RESUMEN
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. CL(CR) + 77 and CL(R) = 1.74. 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.
Asunto(s)
Antiinfecciosos/farmacocinética , Fluoroquinolonas , Enfermedades Renales/metabolismo , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Antiinfecciosos/efectos adversos , Antiinfecciosos/sangre , Femenino , Humanos , Riñón/metabolismo , Pruebas de Función Renal , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Diálisis RenalRESUMEN
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.
Asunto(s)
Antiinfecciosos/farmacología , Cafeína/farmacocinética , Fluoroquinolonas , Fenitoína/farmacocinética , Teofilina/farmacocinética , Warfarina/farmacocinética , Adulto , Anciano , Antiinfecciosos/sangre , Antiinfecciosos/farmacocinética , Anticonvulsivantes/sangre , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/farmacología , Cafeína/sangre , Inhibidores Enzimáticos del Citocromo P-450 , Interacciones Farmacológicas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fenitoína/sangre , Fenitoína/farmacología , Teofilina/sangre , Warfarina/sangreRESUMEN
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.
Asunto(s)
Antiinfecciosos/efectos adversos , Antiinfecciosos/farmacocinética , Fluoroquinolonas , Quinolonas/efectos adversos , Quinolonas/farmacocinética , Adulto , Antiinfecciosos/sangre , Relación Dosis-Respuesta a Droga , Estudios de Evaluación como Asunto , Humanos , Masculino , Quinolonas/sangreRESUMEN
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.