Drug Interactions with Clinafloxacin

Abstract

Many fluoroquinolone antibiotics are inhibitors of cytochrome P450 enzyme systems and may produce potentially important drug interactions when administered with other drugs. Studies were conducted to determine the effect of clinafloxacin on the pharmacokinetics of theophylline, caffeine, warfarin, and phenytoin, as well as the effect of phenytoin on the pharmacokinetics of clinafloxacin. Concomitant administration of 200 or 400 mg of clinafloxacin reduces mean theophylline clearance by approximately 50 and 70%, respectively, and reduces mean caffeine clearance by 84%. (R)-Warfarin concentrations in plasma during clinafloxacin administration are 32% higher and (S)-warfarin concentrations do not change during clinafloxacin treatment. An observed late pharmacodynamic effect was most likely due to gut flora changes. Phenytoin has no effect on clinafloxacin pharmacokinetics, while phenytoin clearance is 15% lower during clinafloxacin administration.Clinafloxacin is a potent quinolone antibacterial with a broad range of activity that is of potential clinical importance in the management of serious infections, including those caused by many bacteria resistant to a wide variety of other antibiotics (5,6,7,11,16,27). It has been studied primarily in adults hospitalized for the treatment of serious and potentially life-threatening infections, including nosocomial pneumonia, community-acquired pneumonia, febrile neutropenia, complicated intra-abdominal infections, complicated skin and soft tissue infections, endocarditis, and acute gynecologic infections.Clinafloxacin pharmacokinetics in healthy subjects have been reported previously (31). Following administration of 200-and 400-mg twice-daily intravenous doses, the mean values for total body clearance and volume of distribution are approximately 320 ml/min and 156 liters, respectively, and the mean terminal elimination half-life (t 1/2 ) is approximately 5.8 h. Clinafloxacin is approximately 50% bound to plasma protein, independent of concentration. Approximately 50 to 70% of a clinafloxacin dose is excreted unchanged in urine, indicating that renal clearance is the primary route of elimination. Clinafloxacin clearance is correlated to degree of renal function as measured by creatinine clearance (CL CR ). Based on the relationship between clinafloxacin clearance and CL CR , patients with CL CR values of Ͻ40 ml/min should have their daily clinafloxacin dose halved (34).The ability of clinafloxacin to inhibit seven major cytochrome P450 enzymes, CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4, was investigated using isoform-selective marker substrates and human liver microsomal preparations (T. F. Woolf and W. F. Trager, personal communication). Clinafloxacin was most effective in inhibiting CYP1A2 with nearly 50% inhibition observed at the 5 M concentration. CYP2A6, CYP2E1, and CYP3A4 were not inhibited even at a clinafloxacin concentration of 125 M. CYP2C19 was 15 and 75% inhibited at 5 and 125 M clinafloxacin concentrations, respectively. A weaker interaction...

Expansion of a PBPK model to predict disposition in pregnant women of drugs cleared via multiple CYP enzymes, including CYP2B6, CYP2C9 and CYP2C19

“…PHT dose used during pregnancy was increased (453 mg day −1 ) compared with post-partum (333 mg day −1 ).We selected Tomson et al's study as the model training set because of its superior study design: a large sample size (n = 29), fixed PHT dose, monotherapy, and trough sampling. Interestingly, following the same fixed dose of 300 mg day −1 , PHT mean Cpre-dose during the post-partum period (10.27 ± 5.25 μg l −1 ) reported in this study was 41% higher than the reported mean Cpre-dose in the nonpregnant, healthy population (∼7.3 μg l −1 , n = 31) [56][57][58]. The difference in Cpre-dose between epileptic patients and healthy subjects may be reflective of disease-related factors on PHT disposition.…”

“…(B) The grey bars represent predicted percent decrease in PHT trough concentration (Cpre-dose) and the white bars represent observed mean percent decrease in PHT Cpre-dose in pregnant women during pregnancy (T1, T2 and T3) vs. post-partum [16]. □, Lim et al [56]; ◊, Purkins et al [58]; •, Randinitis et al [57] …”

“…PK parameters in non-pregnant subjects Cmin,ss (ng ml −1 ) 7.6 ± 1.5 6.3 0.83 Cpre-dose (ng ml −1 ) 7.3 ± 1.1 6.3 0.87 *Mean ± SD of reported values in non-pregnant, healthy subjects (n = 31 total) receiving chronic administration of 300 mg day −1 [56][57][58]. Cmin,ss refers to the last plasma sample taken during the dosing interval and Cpre-dose refers to the plasma trough concentration before the daily dose.…”

“…(A) Predicted (solid line) and observed (symbols) [56][57][58] PHT plasma concentration-time profiles following chronic dosing of 300 mg day −1 (orally) in non-pregnant healthy subjects. (B) The grey bars represent predicted percent decrease in PHT trough concentration (Cpre-dose) and the white bars represent observed mean percent decrease in PHT Cpre-dose in pregnant women during pregnancy (T1, T2 and T3) vs. post-partum [16].…”

Interaction between Warfarin and Linezolid in Patients with Left Ventricular Assist System in Japan

“…S-warfarin is primarily metabolized by cytochrome P-450 (CYP) 2C9 isoenzyme, whereas R-warfarin is metabolized by CYP1A2 and 3A4 (20,21). However, several animal and human studies revealed that linezolid is not detectably metabolized by CYP (22), and it did not induce or inhibit the activities of clinically significant human CYP isoforms, including CYP1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 (20,23). In addition, linezolid metabolism is by non-enzymatic oxidation, and therefore, drug interactions based on CYP inhibition or induction are not expected.…”