Pharmacokinetics of Intravenously Administered Levofloxacin in Men and Women

Brian R. Overholser, Pharm.D.; Michael B. Kays, Pharm.D., FCCP; Seema Lagvankar, D.O.; Mitchell Goldman, M.D.; Bruce A. Mueller, Pharm.D., FCCP; Kevin M. Sowinski, Pharm.D., FCCP

Disclosures

Pharmacotherapy. 2005;25(10):1310-1318. 

In This Article

Abstract and Introduction

Study Objective: To characterize and compare the pharmacokinetics of levofloxacin in men and women after systemic administration.
Design: Prospective, open-label, parallel group pharmacokinetic study.
Setting: University research center.
Subjects: Eleven healthy men and nine healthy women stratified by body mass index.
Intervention: Subjects received levofloxacin as a single 500-mg intravenous dose. Serum and urine were collected over 36 hours.
Measurements and Main Results: Levofloxacin concentrations were determined by high-performance liquid chromatography with ultraviolet detection. Pharmacokinetic analysis was performed with ADAPT II software (University of Southern California, Los Angeles, CA). Median (range) body mass index was 23.2 kg/m2 (19.9-28.3 kg/m2) for men and 23.6 kg/m2 (16.0-32.4 kg/m2) for women (p=0.67). A two-compartment model best fit the pharmacokinetic data: median (range) R2 was 0.996 (0.990-0.999). Women had a 24% greater exposure to levofloxacin, with a significantly smaller steady-state volume of distribution (p<0.01) and a slower clearance (p<0.01).
Conclusions: Differences exist in the disposition of levofloxacin between healthy men and women after systemic administration. Fixed intravenous doses of levofloxacin will lead to greater drug exposure in women. Thus, women may have more of an increased risk of fluoroquinolone toxicity than men, and men may need higher doses to achieve similar drug efficacy than women. Levofloxacin dosage adjustments based on sex should be considered on an individual basis.

Fluoroquinolones are broad-spectrum antibiotics commonly used in the treatment of community-acquired pneumonia, among several other infections. They are generally well tolerated, although central nervous system and gastrointestinal adverse effects are common.[1,2] Observational data suggest that women may have a greater frequency of these adverse effects with certain fluoroquinolone antibiotics than do men.[3,4] This increased toxicity in women may be attributed to an underlying disposition or response difference to fluoroquinolones between the sexes.

Previous reports indicate that women have increased maximum serum concentrations (Cmax) and a greater exposure to several fluoroquinolones.[5,6,7,8,9,10] In most of these studies, the estimated volume of distribution of the compound of interest was found to be smaller in women compared with that in men but was attenuated when normalized to body weight. Other studies report an absence of a sex-related effect on fluoroquinolone disposition when pharmacokinetic parameters are normalized to total body weight, although none of the studies reported pharmacokinetic parameters unadjusted for weight.[2,11,12] Thus, available data suggest that because of smaller body weights, women may be exposed to higher plasma fluoroquinolone concentrations than are men when equal doses are administered. Despite body composition differences, however, to our knowledge, relationships between fluoroquinolone pharmacokinetics and total body weight have not been investigated in men and women to justify weight normalization of pharmacokinetic parameters between the sexes.

We previously published the sex-related effects on the pharmacokinetics of ofloxacin administered as a single 400-mg oral dose in male and female volunteers.[10] Consistent with previous fluoroquinolone studies, the apparent steady-state volume of distribution (Vss) was significantly lower in women than in men, and after weight adjustment the difference was attenuated and no longer statistically significant. Of particular interest, data from that study suggest that differences may exist in the relationship between the apparent Vss of ofloxacin and total body weight in men and women. In men, a strong positive relationship between total body weight and the apparent Vss was observed. In the women, however, no apparent relationship was noted between Vss and total body weight. If a distinct relationship exists between the sexes, pharmacokinetic parameter normalization to total body weight may be inappropriate for ofloxacin. Since that study was performed after administration of an oral dose, differences in the clearance and Vss could not be distinguished from potential differences in oral bioavailability.

Levofloxacin, the pharmacologically active S-enantiomer of racemic ofloxacin, is frequently used in clinical practice, but potential sex-based disposition differences after intravenous administration have not been established.[2] Based on observations from the ofloxacin study, we hypothesized that sex-based differences exist in the pharmacokinetics of levofloxacin after systemic administration. Therefore, we sought to investigate the pharmacokinetics of intravenous levofloxacin in a group of men and women stratified by body mass index. An additional aim was to justify a weight-based normalization of pharmacokinetic parameter estimates by assessing the relationships between body weight and composition with systemic clearance (Cls) and apparent Vss in men and women.

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