CLINICAL PHARMACOLOGY
Mechanism of Action
Fidaxomicin is an antibacterial drug [see Microbiology ].
Pharmacodynamics
Fidaxomicin acts locally in the gastrointestinal tract on C. difficile. In a dose-ranging trial (N=48) of fidaxomicin using 50 mg, 100 mg, and 200 mg twice daily for 10 days, a dose-response relationship was observed for efficacy.
Pharmacokinetics
The pharmacokinetic parameters of fidaxomicin and its main metabolite OP-1118 following a single dose of 200 mg in healthy adult males (N=14) are summarized in Table 2.
Table 2. Mean (± Standard Deviation) Pharmacokinetic Parameters of Fidaxomicin 200 mg in Healthy Adult Males
* Tmax, reported as median (range)
Cmax, maximum observed concentration; Tmax, time to maximum observed concentration; AUC0-t, area under the concentration-time curve from time 0 to the last measured concentration; AUC0-∞, area under the concentration-time curve from time 0 to infinity; t1/2, elimination half-life |
|
Parameter
|
Fidaxomicin
|
OP-1118
|
|
N
|
Value
|
N
|
Value
|
| Cmax (ng/mL) |
14 |
5.20 ± 2.81 |
14 |
12.0 ± 6.06 |
| Tmax (h)* |
14 |
2.00 (1.00-5.00) |
14 |
1.02 (1.00-5.00) |
| AUC0-t (ng-h/mL) |
14 |
48.3 ± 18.4 |
14 |
103 ± 39.4 |
| AUC0-∞ (ng-h/mL) |
9 |
62.9 ± 19.5 |
10 |
118 ± 43.3 |
| t1/2 (h) |
9 |
11.7 ± 4.80 |
10 |
11.2 ± 3.01 |
Absorption
Fidaxomicin has minimal systemic absorption following oral administration, with plasma concentrations of fidaxomicin and OP-1118 in the ng/mL range at the therapeutic dose. In fidaxomicin-treated patients from controlled trials, plasma concentrations of fidaxomicin and OP-1118 obtained within the Tmax window (1-5 hours) were approximately 2- to 6-fold higher than Cmax values in healthy adults. Following administration of DIFICID 200 mg twice daily for 10 days, OP-1118 plasma concentrations within the Tmax window were approximately 50%-80% higher than on Day 1, while concentrations of fidaxomicin were similar on Days 1 and 10.
In a food-effect study involving administration of DIFICID to healthy adults (N=28) with a high-fat meal versus under fasting conditions, Cmax of fidaxomicin and OP-1118 decreased by 21.5% and 33.4%, respectively, while AUC0-t remained unchanged. This decrease in Cmax is not considered clinically significant, and thus, DIFICID may be administered with or without food.
Distribution
Fidaxomicin is mainly confined to the gastrointestinal tract following oral administration. In selected patients (N=8) treated with DIFICID 200 mg twice daily for 10 days from controlled trials, fecal concentrations of fidaxomicin and OP-1118 obtained within 24 hours of the last dose ranged from 639-2710 μg/g and 213-1210 μg/g, respectively. In contrast, plasma concentrations of fidaxomicin and OP-1118 within the Tmax window (1-5 hours) ranged 2-179 ng/mL and 10-829 ng/mL, respectively.
Metabolism
Fidaxomicin is primarily transformed by hydrolysis at the isobutyryl ester to form its main and microbiologically active metabolite, OP-1118. Metabolism of fidaxomicin and formation of OP-1118 are not dependent on cytochrome P450 (CYP) enzymes.
At the therapeutic dose, OP-1118 was the predominant circulating compound in healthy adults, followed by fidaxomicin.
Excretion
Fidaxomicin is mainly excreted in feces. In one trial of healthy adults (N=11), more than 92% of the dose was recovered in the stool as fidaxomicin and OP-1118 following single doses of 200 mg and 300 mg. In another trial of healthy adults (N=6), 0.59% of the dose was recovered in urine as OP-1118 only following a single dose of 200 mg.
Specific Populations
Geriatric
In controlled trials of patients treated with DIFICID® 200 mg twice daily for 10 days, mean and median values of fidaxomicin and OP-1118 plasma concentrations within the Tmax window (1-5 hours) were approximately 2- to 4-fold higher in elderly patients (≥65 years of age) versus non-elderly patients (<65 years of age). Despite greater exposures in elderly patients, fidaxomicin and OP-1118 plasma concentrations remained in the ng/mL range [see Use in Specific Populations].
Gender
Plasma concentrations of fidaxomicin and OP-1118 within the Tmax window (1-5 hours) did not vary by gender in patients treated with DIFICID 200 mg twice daily for 10 days from controlled trials. No dose adjustment is recommended based on gender.
Renal Impairment
In controlled trials of patients treated with DIFICID 200 mg twice daily for 10 days, plasma concentrations of fidaxomicin and OP-1118 within the Tmax window (1-5 hours) did not vary by severity of renal impairment (based on creatinine clearance) between mild (51-79 mL/min), moderate (31-50 mL/min), and severe (≤30 mL/min) categories. No dose adjustment is recommended based on renal function.
Hepatic Impairment
The impact of hepatic impairment on the pharmacokinetics of fidaxomicin has not been evaluated. Because fidaxomicin and OP-1118 do not appear to undergo significant hepatic metabolism, elimination of fidaxomicin and OP-1118 is not expected to be significantly affected by hepatic impairment.
Drug Interactions
In vivo studies were conducted to evaluate intestinal drug-drug interactions of fidaxomicin as a P-gp substrate, P-gp inhibitor, and inhibitor of major CYP enzymes expressed in the gastrointestinal tract (CYP3A4, CYP2C9, and CYP2C19).
Table 3 summarizes the impact of a co-administered drug (P-gp inhibitor) on the pharmacokinetics of fidaxomicin [see Drug Interactions].
Table 3. Pharmacokinetic Parameters of Fidaxomicin and OP-1118 in the Presence of a Co-Administered Drug
|
Parameter
|
Cyclosporine 200 mg + Fidaxomicin 200 mgCyclosporine was administered 1 hour before fidaxomicin
(N=14)
|
Fidaxomicin 200 mg Alone
(N=14)
|
Mean Ratio of Parameters With/Without Co-Administered Drug
(90% CI CI - confidence interval)
No Effect = 1.00
|
|
N
|
Mean
|
N
|
Mean
|
| Fidaxomicin |
|
|
|
|
|
| Cmax (ng/mL) |
14 |
19.4 |
14 |
4.67 |
4.15 (3.23-5.32) |
| AUC0-∞ (ng-h/mL) |
8 |
114 |
9 |
59.5 |
1.92 (1.39-2.64) |
| OP-1118 |
|
|
|
|
|
| Cmax (ng/mL) |
14 |
100 |
14 |
10.6 |
9.51 (6.93-13.05) |
| AUC0-∞ (ng-h/mL) |
12 |
438 |
10 |
106 |
4.11 (3.06-5.53) |
Fidaxomicin had no significant impact on the pharmacokinetics of the following co-administered drugs: digoxin (P-gp substrate), midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). No dose adjustment is warranted when fidaxomicin is co-administered with substrates of P-gp or CYP enzymes.
Microbiology
Spectrum of Activity
Fidaxomicin is a fermentation product obtained from the Actinomycete Dactylosporangium aurantiacum. In vitro, fidaxomicin is active primarily against species of clostridia, including Clostridium difficile.
Mechanism of Action
Fidaxomicin is bactericidal against C. difficile in vitro, inhibiting RNA synthesis by RNA polymerases.
Mechanism of Decreased Susceptibility to Fidaxomicin
In vitro studies indicate a low frequency of spontaneous resistance to fidaxomicin in C. difficile (ranging from <1.4 × 10-9 to 12.8 × 10-9). A specific mutation (Val-ll43-Gly) in the beta subunit of RNA polymerase is associated with reduced susceptibility to fidaxomicin. This mutation was created in the laboratory and seen during clinical trials in a C. difficile isolate obtained from a subject treated with DIFICID who had recurrence of CDAD. The C. difficile isolate from the treated subject went from a fidaxomicin baseline minimal inhibitory concentration (MIC) of 0.06 μg/mL to 16 μg/mL.
Cross-Resistance/Synergy/Post-Antibiotic Effect
Fidaxomicin demonstrates no in vitro cross-resistance with other classes of antibacterial drugs. Fidaxomicin and its main metabolite OP-1118 do not exhibit any antagonistic interaction with other classes of antibacterial drugs. In vitro synergistic interactions of fidaxomicin and OP-1118 have been observed in vitro with rifampin and rifaximin against C. difficile (FIC values ≤0.5). Fidaxomicin demonstrates a post-antibiotic effect vs. C. difficile of 6-10 hrs.
Susceptibility Testing
The clinical microbiology laboratory should provide cumulative results of the in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting appropriate antimicrobial drug therapy.
Dilution Techniques
Quantitative anaerobic in vitro methods can be used to determine the MIC of fidaxomicin needed to inhibit the growth of the C. difficile isolates. The MIC provides an estimate of the susceptibility of C. difficile isolate to fidaxomicin. The MIC should be determined using standardized procedures.1 Standardized methods are based on an agar dilution method or equivalent with standardized inoculum concentrations and standardized concentration of fidaxomicin powder.
Susceptibility Test Interpretive Criteria
In vitro susceptibility test interpretive criteria for fidaxomicin have not been determined. The relation of the in vitro fidaxomicin MIC to clinical efficacy of fidaxomicin against C. difficile isolates can be monitored using in vitro susceptibility results obtained from standardized anaerobe susceptibility testing methods.
Quality Control Parameters for Susceptibility Testing
In vitro susceptibility test quality control parameters were developed for fidaxomicin so that laboratories determining the susceptibility of C. difficile isolates to fidaxomicin can ascertain whether the susceptibility test is performing correctly. Standardized dilution techniques require the use of laboratory control microorganisms to monitor the technical aspects of the laboratory procedures. Standardized fidaxomicin powder should provide the MIC with the indicated quality control strain shown in Table 4.
Table 4. Acceptable Quality Control Ranges for Fidaxomicin
|
Microorganism
|
MIC Range (μg/mL)
|
|
C. difficile (ATCC 700057) |
0.03-0.25 |
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Long-term carcinogenicity studies have not been conducted to evaluate the carcinogenic potential of fidaxomicin.
Neither fidaxomicin nor OP-1118 was mutagenic in the Ames assay. Fidaxomicin was also negative in the rat micronucleus assay. However, fidaxomicin was clastogenic in Chinese hamster ovary cells.
Fidaxomicin did not affect the fertility of male and female rats at intravenous doses of 6.3 mg/kg. The exposure (AUC0-t) was approximately 100 times that in humans.
|
