Summary:Purpose: Pregabalin (PGB) is an α 2 -δ ligand with demonstrated efficacy in epilepsy, neuropathic pain, and anxiety disorders. PGB is highly efficacious as adjunctive therapy in patients with refractory partial seizures.Methods: Given its efficacy as adjunctive therapy, the potential for interaction of PGB with other antiepileptic drugs (AEDs) was assessed in patients with partial epilepsy in open-label, multipledose studies. Patients received PGB, 600 mg/day (200 mg q8h) for 7 days, in combination with their individualized maintenance monotherapy with valproate (VPA), phenytoin (PHT), lamotrigine (LTG), or carbamazepine (CBZ).Results: Trough steady-state concentrations of CBZ (and its epoxide metabolite), PHT, LTG, and VPA were unaffected by concomitant PGB administration. Likewise, PGB steady-state pharmacokinetic parameter values were similar among patients receiving CBZ, PHT, LTG, or VPA and, in general, were similar to those observed historically in healthy subjects receiving PGB alone. The PGB-AED combinations were generally well tolerated. PGB may be added to VPA, LTG, PHT, or CBZ therapy without concern for pharmacokinetic drug-drug interactions.

Atorvastatin is a new 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor that reduces plasma cholesterol by inhibiting cholesterol synthesis and increasing cellular uptake of low density lipoproteins. The effects of age and gender on the pharmacokinetics of atorvastatin after administration of single 20-mg tablets of atorvastatin were studied in 16 young and 16 elderly volunteers (8 men and 8 women in each age group). Plasma equivalent concentrations of atorvastatin were quantitated by a validated enzyme inhibition bioassay. Atorvastatin was well tolerated by the participants. The equivalent maximum concentration (Cmax) of atorvastatin was 42.5% higher in elderly participants (age, 66-92 years) than in young participants (age, 19-35 years) and 17.6% higher in women than in men. In addition, mean area under the concentration-time curve (AUC0-infinity) and half-life (t1/2) were 27.3% greater and 36.2% longer, respectively, in elderly adults than in young adults and 11.3% lower and 19.9% shorter, respectively, in women than in men. Because the primary site of action for HMG-CoA reductase inhibitors is the liver and atorvastatin is subject to extensive first-pass hepatic metabolism, it is unclear whether these age- and gender-related differences in the pharmacokinetics of atorvastatin will be clinically important. Results of subsequent safety and efficacy trials should help clarify the clinical significance of these pharmacokinetic differences.

The single-dose tolerance and pharmacokinetics of clinafloxacin, a new fluoroquinolone antibacterial agent, were evaluated in healthy volunteers. Single oral doses of 25, 50, 100, and 200 mg were well tolerated. Adverse events after placebo and clinafloxacin were similar, with mild drowsiness, dizziness, headache, and rash being reported most frequently. The frequency and intensity of side-effects did not increase with dose. Clinafloxacin was rapidly absorbed, with Cmax occurring at approximately 40 min postdose. Plasma concentrations increased proportionately and, following 100 or 200 mg doses, remained above MIC90s required for most nosocomial pathogens for at least 12 h. Clinafloxacin elimination half-life averaged 5.2 h and renal clearance was approximately 200 mL/min. About 50% of the administered dose was excreted unchanged in the urine.

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...

As the primary route for elimination of clinafloxacin is renal clearance (CL R ) of unchanged drug, studies were conducted to determine the pharmacokinetic profile of clinafloxacin following administration to young and elderly subjects, subjects with various degrees of renal function, and subjects requiring dialysis. These were open-label studies in which subjects received single oral clinafloxacin doses. Sixteen young subjects (18 to 35 years old) and 16 elderly subjects (>65 years old) were enrolled in a study comparing pharmacokinetic profiles of clinafloxacin in young and elderly subjects. Twenty subjects having various degrees of renal function were enrolled into one of three groups based on degree of renal function as measured by creatinine clearance (CL CR ). Twelve subjects with severe renal impairment requiring dialysis enrolled in a third study. Clinafloxacin was generally well tolerated by all subjects. Clinafloxacin pharmacokinetic profiles in elderly subjects were dependent only on age-related decreases in renal function. Clinafloxacin maximum concentrations in plasma, areas under the concentration-time curves, and terminal elimination half-life values increased with decreasing CL CR values. Total apparent body clearance of clinafloxacin from the plasma after oral administration (CL oral ) and CL R were dependent on CL CR according to the following relationships: CL oral ‫؍‬ 2.3 ⅐ CL CR ؉ 77 and CL R ‫؍‬ 1.74 ⅐ CL CR . Hemodialysis had no significant effect on clinafloxacin clearance. Based on the relationship between CL CR and clinafloxacin CL oral and CL R values, the clinafloxacin dose should be halved in patients having a CL CR of <40 ml/min. Further dose adjustment is not warranted in patients requiring hemodialysis.Clinafloxacin is an extremely potent member of the fluoroquinolone class of synthetic antimicrobial agents. Compared with available quinolone antibiotics, clinafloxacin usually requires lower drug concentrations for bacterial inhibition and is active against a broader spectrum of organisms. It is effective against many multiple-drug-resistant organisms, including quinolone-resistant strains (5,6,7,10,12,16). Clinafloxacin has been studied primarily in hospitalized adults 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 (16). It became apparent from initial clinical studies that twice-daily 100-to 400-mg doses were required to maintain concentrations in plasma within the effective range for most infections.Single and multiple-dose pharmacokinetics of clinafloxacin have been reported previously (2, 17). Following administration of 200-and 400-mg twice-daily intravenous doses, the mean total body clearance and volume of distribution values are approximately 320 ml/min and 156 liters, respectively, and the mean terminal elimination half-life (t 1/2 ) ...