Moxifloxacin - How It Works

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Moxifloxacin hydrochloride is a member of the fluoroquinolone class of antibacterial agents [see Microbiology ] .

12.2 Pharmacodynamics Photosensitivity Potential A study of the skin response to ultraviolet (UVA and UVB) and visible radiation conducted in 32 healthy volunteers (8 per group) demonstrated that moxifloxacin hydrochloride does not show phototoxicity in comparison to placebo.

The minimum erythematous dose (MED) was measured before and after treatment with moxifloxacin (200 mg or 400 mg once daily), lomefloxacin (400 mg once daily), or placebo.

In this study, the MED measured for both doses of moxifloxacin were not significantly different from placebo, while lomefloxacin significantly lowered the MED [see Warnings and Precautions ].

12.3 Pharmacokinetics Absorption Moxifloxacin, given as an oral tablet, is well absorbed from the gastrointestinal tract.

The absolute bioavailability of moxifloxacin is approximately 90 percent.

Co-administration with a high fat meal (that is, 500 calories from fat) does not affect the absorption of moxifloxacin.

Consumption of 1 cup of yogurt with moxifloxacin does not significantly affect the extent or rate of systemic absorption (AUC).

Table 7: Mean (± SD) C max and AUC Values Following Single and Multiple Doses of 400 mg Moxifloxacin Given Orally a) Range of means from different studies C max (mg/L) AUC (mg•h/L) Half-life (hr) Single Dose Oral Healthy (n = 372) 3.1 ± 1 36.1 ± 9.1 11.5 - 15.6 a Multiple Dose Oral Healthy young male/female (n = 15) 4.5 ± 0.5 48 ± 2.7 12.7 ± 1.9 Healthy elderly male (n = 8) 3.8 ± 0.3 51.8 ± 6.7 Healthy elderly female (n = 8) 4.6 ± 0.6 54.6 ± 6.7 Healthy young male (n = 8) 3.6 ± 0.5 48.2 ± 9 Healthy young female (n = 9) 4.2 ± 0.5 49.3 ± 9.5 Table 8: Mean (± SD) C max and AUC values following single and multiple doses of 400 mg moxifloxacin given by 1 hour IV infusion a) Range of means from different studies b) Expected C max (concentration obtained around the time of the end of the infusion) C max (mg/L) AUC (mg•h/L) Half-life (hr) Single Dose IV Healthy young male/female (n = 56) 3.9 ± 0.9 39.3 ± 8.6 8.2 - 15.4 a Patients (n = 118) Male (n = 64) 4.4 ± 3.7 Female ( n = 54) 4.5 ± 2 < 65 years ( n = 58) 4.6 ± 4.2 ≥ 65 years (n = 60) 4.3 ± 1.3 Multiple Dose IV Healthy young male (n = 8) 4.2 ± 0.8 38 ± 4.7 14.8 ± 2.2 Healthy elderly (n=12; 8 male, 4 female) 6.1 ± 1.3 48.2 ± 0.9 10.1 ± 1.6 Patients b (n = 107) Male (n = 58) 4.2 ± 2.6 Female (n = 49) 4.6 ± 1.5 <65 years (n = 52) 4.1 ± 1.4 ≥65 years (n = 55) 4.7 ± 2.7 Plasma concentrations increase proportionately with dose up to the highest dose tested (1200 mg single oral dose).

The mean (± SD) elimination half-life from plasma is 12 ± 1.3 hours; steady-state is achieved after at least three days with a 400 mg once daily regimen.

Mean Steady-State Plasma Concentrations of Moxifloxacin Obtained With Once Daily Dosing of 400 mg Either Orally (n=10) or by IV Infusion (n=12) Distribution Moxifloxacin is approximately 30 to 50% bound to serum proteins, independent of drug concentration.

The volume of distribution of moxifloxacin ranges from 1.7 to 2.7 L/kg.

Moxifloxacin is widely distributed throughout the body, with tissue concentrations often exceeding plasma concentrations.

Moxifloxacin has been detected in the saliva, nasal and bronchial secretions, mucosa of the sinuses, skin blister fluid, subcutaneous tissue, skeletal muscle, and abdominal tissues and fluids following oral or intravenous administration of 400 mg.

Moxifloxacin concentrations measured post-dose in various tissues and fluids following a 400 mg oral or IV dose are summarized in Table 7 .

The rates of elimination of moxifloxacin from tissues generally parallel the elimination from plasma.

Table 9: Moxifloxacin Concentrations (mean ± SD) in Tissues and the Corresponding Plasma Concentrations After a Single 400 mg Oral or Intravenous Dose a a) All moxifloxacin concentrations were measured 3 hours after a single 400 mg dose, except the abdominal tissue and exudate concentrations which were measured at 2 hours post-dose and the sinus concentrations which were measured 3 hours post-dose after 5 days of dosing. b) N = 5 c) N = 7 d) N = 12 e) Reflects only non-protein bound concentrations of drug.

Tissue or Fluid N Plasma Concentration (mcg/mL) Tissue or Fluid Concentration (mcg/mL or mcg/g) Tissue Plasma Ratio Respiratory Alveolar Macrophages 5 3.3 ± 0.7 61.8 ± 27.3 21.2 ± 10 Bronchial Mucosa 8 3.3 ± 0.7 5.5 ± 1.3 1.7 ± 0.3 Epithelial Lining Fluid 5 3.3 ± 0.7 24.4 ± 14.7 8.7 ± 6.1 Sinus Maxillary Sinus Mucosa 4 3.7 ± 1.1 b 7.6 ± 1.7 2 ± 0.3 Anterior Ethmoid Mucosa 3 3.7 ± 1.1 b 8.8 ± 4.3 2.2 ± 0.6 Nasal Polyps 4 3.7 ± 1.1 b 9.8 ± 4.5 2.6 ± 0.6 Skin, Musculoskeletal Blister Fluid 5 3 ± 0.5 c 2.6 ± 0.9 0.9 ± 0.2 Subcutaneous Tissue 6 2.3 ± 0.4 d 0.9 ± 0.3 e 0.4 ± 0.6 Skeletal Muscle 6 2.3 ± 0.4 d 0.9 ± 0.2 e 0.4 ± 0.1 Intra-Abdominal Abdominal tissue 8 2.9 ± 0.5 7.6 ± 2 2.7 ± 0.8 Abdominal exudate 10 2.3 ± 0.5 3.5 ± 1.2 1.6 ± 0.7 Abscess fluid 6 2.7 ± 0.7 2.3 ± 1.5 0.8 ± 0.4 Metabolism Approximately 52% of an oral or intravenous dose of moxifloxacin is metabolized via glucuronide and sulfate conjugation.

The cytochrome P450 system is not involved in moxifloxacin metabolism, and is not affected by moxifloxacin.

The sulfate conjugate (M1) accounts for approximately 38% of the dose, and is eliminated primarily in the feces.