Lomefloxacin

Lomefloxacin (lomefloxacin HCl) is a synthetic broad-spectrum antimicrobial agent for oral administration. Lomefloxacin HCl, a difluoroquinolone, is the monohydrochloride salt of (±)-1-ethyl-6, 8-difluoro-1, 4-dihydro-7- (3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid. Its empirical formula is C₁₇H₁₉F₂N₃O₃· HCl.

Lomefloxacin HCl is a white to pale yellow powder with a molecular weight of 387.8. It is slightly soluble in water and practically insoluble in alcohol. Lomefloxacin HCl is stable to heat and moisture but is sensitive to light in dilute aqueous solution.

Pharmacokinetics in healthy volunteers

In 6 fasting healthy male volunteers, approximately 95% to 98% of a single oral dose of lomefloxacin was absorbed. Absorption was rapid following single doses of 200 and 400 mg (T_max 0.8 to 1.4 hours).

Mean plasma concentration increased proportionally between 100 and 400 mg as shown below:

In 6 healthy male volunteers administered 400 mg of lomefloxacin on an empty stomach qd for 7 days, the following mean pharmacokinetic parameter values were obtained:

The elimination half-life in 8 subjects with normal renal function was approximately 8 hours. At 24 hours postdose, subjects with normal renal function receiving single doses of 200 or 400 mg had mean plasma lomefloxacin concentrations of 0.10 and 0.24 µg/mL, respectively. Steady-state concentrations were achieved within 48 hours of initiating therapy with one-a-day dosing. There was no drug accumulation with single-daily dosing in patients with normal renal function.

Approximately 65% of an orally administered dose was excreted in the urine as unchanged drug in patients with normal renal function. Following a 400-mg dose of lomefloxacin administered qd for 7 days, the mean urine concentration 4 hours postdose was in excess of 300 µg/mL. The mean urine concentration exceeded 35 µg/mL for at least 24 hours after dosing.

Following a single 400-mg dose, the solubility of lomefloxacin in urine usually exceeded its peak urinary concentration 2- to 6-fold. In this study, urine pH affected the solubility of lomefloxacin with solubilities ranging from 7.8 mg/mL at pH 5.2, to 2.4 mg/mL at pH 6.5, and 3.03 mg/mL at pH 8.12. The urinary excretion of lomefloxacin was virtually complete within 72 hours after cessation of dosing, with approximately 65% of the dose being recovered as parent drug and 9% as its glucuronide metabolite. The mean renal clearance was 145 mL/min in subjects with normal renal function (GFR = 120 mL/min). This may indicate tubular secretion.

Food effect: When lomefloxacin and food were administered concomitantly, the rate of drug absorption was delayed (Tmax increased to 2 hours [delayed by 41%], C_max decreased by 18%), and the extent of absorption (AUC) was decreased by 12%.

Pharmacokinetics in the geriatric population

In 16 healthy elderly volunteers (61 to 76 years of age) with normal renal function for their age, the half-life of lomefloxacin (mean of 8 hours) and its peak plasma concentration (mean of 4.2 µg/mL) following a single 400-mg dose were similar to those in 8 younger subjects dosed with a single 400-mg dose. Thus, drug absorption appears unaffected in the elderly. Plasma clearance was, however, reduced in this elderly population by approximately 25%, and the AUC was increased by approximately 33%. This slower elimination most likely reflects the decreased renal function normally observed in the geriatric population.

Pharmacokinetics in renally impaired patients: In 8 patients with creatinine clearance (Cl_Cr) between 10 and 40 mL/min/1.73 m², the mean AUC after a single 400-mg dose of lomefloxacin increased 335% over the AUC demonstrated in patients with a Cl_Cr >80 mL/min/1.73 m². Also, in these patients, the mean t_1/2 increased to 21 hours. In 8 patients with Cl_Cr <10 mL/min/1.73 m², the mean AUC after a single 400-mg dose of lomefloxacin increased 700% over the AUC demonstrated in patients with a Cl_Cr >80 mL/min/1.73 m². In these patients with Cl_Cr <10 mL/min/1.73 m², the mean t_1/2 increased to 45 hours. The plasma clearance of lomefloxacin was closely correlated with creatinine clearance, ranging from 31 mL/min/1.73 m² when creatinine clearance was zero to 271 mL/min/1.73 m² at a normal creatinine clearance of 110 mL/min/1.73 m². Peak lomefloxacin concentrations were not affected by the degree of renal function when single doses of lomefloxacin were administered. Adjustment of dosage schedules for patients with such decreases in renal function is warranted. (See Dosage and Administration.)

Pharmacokinetics in patients with cirrhosis

In 12 patients with histologically confirmed cirrhosis, no significant changes in rate or extent of lomefloxacin exposure (C_max, T_max, t_1/2, or AUC) were observed when they were administered 400 mg of lomefloxacin as a single dose. No data are available in cirrhotic patients treated with multiple doses of lomefloxacin. Cirrhosis does not appear to reduce the nonrenal clearance of lomefloxacin. There does not appear to be a need for a dosage reduction in cirrhotic patients, provided adequate renal function is present.

Metabolism and pharmacodynamics of lomefloxacin: Lomefloxacin is minimally metabolized although 5 metabolites have been identified in human urine. The glucuronide metabolite is found in the highest concentration and accounts for approximately 9% of the administered dose. The other 4 metabolites together account for <0.5% of the dose.

Approximately 10% of an oral dose was recovered as unchanged drug in the feces.

Serum protein binding of lomefloxacin is approximately 10%. The following are mean tissue- or fluid-to-plasma ratios of lomefloxacin following oral administration. Studies have not been conducted to assess the penetration of lomefloxacin into human cerebrospinal fluid.

In two studies including 74 healthy volunteers, the minimal dose of UVA light needed to cause erythema (MED-UVA) was inversely proportional to plasma lomefloxacin concentration. The MED-UVA values (16 hours and 12 hours postdose) were significantly higher than the MED-UVA values 2 hours postdose at steady state. Increasing the interval between lomefloxacin dosing and exposure to UVA light increased the amount of light energy needed for photoreaction. In a study of 27 healthy volunteers, the steady state AUC values and C_min values were equivalent whether the drug was administered in the morning or in the evening.

Carcinogenesis, mutagenesis, impairment of fertility

Carcinogenesis

Hairless (Skh-1) mice were exposed to UVA light for 3.5 hours five times every two weeks for up to 52 weeks while concurrently being administered lomefloxacin. The lomefloxacin doses used in this study caused a phototoxic response. In mice treated with both UVA and lomefloxacin concomitantly, the time to development of skin tumors was 16 weeks. In mice treated concomitantly in this model with both UVA and other quinolones, the times to development of skin tumors ranged from 28 to 52 weeks.

Ninety-two percent (92%) of the mice treated concomitantly with both UVA and lomefloxacin developed well-differentiated squamous cell carcinomas of the skin. These squamous cell carcinomas were nonmetastatic and were endophytic in character. Two-thirds of these squamous cell carcinomas contained large central keratinous inclusion masses and were thought to arise from the vestigial hair follicles in these hairless animals. In this model, mice treated with lomefloxacin alone did not develop skin or systemic tumors. There are no data from similar models using pigmented mice and/or fully haired mice. The clinical significance of these findings to humans is unknown.

Mutagenesis

One in vitro mutagenicity test (CHO/HGPRT assay) was weakly positive at lomefloxacin concentrations ≥226 µg/mL and negative at concentrations < 226 µg/mL. Two other in vitro mutagenicity tests (chromosomal aberrations in Chinese hamster ovary cells, chromosomal aberrations in human lymphocytes) and two in vivo mouse micronucleus mutagenicity tests were all negative.

Impairment of fertility

Lomefloxacin did not affect the fertility of male and female rats at oral doses up to 8 times the recommended human dose based on mg/m² (34 times the recommended human dose based on mg/kg).