in culture of stool after 72 hours of therapy) rates for Study 1 are presented in Table 4 for patients with any pathogen at baseline and for the subset of patients with Escherichia coli at baseline. Escherichia coli was the only pathogen with sufficient numbers to allow comparisons between treatment groups.

Even though rifaximin had microbiologic activity similar to placebo, it demonstrated a clinically significant reduction in duration of diarrhea and a higher clinical cure rate than placebo. Therefore, patients should be managed based on clinical response to therapy rather than microbiologic response.

Table 4. Microbiologic Eradication Rates in Study 1 Subjects with a Baseline Pathogen

	Rifaximin	Placebo
Overall	48/70 (68.6)	41/61 (67.2)
E. coli	38/53 (71.7)	40/54 (74.1)

Study 2 provided additional information to support the results presented for Study 1. This study also provided evidence that rifaximin-treated subjects with fever and/or blood in the stool at baseline had prolonged TLUS. These subjects had lower clinical cure rates than those without fever or blood in the stool at baseline. Many of the patients with fever and/or blood in the stool (dysentery-like diarrheal syndromes) had invasive pathogens, primarily Campylobacter jejuni, isolated in the baseline stool.

Also in this study, the majority of the rifaximin-treated subjects who had Campylobacter jejuni isolated as a sole pathogen at baseline failed treatment and the resulting clinical cure rate for these patients was 23.5% (4/17). In addition to not being different from placebo, the microbiologic eradication rates for subjects with Campylobacter jejuni isolated at baseline were much lower than the eradication rates seen for Escherichia coli.

In an unrelated Phase 1, open-label, pharmacokinetic study of oral XIFAXAN™ Tablets 200 mg taken every 8 hours for 3days, 15 adult subjects were challenged with Shigella flexneri 2a, of whom 13 developed diarrhea or dysentery and were treated with rifaximin. Although this open-label challenge trial was not adequate to assess the effectiveness of rifaximin in the treatment of shigellosis, the following observations were noted. Eight subjects received rescue treatment with ciprofloxacin either because of lack of response to rifaximin treatment within 24 hours (2), or because they developed severe dysentery (5), or because of recurrence of Shigella flexneri in the stool (1). Five of the 13 subjects received ciprofloxacin although they did not have evidence of severe disease or relapse.