Pharmacokinetics and safety of levofloxacin in patients with human immunodeficiency virus infection

Abstract

Levofloxacin, the bacteriologically active isomer of ofloxacin, has microbiologic activity against many pathogens common in human immunodeficiency virus (HIV)-infected patients, including Mycoplasma species which may be cofactors in the progression of HIV disease. The purpose of this phase I, double-blind, randomized (1:1), placebo-controlled trial was to evaluate the pharmacokinetics and safety of levofloxacin hemihydrate in 10 asymptomatic HIV-infected males. Plasma concentrations by chiral high-performance liquid chromatography (HPLC) were evaluated for 48 h after a single 350-mg oral dose, at morning predose during the multiple-dosing phase, and for 72 h at steady state after a week of 350 mg every 8 h orally. Mean +/- standard deviation levofloxacin pharmacokinetic parameters (by noncompartmental moment method) after multiple dosing were as follows: area under the concentration-time curve, 31.24 +/- 5.60 mg.h/liter; apparent total body clearance, 11.18 +/- 1.76 liters/h; renal clearance, 8.63 +/- 2.82 liters/h; steady-state volume of distribution, 104.10 +/- 12.48 liters; and effective half-life, 6.50 +/- 0.51 h. Single-dose parameters were not significantly different from the multiple-dose parameters, with the exception of peak concentrations in plasma, which were 4.79 +/- 1.00 and 6.92 +/- 1.56 mg/liter for single- and multiple-dose data, respectively. Essentially identical parameter values were obtained from curve-fitting analysis when the entire 13-day plasma concentration profiles of the subjects were analyzed simultaneously by a two-compartmental distribution model. Levofloxacin pharmacokinetics in HIV-infected patients remained linear upon multiple dosing. The dosing regimen studied provides levels in plasma and urine well above those found to be effective in vitro against pathogens common in HIV-infected patients. Levofloxacin was well- tolerated in this group of asymptomatic HIV-infected males: there were no statistically significant differences in adverse effects in the two groups (P = 0.22). Use of placebo control helped to differentiate disease-related adverse effects from those related to the study drug.

Open-label crossover study to determine pharmacokinetics and penetration of two dose regimens of levofloxacin into inflammatory fluid

“…There is little published information on the pharmacokinetics of levofloxacin at doses greater than 200 mg (2), but measurements of C max and AUC suggest oral dose-response curve linearity from 50 to 200 mg. A study of the pharmacokinetics of both single and three times daily 350-mg doses of levofloxacin in patients with human immunodeficiency virus infection (6) showed a mean C max of 6.92 g/ml on day 7 following administration of 350 mg three times a day. Assuming dose-response curve linearity, this value is similar to our finding of a C max of 9.3 g/ml after administration of 500 mg twice a day.…”

“…A two-compartment distribution model was fitted simultaneously to the plasma and blister fluid data of a subject. This model has been successfully applied to characterize the pharmacokinetics of levofloxacin following single-and multiple-dose oral administration (6). Plasma compartment absorption and elimination rates were assumed to be zero order and first order, respectively.…”

“…Pharmacokinetic analysis of the plasma and blister fluid samples was performed by the PCNONLIN program (10) with the Gauss-Newton algorithm and the Levenberg modification, as previously described (6). A two-compartment distribution model was fitted simultaneously to the plasma and blister fluid data of a subject.…”

Altered Drug Metabolism and Transport in Pathophysiological Conditions

“…These children had a significant decrease in CL and increase in T 1/2 of theophylline. HIV infections could also lead to altered PK of levofloxacin and fluconazole (Goodwin et al, 1994;Tett et al, 1995). End-stage liver disease, which is largely the result of HCV infection, now accounts for up to 50% of deaths among persons with HIV-1 infection (Bica et al, 2001).…”

Effects of traditional Chinese medicines on pharmacokinetics of levofloxacin

“…Several articles on the pharmacokinetics of LVFX in human beings have been published (1,4,6,13); LVFX is completely absorbed from the gastrointestinal tract, is largely distributed throughout the body, and is for the most part excreted into the urine by the kidneys. The pharmacokinetic interactions between LVFX and Chinese medicines, however, are not yet fully understood.…”