Metronidazole - How It Works

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Metronidazole is a nitroimidazole antimicrobial drug [ see Microbiology ] .

12.3 Pharmacokinetics Metronidazole pharmacokinetics are similar for both oral and intravenous dosage forms.

The C max is dose proportional between 250 mg, 500 mg, and 2,000 mg for metronidazole oral tablets, producing peak plasma concentrations of 6 mcg/mL, 12 mcg/mL, and 40 mcg/mL, respectively.

Absorption Following oral administration, LIKMEZ is well absorbed, with peak plasma concentrations occurring between 0.25 and 6 hours after administration.

Two pharmacokinetic studies (Study 1 and Study 2) performed in healthy adult volunteers evaluated the bioavailability of LIKMEZ under fasting and fed conditions.

Effect of Food Food delays T max and lowers C max when compared to fasted conditions, but systemic exposure (AUC) is similar in fed and fasted state (see Table 1).

Table 1: Mean (± S.D.) Pharmacokinetic Parameters Following Single Oral Doses of 500 mg LIKMEZ in Healthy Adults Under Fed and Fasting Conditions Formulation C max (mcg/mL) AUC 0-∞ (mcg.h/mL) Tmax Median (min max) (h) Study 1- Fasting state (n = 44) LIKMEZ 13 ± 3 146 ± 36 0.75 (0.25 to 6) Study 2- Fed State Fed study administered LIKMEZ following a high-fat, high-calorie breakfast (approximately 1,000 calories, 26.5% carbohydrates, 16.5% protein, and 57% fat). (n = 46) LIKMEZ 10 ± 1 144 ± 30 2.33 (0.25 to 4) Distribution Metronidazole is the major component appearing in the plasma, with lesser quantities of metabolites also being present.

Less than 20% of the circulating metronidazole is bound to plasma proteins.

Metronidazole appears in cerebrospinal fluid, saliva, and breast milk in concentrations similar to those found in plasma.

Bactericidal concentrations of metronidazole have also been detected in pus from hepatic abscesses.

Elimination Metabolism The metabolites of metronidazole that appear in the urine result primarily from side-chain oxidation [1-(-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole and 2-methyl-5-nitroimidazole-1-ylacetic acid] and glucuronide conjugation, with unchanged metronidazole accounting for approximately 20% of the total.

Both the parent compound and the hydroxyl metabolite possess in vitro antimicrobial activity.

Excretion The major route of elimination of metronidazole and its metabolites is via the urine (60% to 80% of the dose), with fecal excretion accounting for 6% to 15% of the dose.

Renal clearance of metronidazole is approximately 10 mL/min/1.73 m 2 .

The average elimination half-life of LIKMEZ in healthy adult subjects is nine hours.

Specific Populations Geriatric Patients Following a single 500 mg oral or IV dose of metronidazole, subjects >70 years old with no apparent renal or hepatic dysfunction had a 40% to 80% higher mean AUC of hydroxy‑metronidazole (active metabolite), with no apparent increase in the mean AUC of metronidazole (parent compound), compared to young healthy controls <40 years old [ see Use in Specific Populations ] .

Pediatric Patients In one study, newborn infants appeared to demonstrate diminished capacity to eliminate metronidazole.

The elimination half-life, measured during the first 3 days of life, was inversely related to gestational age.

In infants whose gestational ages were between 28 weeks and 40 weeks, the corresponding elimination half-lives ranged from 109 hours to 22.5 hours.

Male and Female Patients Studies reveal no significant bioavailability differences between males and females; however, because of weight differences, the resulting plasma levels in males are generally lower.