Temafloxacin pharmacokinetics in subjects with normal and impaired renal function

Abstract

The pharmacokinetics of temafloxacin were investigated following oral administration of single 400-mg doses to 6 normal subjects and 18 subjects with various degrees of impaired renal function. Renal impairment did not significantly affect the peak concentration, time to peak concentration, or the nonrenal clearance of temafloxacin. Both renal clearance (CLR) and total apparent clearance (CLT/F, where F represents the fraction of dose absorbed) of temafloxacin were highly correlated with creatinine clearance (CLCR). The regression equations were as follows: CLR = 0.85. CLCR, with R2 = 0.907, and CLT/F = 56.0 + 0.92 .' CLCR, with R2 = 0.656. The half-life (mean ± standard devi'ation) increased from 10.6 ± 2.4 h in the normal volunteers to 24.6 ± 7.3 h in the subjects with a CLCR of <10 ml/min; the respective CLIJF decreased from 169 + 58 to 70 + 27 m/min. Compared with the CLT/F in the subjects with normal renal function, CLT/F was reduced 60% in subjects with a CLCR of <40 ml/min, indicating that the dosage should be reduced by at least one-half for patients with comparable impairment. For the subjects on chronic hemodialysis, most of the variability in the nonrenal clearance and the terminal-phase rate constant of temafloxacin' was associated with the quantity of calcium carbonate and related medication taken for the treatment of hyperphosphatemia. Supplemental dosage is not required for patients undergoing hemodialysis, since the distribution of temafloxacin in tissue is extensive and the recoveries from 4-h dialysis sessions accounted for less than 10% of the drug present at the start of the dialysis.Temafloxacin (Abbott-63004) is a new quinolone antibacterial agent with marked activity against gram-positive and gram-negative bacteria. Its activity against gram-negative organisms is similar to those of ciprofloxacin and ofloxacin (1), while its activity against gram-positive, anaerobic, and intracellular organisms rivals or exceeds those of ciprofloxacin and ofloxacin (15,23,27). Clinical studies in humans have demonstrated its efficacy in the treatment of various infections, including urinary tract infections (4), respiratory tract infections (5), and skin and soft tissue infections (20).With the exception of quinolones with high octanol/water partition coefficients such as pefloxacin, which are filtered and efficiently reabsorbed by the kidneys and which are therefore cleared predominantly by metabolic processes, the major route of elimination of most fluoroquinolones is renal excretion. As a result, the total apparent clearances (CLT/F, where F represents the fraction of dose absorbed) of these agents decrease with declining renal function. Studies of the kinetics of the relatively polar quinolones norfloxacin (17), ciprofloxacin (2, 6), and enoxacin (3, 21) have typically found two-to threefold reductions in CLT/F in patients with chronic renal failure, resulting in recommendations for a 50% dosage reduction. Relatively high intersubject variability has been observed with some of these agents in anuric pa...

Garenoxacin pharmacokinetics in subjects with renal impairment

“…These include fluoroquinolones that predominantly use renal elimination pathways (e.g., levofloxacin, ciprofloxacin, temafloxacin, and clinafloxacin) and those that favor non-renal elimination pathways (e.g., sparfloxacin eliminated via glucuronide metabolism, biliary excretion, and possibly intestinal secretion) [18][19][20][21][22] . Our results are similar to those reported for moxifloxacin in that no dosage adjustment is indicated in subjects with renal impairment.…”

Pharmacokinetic Role of P-Glycoprotein in Oral Bioavailability and Intestinal Secretion of Grepafloxacin in Vivo

“…Some quinolone antibacterial drugs such as ciprofloxacin and temafloxacin are known to be eliminated from the gastrointestinal tract in humans (Granneman et al, 1991;Sör-gel et al, 1989bSör-gel et al, , 1991. We previously reported that gastrointestinal secretion of grepafloxacin and levofloxacin was mediated by P-glycoprotein and another transport system distinct from organic cation and anion transporters in Caco-2 cells (Yamaguchi et al, 2000).…”

“…The intestine has been shown to play an important role as an elimination tissue or absorption barrier. It was reported that at least 10.6% of intravenously administered ciprofloxacin was eliminated by intestinal secretion (Sörgel et al, 1989b(Sörgel et al, , 1991, and temafloxacin showed significant gastrointestinal secretion into feces in humans (Granneman et al, 1991). Dautrey et al (1999) suggested that the pharmacokinetics of ciprofloxacin involved one or more active secretory mechanisms in the intestine in rats.…”

Killing Kinetics of Four Quinolones against Gram-Positive Cocci

“…The new fluoroquinolones sparfloxacin and temafloxacin show greater lethal rates than nor floxacin and ciprofloxacin, though killing ki netics are slower and not as great as those de tected in the case of gram-negative bacteria [19,20,22,23] (however it must be stressed here that temafloxacin has been withdrawn from clinical use after the experimental part of this work was performed). On the other hand, the paradoxical effect shown by quinolones has no relevance in systemic infections, as clinically achievable quinolone levels in se rum and tissues are currently within the OBC [17,18,[24][25][26], but they could have implica tions in the treatment of urinary-tract infec tions because quinolone concentrations in urine are higher than their respective OBCs [7,14,20,23,27], and are thus less effective at killing bacteria. Tenney et al [28], by repeated exposure of bacteria to subinhibitory concen trations of ciprofloxacin and norfloxacin, rap idly produced isolates with MICs up to 512-fold higher than the original strain, so, high drug concentrations, being less bactericidal, may behave similarly to subinhibitory concen trations and could produce isolates with higher MICs.…”