RESUMO
BACKGROUND: Metastatic colorectal cancer (mCRC) is commonly treated with 5-fluorouracil, folinic acid, and oxaliplatin or irinotecan. The multitargeted kinase inhibitor, regorafenib, was combined with chemotherapy as first- or second-line treatment of mCRC to assess safety and pharmacokinetics (primary objectives) and tumor response (secondary objective). PATIENTS AND METHODS: Forty-five patients were treated every 2 weeks with 5-fluorouracil 400 mg/m(2) bolus then 2400 mg/m(2) over 46 h, folinic acid 400 mg/m(2), and either oxaliplatin 85 mg/m(2) or irinotecan 180 mg/m(2). On days 4-10, patients received regorafenib 160 mg orally once daily. RESULTS: The median duration of treatment was 108 (range 2-345 days). Treatment was stopped for adverse events or death (17 patients), disease progression (11 patients), and consent withdrawal or investigator decision (11 patients). Six patients remained on regorafenib at data cutoff (two without chemotherapy). Drug-related adverse events occurred in 44 patients [grade ≥ 3 in 32 patients: mostly neutropenia (17 patients) and leukopenia, hand-foot skin reaction, and hypophosphatemia (four patients each)]. Thirty-three patients achieved disease control (partial response or stable disease) for a median of 126 (range 42-281 days). CONCLUSION: Regorafenib had acceptable tolerability in combination with chemotherapy, with increased exposure of irinotecan and SN-38 but no significant effect on 5-fluorouracil or oxaliplatin pharmacokinetics.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Camptotecina/farmacocinética , Neoplasias Colorretais/metabolismo , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/farmacocinética , Humanos , Leucovorina/administração & dosagem , Leucovorina/farmacocinética , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/farmacocinética , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/farmacocinética , Piridinas/administração & dosagem , Piridinas/farmacocinética , Resultado do Tratamento , Adulto JovemRESUMO
Microelectromechanical systems (MEMS) incorporating active piezoelectric layers offer integrated actuation, sensing, and transduction. The broad implementation of such active MEMS has long been constrained by the inability to integrate materials with giant piezoelectric response, such as Pb(Mg(1/3)Nb(2/3))O(3)-PbTiO(3) (PMN-PT). We synthesized high-quality PMN-PT epitaxial thin films on vicinal (001) Si wafers with the use of an epitaxial (001) SrTiO(3) template layer with superior piezoelectric coefficients (e(31,f) = -27 ± 3 coulombs per square meter) and figures of merit for piezoelectric energy-harvesting systems. We have incorporated these heterostructures into microcantilevers that are actuated with extremely low drive voltage due to thin-film piezoelectric properties that rival bulk PMN-PT single crystals. These epitaxial heterostructures exhibit very large electromechanical coupling for ultrasound medical imaging, microfluidic control, mechanical sensing, and energy harvesting.
RESUMO
OBJECTIVE: Infection is a potential complication of transrectal needle biopsy of the prostate (TRNBP), and antibiotic prophylaxis with a fluoroquinolone is commonly used. The objective of this study was to demonstrate penetration of ciprofloxacin into prostate tissue after administration of a ciprofloxacin 1000 mg extended-release formulation prior to TRNBP. SUBJECTS AND METHODS: The study enrolled 13 men aged 45-78 years scheduled for TRNBP. They received a single, 1000 mg, extended-release tablet of ciprofloxacin at about 3 hours or at about 1 hour prior to the scheduled biopsy time. Blood and urine samples were taken just prior to the biopsy procedure, and prostate tissue samples after all needle biopsy specimens required for diagnostic purposes had been obtained, for determination of ciprofloxacin concentrations. Population data from a previous crossover study of 25 healthy male volunteers was used to model the prostate tissue concentrations for extended-release ciprofloxacin up to 24 hours after administration. These data were used to predict the normal range data for the current study. RESULTS: The mean sampling time in the 1-hour group was 1.47 hours (range, 1.25-1.75 hours) and in the 3-hour group was 3.27 hours (range, 3.03-3.42 hours) after ciprofloxacin dosing. The mean concentrations of ciprofloxacin at 1 hour and 3 hours were 4.75 +/- 1.33 microg/g and 4.29 +/- 1.61 microg/g in prostate tissue, 2.11 +/- 1.00 mg/L and 3.08 +/- 1.44 mg/L in serum, and 126.2 +/- 141.7 mg/L and 803.3 +/- 596.3 mg/L in urine. The mean prostate : serum ciprofloxacin concentration ratio was 1.9 : 1 for the 1-hour group and 1.6 : 1 for the 3-hour group. The measured concentrations of ciprofloxacin in prostate tissue fell within the range modelled from the pharmacokinetic data from the 25 healthy, male subjects. No drug-related adverse events were reported. CONCLUSIONS: Extended-release ciprofloxacin is well tolerated and penetrates effectively into prostate tissue. Tissue levels of ciprofloxacin are similar whether the extended-release ciprofloxacin is administered 1 hour or 3 hours before TRNBP, indicating that tissue levels are maintained for several hours after administration. PK modelling as used in this trial is suitable to prospectively outline clinical designs. Further investigation of single-dose, extended-release ciprofloxacin as prophylaxis for TRNBP is warranted.
Assuntos
Antibacterianos/farmacocinética , Ciprofloxacina/farmacocinética , Próstata/metabolismo , Idoso , Antibacterianos/administração & dosagem , Antibioticoprofilaxia , Biópsia por Agulha Fina , Ciprofloxacina/administração & dosagem , Preparações de Ação Retardada , Humanos , Masculino , Pessoa de Meia-Idade , Distribuição TecidualRESUMO
OBJECTIVE: Moxifloxacin is a new 8-methoxyfluoroquinolone with a broad antibacterial spectrum. The purpose of the present study was to determine the effects of age and gender on pharmacokinetics, surrogate pharmacodynamics, safety and tolerability of a single dose of moxifloxacin. DESIGN: This was a randomised, double-blind, placebo-controlled, parallel-group single dose trial in young and elderly healthy volunteers. PATIENTS AND PARTICIPANTS: The study included 36 volunteers in 3 age and gender groups: young males (mean age 32 years), elderly males (mean age 74 years), and elderly females (mean age 74 years). METHODS: Participants received either a single 200mg oral dose of moxifloxacin (8/group) or placebo (4/group). Blood samples for moxifloxacin pharmacokinetics were obtained before and up to 48 hours after administration. Urine samples were collected for pharmacokinetics, and volunteers were monitored for clinical adverse events and laboratory abnormalities. RESULTS: Maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) were higher in elderly females than in elderly males; however, when normalised for bodyweight, these pharmacokinetic parameters were not significantly different between the groups. Moreover, the plasma pharmacokinetics in elderly males were not meaningfully different from those in young males. Elimination half-life averaged 12 to 13 hours for the 3 groups. Surrogate pharmacodynamic measures were derived using AUC/MIC (minimal inhibitory concentration) and Cmax/MIC ratios. These assessments indicated that, given the linear pharmacokinetics of moxifloxacin previously demonstrated, a dose of 400mg would produce mean Cmax/MIC values in the different subgroups ranging from 10.4 to 15.4 for an MIC of 0.25, and 20.8 to 30.8 for an MIC of 0.125. The corresponding ranges of projected AUC/MIC ratios would be 112 to 158 for an MIC of 0.25, and 224 to 314 for an MIC of 0.125. The accepted target values of AUC/MIC and Cmax/MIC for quinolones are 125 and 10, respectively. There were no serious adverse events or differences in adverse event profiles between the groups. CONCLUSIONS: Moxifloxacin does not exhibit age- or gender-dependent pharmacokinetics. Oral doses of 200 to 400mg yield effective antibacterial concentrations on the first day of administration.
Assuntos
Anti-Infecciosos/farmacocinética , Compostos Aza , Fluoroquinolonas , Quinolinas , Administração Oral , Adulto , Distribuição por Idade , Idoso , Anti-Infecciosos/efeitos adversos , Anti-Infecciosos/sangue , Anti-Infecciosos/urina , Área Sob a Curva , Cromatografia Líquida de Alta Pressão , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Moxifloxacina , Distribuição por SexoRESUMO
OBJECTIVE: To investigate the effects of concomitant food intake on the pharmacokinetics of a single oral dose of moxifloxacin 400mg. DESIGN: This was a randomised 2-way nonblinded crossover study in healthy volunteers. PARTICIPANTS: 18 young, healthy, male volunteers were enrolled in the study, of whom 16 were considered evaluable for the pharmacokinetic analysis. METHODS: Moxifloxacin was given under 2 conditions separated by a 1-week washout period: fasted and fed (immediately after a standardised high fat breakfast). Concentrations of moxifloxacin in serum were determined by a validated high performance liquid chromatography procedure with fluorescence detection. OUTCOME MEASURES: Pharmacokinetic parameters such as maximum concentration (Cmax), time to reach Cmax (tmax), area under the concentration-time curve from zero to 48 hours (AUC48h), AUC from zero extrapolated to infinity (AUCinfinity) and elimination half-life (t1/2z) were estimated using noncompartmental methods. The natural logarithms of AUC and Cmax were analysed using analysis of variance. Bioequivalence of the 2 treatments was determined at the 5% significance level with the two 1-sided tests procedure and limits of 80% and 125% for AUC and 70 to 143% for Cmax. RESULTS: The mean serum concentration versus time profiles were similar between the 2 treatments. The geometric mean AUCinfinity values under fed and fasted conditions were almost identical, 37.7 versus 38.5 mg/L x h, respectively [90% confidence interval (CI) of the ratio of fed versus fasted based on geometric least-square means was 0.95, 1.00]. Geometric mean Cmax values were slightly reduced by food, 2.5 versus 2.8 mg/L, respectively (90% CI of fed versus fasted based on geometric least-square means was 0.78, 0.98). The absorption of moxifloxacin seems to be mildly delayed because of the effect of food; the median tmax values were 1.0 and 2.5 hours for fasted and fed conditions, respectively. The single oral dose of moxifloxacin 400mg was well tolerated when taken with and without food.
Assuntos
Anti-Infecciosos/farmacocinética , Compostos Aza , Fluoroquinolonas , Alimentos , Quinolinas , Administração Oral , Adulto , Análise de Variância , Anti-Infecciosos/sangue , Área Sob a Curva , Estudos Cross-Over , Meia-Vida , Humanos , Masculino , MoxifloxacinaRESUMO
The pharmacokinetics, safety, and tolerability of cerivastatin, a synthetic HMG-CoA reductase inhibitor were studied in 49 healthy volunteers. In this double-blind, parallel group, multiple-dose study, volunteers were randomized as age-matched, male-female pairs and stratified into younger (18-65 years, premenopausal females) or older (65-85 years, postmenopausal females) groups. Thirty-two (16 female, 16 male) subjects received 0.2 mg cerivastatin daily for 7 days; 17 received placebo. Between all males and females, no differences in cerivastatin pharmacokinetics were observed. The AUCnorm in older females was 21% higher than in older males, while the AUCnorm in younger females was 26% lower than in younger males. The Cmax in older females was 30% higher than in age-matched males or younger males and females. All other pharmacokinetic parameters, including half-life, tmax, accumulation ratios, and steady state plasma levels were similar in all treatment groups. The most common adverse events, including headache (4), dyspepsia (4), and rash (4), were equally distributed between groups. Treatment-emergent elevations (< 2 x ULN) in creatine kinase occurred in one subject. Transaminase elevations occurred in nine subjects, most were less than 3 x ULN, and were equally distributed between groups. In conclusion, cerivastatin was well tolerated. The minor differences in the pharmacokinetics of cerivastatin 0.2 mg between genders does not require modification of dosage.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Piridinas/farmacocinética , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Área Sob a Curva , Cromatografia Líquida de Alta Pressão , Método Duplo-Cego , Tolerância a Medicamentos , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/sangue , Masculino , Pessoa de Meia-Idade , Piridinas/efeitos adversos , Piridinas/sangue , Fatores SexuaisRESUMO
BACKGROUND: 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are metabolized by distinct pathways that may alter the extent of drug-drug interactions. Cerivastatin is metabolized by cytochrome P450 (CYP)3A4 and CYP2C8. Atorvastatin is metabolized solely by CYP3A4, and pravastatin metabolism is not well defined. Coadministration of higher doses of these statins with CYP3A4 inhibitors has the potential for eliciting adverse drug-drug interactions. OBJECTIVE: To determine the comparative effect of itraconazole, a potent CYP3A4 inhibitor, on the pharmacokinetics of cerivastatin, atorvastatin, and pravastatin. METHODS: In this single-site, randomized, three-way crossover, open-labeled study, healthy subjects (n = 18) received single doses of cerivastatin 0.8 mg, atorvastatin 20 mg, or pravastatin 40 mg without and with itraconazole 200 mg. Pharmacokinetic parameters [AUC(0-infinity), AUC(0-tn), peak concentration (Cmax), time to reach Cmax (tmax), and half-life (t1/2)] were determined for parent statins and major metabolites. RESULTS: Concomitant cerivastatin/itraconazole treatment produced small elevations in the cerivastatin AUC(0-infinity), Cmax, and t1/2 (27%, 25%, and 19%, respectively; P < .05 versus cerivastatin alone). Itraconazole coadministration produced similar changes in pravastatin pharmacokinetics [AUC elevated 51% (P < .05 versus pravastatin alone), 24% (Cmax), and 23% (t1/2), respectively]. However, itraconazole dramatically increased atorvastatin AUC (150%), Cmax (38%), and t1/2 (30%) (P < .05). The elevation in atorvastatin AUC was significantly greater than that of cerivastatin (P < .005) or pravastatin (P < .005). CONCLUSION: Itraconazole markedly elevated atorvastatin plasma levels (2.5-fold) after 20 mg dosing, suggesting that concomitant itraconazole/atorvastatin therapy be carefully considered. Itraconazole produced modest elevations in the plasma levels of cerivastatin 0.8 mg or pravastatin 40 mg (1.3-fold and 1.5-fold, respectively), indicating that combination treatment with itraconazole with cerivastatin or pravastatin may be preferable.
Assuntos
Antifúngicos/farmacologia , Ácidos Heptanoicos/farmacocinética , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Itraconazol/farmacologia , Pravastatina/farmacocinética , Piridinas/farmacocinética , Pirróis/farmacocinética , Adulto , Anticolesterolemiantes/farmacocinética , Antifúngicos/administração & dosagem , Área Sob a Curva , Atorvastatina , Estudos Cross-Over , Feminino , Ácidos Heptanoicos/administração & dosagem , Ácidos Heptanoicos/sangue , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/sangue , Itraconazol/administração & dosagem , Masculino , Pravastatina/administração & dosagem , Pravastatina/sangue , Piridinas/administração & dosagem , Piridinas/sangue , Pirróis/administração & dosagem , Pirróis/sangue , Valores de Referência , Fatores de TempoRESUMO
OBJECTIVE: The influence of impaired renal function on the pharmacokinetics of single and multiple doses of cerivastatin was evaluated in this nonrandomized, non-blinded, 7-day, multiple-dose study. METHODS: Thirty-five adults between the ages of 21 years and 75 years with normal renal function (CL(CR) >90 ml/min/1.73 m2, n = 9), or patients with either mild (CL(CR) 61 ml/min/1.73 m2 to < or =90 ml/min/1.73 m2, n = 9), moderate (CL(CR) 30 ml/min/1.73 m2 to < or =60 ml/ min/1.73 m2, n = 8), or severe (CL(CR) <30 ml/min/ 1.73 m2, but not on dialysis, n = 9) renal impairment were given cerivastatin 0.3 mg daily each evening for 7 days. The steady-state pharmacokinetics of cerivastatin, including the area under the concentration-time curve (AUC)0-24, peak plasma concentration (Cmax), time to reach Cmax (tmax) and elimination half-life (t1/2), were determined on day 1 and day 7. The logarithm of the pharmacokinetic variables was analyzed using analysis of variance (ANOVA). Safety assessments included physical examination, fundoscopy, vital signs, electrocardiogram (ECG), adverse events, and laboratory safety indices. RESULTS: The day-1 AUC in patients with mild renal impairment was similar to that of patients with normal function (19.6 microg/h/l vs 19.2 microg/h/l, respectively). However, the AUC for cerivastatin patients with moderate or severe renal impairment was 40-60% higher (30.8 microg/h/l and 29.0 microg/h/l, respectively). Cmax values for patients with normal, mild, moderate, and severe renal impairment were 3.3, 3.4, 4.6, and 5.2 microg/l, respectively. This modest increase in plasma cerivastatin levels is nearly equivalent to a 0.4-mg daily dose, which has been recently approved in the United States. The mean t1/2 of cerivastatin was less than 4.5 h in all patients, indicating that renal dysfunction did not promote cerivastatin accumulation. This observation was confirmed by the finding that the cerivastatin plasma levels on day 1 and day 7 were similar in all patient groups. Furthermore, the mean AUC and Cmax values for both demethylated and hydroxylated cerivastatin were similar in the patients with the most severe renal dysfunction to the corresponding values in healthy subjects. Cerivastatin was well tolerated in all patients irrespective of renal function. Adverse events were observed in 37% of the subjects; nearly all were mild and generally of short duration, and most resolved without intervention. Incidence of adverse events was similar across all three renal groups and the control group. There were no clinically significant laboratory changes other than those consistent with renal disease. CONCLUSION: This study demonstrates that dosage adjustment of the daily 0.3-mg cerivastatin dose in patients with significant renal impairment is likely unnecessary.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Piridinas/farmacocinética , Insuficiência Renal/metabolismo , Adulto , Idoso , Análise de Variância , Área Sob a Curva , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/sangue , Masculino , Pessoa de Meia-Idade , Piridinas/administração & dosagem , Piridinas/sangue , Análise de Regressão , Insuficiência Renal/tratamento farmacológicoRESUMO
The biopharmaceutical properties of cerivastatin were evaluated in a series of worldwide clinico-pharmacological studies. Young healthy males aged 18-45 years were randomized to receive 0.05-0.8 mg cerivastatin orally, given either as single or multiple once-daily doses under fed or fasting conditions in the morning, with evening meal or at bedtime. Following administration, cerivastatin was rapidly and almost completely absorbed into the gastrointestinal tract (> 98%), with maximum plasma concentrations (Cmax) reached at 2-3 h post dose. The plasma concentration/time profile of the tablet is similar to an aqueous oral solution (relative bioavailability is 100%). The dose-proportionality of cerivastatin (0.05-0.8 mg) in area under the curve and Cmax showed low intra- and interindividual variability. The effect of food (single-dose studies testing administration of cerivastatin with a high-fat meal and clinical investigations in patients) or time of administration (single- and multiple-dose once-daily/twice-daily studies) had no clinically relevant effects on the pharmacokinetics of cerivastatin. Marketed tablet strengths and drug formulations from different sources were found to be bioequivalent. Cerivastatin is a noncomplicated drug with respect to its biopharmaceutical profile and bioavailability.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Piridinas/administração & dosagem , Piridinas/farmacocinética , Administração Oral , Adolescente , Adulto , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Masculino , Pessoa de Meia-Idade , Piridinas/efeitos adversosRESUMO
The pharmacokinetics, safety, and tolerability of oral moxifloxacin, a new 8-methoxy quinolone, were assessed in a randomized, double-blind, placebo-controlled study in which healthy male and female volunteers received either 400 mg of moxifloxacin once daily (n = 10) or a placebo once daily (n = 5) for 10 days. Plasma moxifloxacin concentrations on days 1 and 10 were measured by high-performance liquid chromatography and fluorometric detection. Standard pharmacokinetic parameters were estimated by noncompartmental methods. Natural logarithmic estimates for each pharmacokinetic variable of each subject were analyzed by a two-way analysis of variance. Hematology, blood chemistry, vital signs, and adverse events were monitored, and electrocardiograms (ECG) were performed. Plasma moxifloxacin concentrations of predicted therapeutic relevance were achieved in this study. For day 1, the mean maximum concentration of drug in serum (C(max)) and the area under the concentration-time curve from 0 to 24 h (AUC(0-24)) were 3. 4 mg/liter and 30.2 mg. h/liter, respectively. Corresponding means on day 10 were 4.5 mg/liter and 48 mg. h/liter, respectively. On day 10, the mean elimination half-life was approximately 12 h. Plasma moxifloxacin concentrations exceeded the MIC for Streptococcus pneumoniae throughout the 24-h dosing period. The day 1 and day 10 mean AUC/MIC ratios were 121 and 192, respectively, and the mean C(max)/MIC ratios were 13 and 18, respectively. Moxifloxacin was well tolerated; no clinically relevant changes in the standard laboratory tests, vital signs, or ECG were observed. Pharmacokinetic parameters demonstrated linearity, and estimates of pharmacokinetic/pharmacodynamic ratios (AUC/MIC and C(max)/MIC) indicate that the regimen of 400-mg once daily should be effective for treating a variety of infections. Moxifloxacin was found to be safe and well tolerated in healthy volunteers when it was given as a single daily 400-mg dose for 10 days.
Assuntos
Anti-Infecciosos/farmacocinética , Compostos Aza , Fluoroquinolonas , Quinolinas , Adolescente , Adulto , Anti-Infecciosos/efeitos adversos , Área Sob a Curva , Método Duplo-Cego , Feminino , Meia-Vida , Humanos , Masculino , Pessoa de Meia-Idade , Moxifloxacina , EstereoisomerismoRESUMO
The potential mutual interaction between cerivastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, and digoxin was assessed in this nonmasked, nonrandomized, multiple-dose study. The effect of cerivastatin 0.2 mg on mean plasma digoxin levels and the effect of digoxin on the single-dose pharmacokinetics of cerivastatin were assessed in 20 healthy normocholesterolemic men between 18 and 45 years of age weighing 140 to 200 lbs (63.3 to 90.0 kg). Subjects were given a single dose of cerivastatin 0.2 mg. After a 2-day washout period, subjects were given a loading dose of digoxin 0.5 mg for 3 days followed by 0.25 mg daily for 5 additional days (period 1-digoxin alone). Concurrent dosing with cerivastatin 0.2 mg continued for 14 days (period 2-digoxin and cerivastatin), followed by an 8-day course of digoxin-only administration and an optional 6-day extension of digoxin-only treatment for a total of 14 days (period 3). Safety was assessed through physical examination, electrocardiography, laboratory tests, and ophthalmologic examination. Ratio analyses of mean digoxin plasma trough levels, 24-hour urinary digoxin levels, and digoxin clearance with and without concurrent cerivastatin dosing also were carried out. In addition, single-dose pharmacokinetic variables for cerivastatin, including area under the curve (AUC(0-24)), peak concentration (C(max)), time to peak concentration (T(max)), and elimination half-life (t1/2), were examined with and without concurrent digoxin dosing. Eleven of the 20 subjects completed the entire study. Seven subjects discontinued the study because of treatment-emergent adverse events or laboratory abnormalities that were mostly unrelated to cerivastatin, and 2 subjects were discontinued because of protocol violations. Treatment-emergent adverse events developed in 12 subjects receiving cerivastatin; 11 of these subjects were receiving digoxin concurrently. Six adverse events that led to discontinuation of treatment were unrelated to cerivastatin but were related to digoxin or to a preexisting condition. The most commonly reported event was headache, which occurred with equal frequency compared with placebo groups in large cerivastatin clinical trials. Other events were mild or moderate and resolved without intervention. Mild and transient elevations in hepatic transaminase and creatine kinase values (all <2 times the upper limit of normal) were observed in 7 subjects. After 14 days of concurrent dosing of cerivastatin and digoxin, steady-state digoxin plasma levels, urinary digoxin levels, and urinary digoxin clearance were unchanged compared with steady-state digoxin levels when digoxin was given alone. Compared with dosing with digoxin alone, the AUC(0-24), Cmax, and t1/2 for cerivastatin increased 3%, 20%, and 7%, respectively, while the T(max) was reduced by 18% during concurrent treatment with digoxin. These changes are minimal and would not be expected to be clinically relevant. These results demonstrate that when cerivastatin is administered concurrently with digoxin, neither digoxin nor cerivastatin plasma levels are altered. The combination therapy was generally well tolerated.
Assuntos
Cardiotônicos/farmacocinética , Digoxina/farmacocinética , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Piridinas/farmacocinética , Adulto , Cardiotônicos/efeitos adversos , Digoxina/efeitos adversos , Digoxina/sangue , Digoxina/urina , Relação Dose-Resposta a Droga , Interações Medicamentosas , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Masculino , Pessoa de Meia-Idade , Pacientes Desistentes do Tratamento , Piridinas/efeitos adversos , Fatores de TempoRESUMO
Moxifloxacin (BAY 12-8039) is an investigational 8-methoxy-fluoroquinolone with broad-spectrum gram-positive and gram-negative activity. To determine the absolute bioavailability of moxifloxacin, this open-label, randomized, crossover study compared the pharmacokinetic characteristics of a single 100-mg dose administered either orally or intravenously as a 60-minute infusion in 10 healthy male volunteers (mean age [+/- SD], 29.3+/-7.1 years; mean weight [+/- SD], 77.7+/-8.7 kg). Geometric mean values for oral/IV moxifloxacin were as follows: peak serum concentration, 1.15/1.34 mg/L, and area under the concentration-time curve over 48 hours, 9.86/10.89 mg x h/L. The geometric mean absolute bioavailability of oral moxifloxacin was 91.8%. Mean renal clearance was approximately 2.3 L/h after administration of both the single oral and IV formulations, which suggests lack of active tubular secretion of moxifloxacin. Both the oral and IV formulations were well tolerated, with 5 reported possible or probable drug-related adverse events; they included headache, nausea, and localized urticaria. In summary, a single oral dose of moxifloxacin was extensively absorbed in healthy young men. Further studies are necessary in actual patients to confirm the viability of IV to oral conversion at the same dose of moxifloxacin.
Assuntos
Anti-Infecciosos/farmacocinética , Compostos Aza , Fluoroquinolonas , Quinolinas , Administração Oral , Adulto , Anti-Infecciosos/administração & dosagem , Anti-Infecciosos/efeitos adversos , Disponibilidade Biológica , Estudos Cross-Over , Relação Dose-Resposta a Droga , Humanos , Infusões Intravenosas , Masculino , MoxifloxacinaRESUMO
The safety, tolerability, and pharmacokinetics of cerivastatin, a novel, synthetic, potent, and highly selective HMG-CoA reductase inhibitor, were studied in 48 young and elderly male volunteers in a randomized, double-blind, placebo-controlled study. Eight men ranging from 18 to 38 years of age (young) and 15 men ranging from 65 to 78 years of age (elderly) received 0.1-mg cerivastatin tablets daily for 7 days. The remaining subjects (8 young and 17 elderly) received matching placebo tablets. Cerivastatin was well tolerated in elderly and young subjects. Adverse events were mild and occurred less frequently in the participants receiving cerivastatin than in those receiving placebo. In those participants given cerivastatin, the incidence of adverse events was similar for both age groups (4 of 8 young subjects and 8 of 15 elderly subjects). Transient and mild elevations in creatine kinase and transaminase levels were evenly distributed across the cerivastatin and placebo groups. Pharmacokinetic parameters, including area under the concentration curve (AUC), peak plasma concentration (Cmax), time to Cmax (tmax), and elimination half-life (t1/2), were similar between the two age groups. The mean elimination t1/2 for both groups was approximately 4 hours. These results indicate that cerivastatin is well tolerated in elderly male volunteers at a dosage of 0.1 mg/day. Further, the pharmacokinetics of cerivastatin are not altered as a consequence of age. Dose adjustment is therefore not required in elderly men.
Assuntos
Envelhecimento/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Piridinas/efeitos adversos , Piridinas/farmacocinética , Adulto , Idoso , Área Sob a Curva , Método Duplo-Cego , Meia-Vida , Humanos , MasculinoRESUMO
Acarbose is an alpha-glucosidase inhibitor approved for the treatment of type 2 diabetes mellitus. Acarbose inhibits carbohydrate digestion, allowing an excessive amount of undigested carbohydrate to reach the colon. Bacterial fermentation of the carbohydrate produces intestinal gas, which can cause flatulence and abdominal pain. Beano, an over-the-counter enzyme preparation (alpha-galactosidase), diminishes intestinal gas production by enhancing the breakdown of certain carbohydrates before they reach the lower intestine. This study was undertaken to investigate whether concomitant administration of Beano and acarbose could reduce the flatulence associated with acarbose and, if so, whether Beano would interfere with the effects of acarbose on postprandial serum glucose concentration. In this randomized, double-masked, placebo-controlled, three-period crossover study, 37 patients with type 2 diabetes mellitus received acarbose 100 mg, acarbose 100 mg plus Beano, or placebo. The study population consisted of 20 males and 17 females who ranged in age from 36 to 72 years (mean, 56 years) and in weight from 62 to 142 kg (mean, 92 kg). Each treatment period consisted of 3 days, during which both acarbose and Beano were given at the beginning of each of three meals. There was a 4-day washout interval between each treatment period. The frequency and severity of flatulence were measured using a score compiled from patient diaries. As an additional measure of intestinal gas production, breath hydrogen concentration was measured on day 3 of each treatment period. Postprandial serum glucose concentration was measured at predetermined times after each morning dose to assess pharmacodynamic activity. Patients who took Beano with acarbose had a significantly lower flatulence score than did those who took acarbose alone (0.79 vs 1.09). Consistent with this finding, breath hydrogen concentration was lower after administration of acarbose plus Beano than with acarbose alone (31.2 ppm vs 50.5 ppm). Beano had variable effects on the ability of acarbose to reduce the postprandial serum glucose concentration. Although postprandial serum glucose levels were higher in patients who received acarbose plus Beano than in those who received acarbose alone, both treatments (with or without Beano) resulted in postprandial serum glucose levels that were significantly lower than those seen with placebo. Therefore, although Beano appeared to diminish the activity of acarbose, postprandial serum glucose concentrations still decreased significantly in patients taking Beano with acarbose. Beano has been shown to alleviate the flatulence accompanying acarbose treatment, but it may also interfere with the glucose-lowering effect of acarbose.
Assuntos
Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Inibidores de Glicosídeo Hidrolases , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacocinética , Trissacarídeos/efeitos adversos , Trissacarídeos/farmacocinética , alfa-Galactosidase/uso terapêutico , Acarbose , Adulto , Idoso , Glicemia/metabolismo , Testes Respiratórios , Estudos Cross-Over , Diabetes Mellitus Tipo 2/tratamento farmacológico , Método Duplo-Cego , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Hidrogênio/metabolismo , Hipoglicemiantes/uso terapêutico , Masculino , Pessoa de Meia-Idade , Trissacarídeos/uso terapêutico , alfa-Galactosidase/efeitos adversosRESUMO
Metrifonate is converted nonenzymatically to 2.2, dimethyl dichlorovinyl phosphate (DDVP), an inhibitor of acetylcholinesterase (AChE). This 21-day, randomized, double-blind, placebo-controlled trial of metrifonate in patients with Alzheimer's disease (n = 27) evaluated four doses, each administered orally once daily. All patients received a loading dose (LD) for 6 days followed by a maintenance dose (MD) for 15 days. The treatment groups were: panel 1, LD = 1.5 mg/kg (75-135 mg), MD = 0.25 mg/kg (12.5-25 mg); panel 2, LD = 2.5 mg/kg (125-225 mg), MD = 0.40 mg/kg (20-35 mg); panel 3, LD = 4.0 mg/kg (200-335 mg), MD = 0.65 mg/kg (30-60 mg); and panel 4, LD = 4.0 mg/kg (200-335 mg), MD = 1.0 mg/kg (50-90 mg). All metrifonate doses were well tolerated. Most adverse events were mild to moderate in intensity, gastrointestinal in nature, and transient. Mean area under the concentration-time curve (AUC) and maximum concentration (Cmax) for both metrifonate and DDVP increased in relation to dose. Metrifonate and DDVP had similar, largely dose-independent mean values for time to Cmax (tmax) and half-life (t1/2). There was little or no accumulation of either metrifonate or DDVP with long-term administration. After 21 days of treatment, mean percent erythrocyte AChE inhibition was 14%, 35%, 66%, 77%, and 82% for placebo and panels 1 through 4, respectively. Cognitive improvement was observed with the two highest metrifonate doses. These results reflect favorable safety and pharmacokinetic profiles for the use of metrifonate in the treatment of Alzheimer's disease.
Assuntos
Acetilcolinesterase/efeitos dos fármacos , Doença de Alzheimer/metabolismo , Inibidores da Colinesterase/farmacocinética , Triclorfon/farmacocinética , Acetilcolinesterase/sangue , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/enzimologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Fosfatos/análise , Resultado do Tratamento , Triclorfon/farmacologia , Triclorfon/uso terapêuticoRESUMO
OBJECTIVE: Information about the pharmacokinetics of fluoroquinolone antibiotics in high risk children is scant. This study examined the disposition of sequentially administered intravenous and oral ciprofloxacin, as well as provided dosing recommendations, for the treatment of acute pulmonary exacerbations in pediatric cystic fibrosis patients. METHODS: After enrollment in a Food and Drug Administration approved protocol, the pharmacokinetic profiles of ciprofloxacin (CIP) administered to 18 children with cystic fibrosis (ages 5 to 17 years) were studied at steady state after sequentially administered intravenous (10 mg/kg every 8 h) and oral (20 mg/kg every 12 h) doses. All children enrolled met published criteria for exacerbation of Pseudomonas aeruginosa lung infection and received CIP intravenously (given as a 1-h infusion) followed by oral administration, each for a minimum of 3 days. All patients were at a mild to moderate stage in their disease with National Institutes of Health scores between 37 and 83. Blood samples were drawn at 0, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0 (after both i.v. and oral dosing) and 12 h (oral only) after CIP administration. CIP serum concentrations were determined by high performance liquid chromatography. RESULTS: After oral CIP mean +/- SD peak serum concentrations and peak times were 3.7 +/- 1.4 mg/l and 2.5 +/- 1.8 h, respectively, compared with 5.0 +/- 1.5 mg/l and 1.0 +/- 0.3 h after completion of the i.v. infusion. Maximum concentrations, when normalized for dose, were 0.52 +/- 0.12 and 0.19 +/- 0.07 mg/l/kg after i.v. and oral dosing, respectively. The mean bioavailability of oral CIP for all patients was 76%; younger patients appeared to absorb oral CIP less than older subjects, 68% vs. 95%, respectively. For all patients elimination half-lives were 2.6 +/- 0.6 and 3.4 +/- 0.7 h after i.v. and oral administration, respectively, and did not differ by age. Total clearance after i.v. administration was 19.5 +/- 10.9 liters/h. No significant CIP-related adverse effects were noted. CONCLUSIONS: CIP doses of 30 mg/kg/day i.v. and 40 mg/kg/day orally must be administered to children with cystic fibrosis to achieve optimal therapeutic concentrations.
Assuntos
Anti-Infecciosos/farmacocinética , Ciprofloxacina/farmacocinética , Fibrose Cística/tratamento farmacológico , Pneumonia Bacteriana/tratamento farmacológico , Infecções por Pseudomonas/tratamento farmacológico , Doença Aguda , Administração Oral , Adolescente , Anti-Infecciosos/administração & dosagem , Anti-Infecciosos/uso terapêutico , Disponibilidade Biológica , Criança , Pré-Escolar , Ciprofloxacina/administração & dosagem , Ciprofloxacina/uso terapêutico , Fibrose Cística/complicações , Feminino , Humanos , Injeções Intravenosas , Masculino , Pneumonia Bacteriana/complicações , Estudos Prospectivos , Infecções por Pseudomonas/complicaçõesRESUMO
The pharmacokinetics of intravenous ciprofloxacin and its metabolites were characterized in 42 subjects with various degrees of renal function (group 1, Clcr (mL/min/1.73 m2) > 90, n = 10; group 2, Clcr 61-90, n = 11; group 3, Clcr 31-60, n = 11; group 4, Clcr < or = 30, n = 10). The dosage regimens were-groups 1 and 2: 400 mg i.v. at 8 hourly intervals; group 3: 400 mg i.v. at 12 hourly intervals and group 4: 300 mg i.v. at 12 hourly intervals. Subjects received a single dose on days 1 and 5 and multiple doses on days 2-4. Multiple plasma and urine samples were collected on days 1 and 5 for the analysis of ciprofloxacin and its metabolites (M1, M2 and M3). Plasma concentrations (Cmax and AUC) of ciprofloxacin and its M1 and M2 metabolites were significantly increased in subjects with reduced Clcr values (Clcr < 60 mL/min/1.73 m2) compared with normal subjects (Clcr > 90 mL/min/1.73 m2). A positive correlation was observed between ciprofloxacin clearance (Cl) and Clcr with a slope of 0.29 (r2 = 0.78) and between renal clearance (Clr) and Clcr with a slope of 0.19 (r2 = 0.84). For patients with severe infections a dosage regimen of 400 mg iv 8 hourly is appropriate in patients with Clcr > 60 mL/min/1.73 m2. In patients with Clcr values of 31-60 mL/min/1.73 m2 a dosage regimen of 400 mg 12 hourly provides similar plasma concentrations to those observed for subjects with Clcr 61-90 mL/min/1.73 m2 receiving 400 mg 8 hourly. Based on modeling of the plasma concentrations in subjects with Clcr < or = 30 ml/min/1.73 m2, a dosage regimen of 400 mg every 24 h will provide plasma concentrations similar to those observed in subjects with Clcr between 61-90 mL/min/1.73 m2 given 400 mg every 8 h.
Assuntos
Anti-Infecciosos/farmacologia , Ciprofloxacina/farmacologia , Nefropatias/metabolismo , Falência Renal Crônica/tratamento farmacológico , Adulto , Idoso , Anti-Infecciosos/administração & dosagem , Anti-Infecciosos/farmacocinética , Ciprofloxacina/administração & dosagem , Ciprofloxacina/farmacocinética , Creatinina/metabolismo , Demografia , Progressão da Doença , Relação Dose-Resposta a Droga , Feminino , Humanos , Bombas de Infusão , Infusões Intravenosas , Nefropatias/sangue , Nefropatias/patologia , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Estudos Prospectivos , Análise de RegressãoRESUMO
Many drugs exhibit altered pharmacokinetic parameters in burn patients. We prospectively evaluated the pharmacokinetics of ciprofloxacin in eight burn patients with active infections. Each patient received a 400-mg dose of ciprofloxacin intravenously (i.v.) every 8 h, with each dose infused over 1 h by using a rate control device. Blood samples for analysis of plasma ciprofloxacin concentrations, determined by high-performance liquid chromatography, were obtained immediately predose, at the end of the infusion, and 1, 2, 3, 4, 5, 6, and 7 h after the end of the infusion. Urine was collected from 0 to 2, 2 to 4, and 4 to 8 h following the same dose, and an aliquot was saved for determination of the ciprofloxacin concentration. Urine was also collected for 24 h prior to this dose for measurement of creatinine clearance (CLCR). Pharmacokinetic parameters were estimated by noncompartmental analysis. Mean maximum and minimum plasma ciprofloxacin concentrations were 4.2 +/- 1.1 and 0.70 +/- 0.55 microgram/ml, respectively. Mean values for clearance (CL), renal clearance (CLR), volume of distribution, terminal elimination rate constant, half-life (t1/2), and area under the concentration-time curve (AUC) were 29.1 +/- 17.5 liters/h, 13.5 +/- 10.1 liters/h, 1.75 +/- 0.41 liters/kg, 0.222 +/- 0.098 h-1, 4.5 +/- 3.9 h, and 20.7 +/- 16.6 micrograms.h/ml, respectively. CL was higher and t1/2 was shorter than noted in previous studies of acutely ill, hospitalized patients. A good correlation was noted between creatinine clearance CL(CR) and both total ciprofloxacin CL (r = 0.85) and CLR (r = 0.84). A moderate inverse correlation was noted between percent body surface area burned and total ciprofloxacin CL (r = -0.55). An AUC/MIC ratio above 125 SIT-1 (where SIT is serum inhibitory titer), which has been strongly correlated with clinical response and time to bacterial eradication, was achieved in five of eight patients (63%) with a MIC of 0.25 microgram/ml. At a ciprofloxacin dosage of 400 mg i.v. every 12 h, an AUC/MIC ratio above 125 SIT-1 would have been achieved in only two of eight patients (25%). We conclude that ciprofloxacin CL is highly variable, but generally increased, in burn patients compared with that in acutely ill, general medical and surgical patients. Because of an increase in CL, a ciprofloxacin dosage of 400 mg i.v. every 8 h is more likely to produce the desired response in burn patients than the same dose given every 12 h.
Assuntos
Anti-Infecciosos/farmacocinética , Queimaduras/metabolismo , Ciprofloxacina/farmacocinética , Adolescente , Adulto , Queimaduras/tratamento farmacológico , Ciprofloxacina/uso terapêutico , Relação Dose-Resposta a Droga , Feminino , Humanos , Infusões Intravenosas , Masculino , Estudos ProspectivosRESUMO
To determine if ciprofloxacin therapy alters the response to warfarin treatment, 36 adult patients attending three university-affiliated outpatient anticoagulation clinics randomly received a 12-day course of ciprofloxacin (750 mg twice daily) and a 12-day course of placebo; each course was separated by a 2-week washout period. Prothrombin times (PTs), concentrations of S-warfarin and R-warfarin (the isomers of warfarin), and concentrations of clotting factors II and VII were determined three times weekly for 9 weeks. By day 12 of ciprofloxacin therapy, concentrations of S-warfarin remained unchanged compared with those after placebo therapy, but R-warfarin concentrations increased significantly (1.15 times those after placebo therapy; P = .001); concentrations of clotting factors II and VII decreased (0.903 and 0.872 times those after placebo therapy, respectively, P < or = .020). The mean PT ratio after 12 days of ciprofloxacin therapy increased slightly (1.032 times that after placebo therapy; P = .057), but no patient had bleeding or a change in PT that required alteration in warfarin or ciprofloxacin therapy. We conclude that warfarin therapy is not a contraindication to the use of ciprofloxacin.
Assuntos
Anti-Infecciosos/farmacologia , Anticoagulantes/farmacocinética , Ciprofloxacina/farmacologia , Varfarina/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/uso terapêutico , Método Duplo-Cego , Interações Medicamentosas , Fator VII/análise , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Protrombina/análise , Tempo de Protrombina , Varfarina/uso terapêuticoRESUMO
The effects of age and gender on the pharmacokinetics of high-dose intravenous ciprofloxacin in a healthy volunteer study were investigated. Plasma ciprofloxacin concentrations were higher in the elderly than in the young, and the pharmacokinetic parameters were not significantly different between the genders. Ciprofloxacin was well tolerated, with the majority of adverse events related to local reactions at the IV site.