RESUMO
The development of chemical sensors made from porous silicon is a task that has been addressed for several years. In order to have a reliable sensing material, stability must be guaranteed. Oxidation in silicon degrades the sensing capability. The data presented in this article provides some important insights concerning the treatment of samples that can improve the material stability against oxidation. For this purpose, Fourier Transformed Infrared (FTIR) measurements using an Attenuated Total Reflectance (ATR) additament were employed to extract information concerning oxidation on the samples submitted to different temperatures. Photoluminescent (PL) measurements were also performed on the samples in order to extract information on nanocrystals sizes and their relationship with oxidation.
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BACKGROUND AND OBJECTIVE: Bisphosphonates are commonly used to treat and prevent osteoporosis. These compounds have unusual pharmacokinetic characteristics because they bind strongly to bone, and a portion becomes buried under newly formed bone. Once incorporated into bone tissue, the subsequent release during bone remodeling is probably the rate-limiting step in the terminal elimination of bisphosphonates. Because of this unique property of bisphosphonates, pharmacokinetic studies with insufficient lengths of follow-up might entirely miss the true terminal elimination phase. A terminal half-life (t((1/2)gamma)) of approximately 11 years, similar to that of calcium and other minerals in bone, was reported from an 18-month study of alendronic acid in postmenopausal women with osteoporosis. We are not aware of any other published reports in which the elimination of a bisphosphonate has been followed for more than a few weeks post-dose. The purpose of the present study was to reanalyse the alendronic acid data to examine the effect of truncating the length of follow-up on the calculated t((1/2)gamma). PATIENTS AND METHODS: Twenty-one postmenopausal women with osteoporosis (mean age 66 years) received intravenous alendronic acid 30mg over 4 consecutive days (7.5 mg/day), and urinary excretion of alendronic acid was monitored over the following 18-24 months. Terminal elimination half-life was originally calculated by log-linear regression of the percentage retained versus time curve between days 240 and 540 and substituting the slope of the regression line into the equation, t((1/2)gamma) = -log 2/slope. These data were reanalysed based on the period up to 30 days. RESULTS: Data were sufficient for analysis of pharmacokinetics in 11 patients. A mean t((1/2)gamma) of approximately 11 years was reported previously, based on analysis of data between days 240 and 540. Recalculating the 'terminal' half-life of alendronic acid using only data from the first 30 days resulted in an 'observed' half-life of only 11 days. CONCLUSION: This analysis illustrates the importance of sufficient length of follow-up to accurately characterise the true terminal elimination half-life of bisphosphonates. The relatively short (expressed in units of days rather than years) terminal elimination half-lives reported for some bisphosphonates based on only 30 days of follow-up or less are likely to substantially underestimate the true terminal elimination half-lives.
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The effect of rofecoxib, a highly selective cyclooxygenase (COX)-2 inhibitor, on the pharmacokinetics of ethinyl estradiol (EE) and norethindrone (NET), two common components of a combination oral contraceptive product, was examined. A double-blind, two-period crossover study was conducted in 18 healthy women who received ORTHO-NOVUM 1/35, a combination of EE (35 microg) and NET (1 mg), concurrently for 14 days with either 175 mg rofecoxib or matching placebo during two consecutive menstrual cycles. Plasma was sampled for EE, NET, sex hormone binding globulin (SHBG), and albumin. The AUC(0-24 h) geometric mean ratio (GMR: rofecoxib/placebo) with corresponding 90% confidence interval (CI) of EE and NET was 1.13 (1.06, 1.19) and 1.18 (1.13, 1.24), respectively. The Cmax GMR of EE and NET was 1.06 (0.98, 1.16) and 1.04 (0.99, 1.09), respectively. In each case, the 90% CIs satisfied the predefined bioequivalence limits of (0.80, 1.25). Measures of SHBG and albumin and routine clinical and laboratory safety parameters showed no clinically meaningful changes. The addition of rofecoxib to the oral contraceptive was not associated with any clinically important changes in EE or NET pharmacokinetics and thus would not be anticipated to influence the efficacy of this contraceptive regimen.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Anticoncepcionais Orais Hormonais/farmacocinética , Lactonas/farmacologia , Adolescente , Adulto , Anti-Inflamatórios não Esteroides/efeitos adversos , Área Sob a Curva , Anticoncepcionais Orais Hormonais/efeitos adversos , Estudos Cross-Over , Método Duplo-Cego , Congêneres do Estradiol/farmacocinética , Etinilestradiol/farmacocinética , Feminino , Humanos , Lactonas/efeitos adversos , Pessoa de Meia-Idade , Noretindrona/farmacocinética , Albumina Sérica/metabolismo , Globulina de Ligação a Hormônio Sexual/metabolismo , SulfonasRESUMO
This study was undertaken to determine whether rofecoxib can interfere with CYP1A2 activity in humans using theophylline as a probe substrate. Single oral doses of theophylline were administered to each of three panels of 12 healthy subjects receiving daily doses of rofecoxib for 7 days to examine the effect of rofecoxib administration on the absorption and disposition of theophylline. Each panel was administered doses of 12.5, 25, or 50 mg of rofecoxib or a matching placebo in a two-way, randomized, crossover fashion and administered a single oral 300-mg dose of theophylline on day 7 of rofecoxib or placebo administration. Plasma concentrations of theophylline were monitored for 48 hours postdose to assess differences in pharmacokinetics. All three commercially marketed doses of rofecoxib were found to slow the clearance of theophylline with no detectable effect on absorption. CL/F values for theophylline were estimated from AUC infinity and by point estimates from the concentrations of drug in plasma at 12 and 24 hours postdose. The point estimates of CL/F were found to be in agreement with those derived from AUC.
Assuntos
Inibidores do Citocromo P-450 CYP1A2 , Citocromo P-450 CYP1A2/efeitos dos fármacos , Relação Dose-Resposta a Droga , Lactonas/metabolismo , Lactonas/farmacocinética , Sondas Moleculares/efeitos dos fármacos , Teofilina/metabolismo , Teofilina/farmacocinética , Administração Oral , Adulto , Estudos Cross-Over , Citocromo P-450 CYP1A2/biossíntese , Método Duplo-Cego , Humanos , Lactonas/administração & dosagem , Masculino , Pessoa de Meia-Idade , Sulfonas , Teofilina/administração & dosagemRESUMO
Patients receiving nonsteroidal anti-inflammatory drug therapy may also require administration of corticosteroids, particularly patients with rheumatoid arthritis. To investigate the effect of rofecoxib on the single-dose pharmacokinetics of oral prednisone and intravenous prednisolone, the authors conducted a randomized, double-blind, placebo-controlled crossover study in 12 healthy subjects. Oral rofecoxib (250.0 mg/day for 14 days) failed to influence prednisone or prednisolone pharmacokinetics after intravenous prednisolone or oral prednisone administration. The geometric mean ratio (GMR) (90% confidence interval) of prednisolone AUC infinity (rofecoxib/placebo) following intravenous and oral corticosteroid was 0.97 (0.94, 1.01) and 0.99 (0.91, 1.08), respectively. Similarly, the prednisone AUC infinity GMRs (rofecoxib/placebo) after intravenous and oral corticosteroid were 1.03 (0.95, 1.11) and 1.08 (0.92, 1.28), respectively. The absence of an effect of rofecoxib on the pharmacokinetics of oral prednisone or intravenous prednisolone indicates that no adjustment in dose of this corticosteroid is necessary when administered concurrently with rofecoxib.
Assuntos
Lactonas/farmacologia , Prednisolona/farmacocinética , Prednisona/farmacocinética , Adulto , Área Sob a Curva , Estudos Cross-Over , Interações Medicamentosas , Meia-Vida , Humanos , Masculino , Taxa de Depuração Metabólica , Prednisolona/sangue , Prednisona/sangue , SulfonasRESUMO
Safety and pharmacokinetics (PK) of the antiparasitic drug ivermectin, administered in higher and/or more frequent doses than currently approved for human use, were evaluated in a double-blind, placebo-controlled, dose escalation study. Subjects (n = 68) were assigned to one of four panels (3:1, ivermectin/placebo): 30 or 60 mg (three times a week) or 90 or 120 mg (single dose). The 30 mg panel (range: 34 7-594 microg/kg) also received a single dose with food after a 1-week washout. Safety assessments addressed both known ivermectin CNS effects and general toxicity. The primary safety endpoint was mydriasis, accurately quantitated by pupillometry. Ivermectin was generally well tolerated, with no indication of associated CNS toxicity for doses up to 10 times the highest FDA-approved dose of 200 microg/kg. All dose regimens had a mydriatic effect similar to placebo. Adverse experiences were similar between ivermectin and placebo and did not increase with dose. Following single doses of 30 to 120 mg, AUC and Cmax were generally dose proportional, with t(max) approximately 4 hours and t1/2 approximately 18 hours. The geometric mean AUC of 30 mg ivermectin was 2.6 times higher when administered with food. Geometric mean AUC ratios (day 7/day 1) were 1.24 and 1.40 for the 30 and 60 mg doses, respectively, indicating that the accumulation of ivermectin given every fourth day is minimal. This study demonstrated that ivermectin is generally well tolerated at these higher doses and more frequent regimens.
Assuntos
Antiparasitários/farmacocinética , Ivermectina/farmacocinética , Administração Oral , Adolescente , Adulto , Antiparasitários/administração & dosagem , Antiparasitários/efeitos adversos , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Feminino , Interações Alimento-Droga , Humanos , Ivermectina/administração & dosagem , Ivermectina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Midríase/induzido quimicamente , Pupila/efeitos dos fármacosRESUMO
To investigate the influence of modifying in vivo cytochrome P450 3A (CYP3A) activity on the pharmacokinetics of etoricoxib, a selective inhibitor of cyclooxygenase-2, and of etoricoxib administration on CYP3A activity, a 3-part, randomized, crossover study was conducted in 3 panels of healthy volunteers. In part I, 8 subjects were administered a single dose of 60 mg etoricoxib alone and following daily doses of 400 mg ketoconazole, a known strong inhibitor of CYP3A. In part II, 8 different subjects were administered a single dose of 60 mg etoricoxib alone and following daily doses of 600 mg rifampin, a known strong inducer of CYP3A. In parts I and II, plasma samples were collected following each etoricoxib dose and analyzed for etoricoxib. In part III, 8 different subjects were administered 120 mg etoricoxib or placebo once daily for 11 days, and the erythromycin breath test was administered on day 11 of each period. Coadministration of etoricoxib with daily doses of ketoconazole resulted in an average 43% increase in etoricoxib AUC; based on previous studies, this increase would not be expected to have any clinically meaningful effect. In contrast, coadministration of etoricoxib with daily doses of rifampin had a potentially clinically important effect on etoricoxib pharmacokinetics (average 65% decrease in etoricoxib AUC). Etoricoxib had no effect on hepatic CYP3A activity, as assessed by the erythromycin breath test.
Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Piridinas/administração & dosagem , Piridinas/farmacocinética , Sulfonas/administração & dosagem , Sulfonas/farmacocinética , Adulto , Análise de Variância , Intervalos de Confiança , Estudos Cross-Over , Citocromo P-450 CYP3A , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Etoricoxib , Feminino , Humanos , Masculino , Piridinas/sangue , Sulfonas/sangueRESUMO
The effect of hepatic insufficiency on the pharmacokinetics of etoricoxib, a selective inhibitor of cyclooxygenase-2, was investigated following administration of single and multiple oral doses to mild hepatic insufficiency patients (Child-Pugh score of 5 to 6), multiple oral doses to moderate hepatic insufficiency patients (Child-Pugh score of 7 to 9), and single intravenous doses to both mild and moderate hepatic insufficiency patients. A trend of decreasing systemic clearance with increasing hepatic impairment was observed. Absorption of etoricoxib was unaffected by hepatic impairment. Binding of etoricoxib to plasma proteins was also found to be unaffected by hepatic disease. Etoricoxib was generally well tolerated by patients with mild and moderate hepatic insufficiency. Together, these results support a 60-mg once-daily dosing regimen for mild hepatic insufficiency patients and a 60-mg every-other-day dosing regimen for moderate hepatic insufficiency patients. There are no clinical or pharmacokinetic data in patients with severe hepatic insufficiency (Child-Pugh score > 9).
Assuntos
Hepatopatias/tratamento farmacológico , Piridinas/farmacocinética , Piridinas/uso terapêutico , Sulfonas/farmacocinética , Sulfonas/uso terapêutico , Administração Oral , Idoso , Área Sob a Curva , Disponibilidade Biológica , Estudos Cross-Over , Relação Dose-Resposta a Droga , Esquema de Medicação , Etoricoxib , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Piridinas/sangue , Sulfonas/sangueRESUMO
The single- and multiple-dose pharmacokinetics of etoricoxib, a selective inhibitor of cyclooxygenase-2, were examined in two clinical studies. Single-dose pharmacokinetics--including dose proportionality, absolute bioavailability of the highest dose-strength (120-mg) tablet, and the effect of a high-fat meal on the bioavailability of that tablet--were investigated in a two-part, open, balanced crossover study in two panels of healthy subjects (12 per panel). Steady-state pharmacokinetics were investigated in an open-label study in which 24 healthy subjects were administered 120-mg single and multiple (once daily for 10 days) oral doses of etoricoxib tablets. The pharmacokinetics of etoricoxib were found to be consistent with linearity through doses at least twofold greater than the highest anticipated clinical dose of 120 mg. Etoricoxib administered as a tablet was rapidly and completely absorbed and available; the absolute bioavailability was estimated to be 100%. A high-fat meal decreased the rate of absorption without affecting the extent of absorption of etoricoxib; therefore, etoricoxib can be dosed irrespective of food. Steady-state pharmacokinetics of etoricoxib, achieved following 7 days of once-daily dosing, were found to be reasonably predicted from single doses. The accumulation ratio averaged 2.1, and the corresponding accumulation t1/2 averaged 22 hours, supporting once-daily dosing. Etoricoxib was generally well tolerated.
Assuntos
Inibidores de Ciclo-Oxigenase/farmacocinética , Isoenzimas/antagonistas & inibidores , Piridinas/farmacocinética , Sulfonas/farmacocinética , Adulto , Área Sob a Curva , Disponibilidade Biológica , Estudos Cross-Over , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase/administração & dosagem , Inibidores de Ciclo-Oxigenase/efeitos adversos , Gorduras na Dieta , Relação Dose-Resposta a Droga , Esquema de Medicação , Etoricoxib , Jejum , Feminino , Interações Alimento-Droga , Humanos , Masculino , Proteínas de Membrana , Pessoa de Meia-Idade , Prostaglandina-Endoperóxido Sintases , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Sulfonas/administração & dosagem , Sulfonas/efeitos adversos , Comprimidos , Fatores de TempoRESUMO
The effect of renal insufficiency on the pharmacokinetics of etoricoxib, a selective inhibitor of cyclooxygenase-2, was examined in 23 patients with varying degrees of renal impairment (12 moderate [creatinine clearance between 30 and 50 mL/min/1.73 m2], 5 severe [creatinine clearance below 30 mL/min/1.73 m2], and 6 with end-stage renal disease requiring hemodialysis) following administration of single 120-mg oral doses of etoricoxib. Even the most severe renal impairment was found to have little effect on etoricoxib pharmacokinetics. The low recovery of etoricoxib in dialysate (less than 6% of the dose) supports that hemodialysis also has little effect on etoricoxib pharmacokinetics, and binding of etoricoxib to plasma proteins was generally unaffected by renal disease. Single doses of etoricoxib were generally well tolerated by patients with renal impairment. Based on pharmacokinetic considerations, dosing adjustments are not necessary for patients with any degree of renal impairment. However, because patients with advanced renal disease (creatinine clearance below 30 mL/min/1.73 m2) are likely to be very sensitive to any further compromise of renal function, and there is no long-term clinical experience in these patients, the use of etoricoxib is not recommended in patients with advanced renal disease.
Assuntos
Inibidores de Ciclo-Oxigenase/farmacocinética , Falência Renal Crônica/metabolismo , Piridinas/farmacocinética , Sulfonas/farmacocinética , Administração Oral , Adulto , Idoso , Área Sob a Curva , Disponibilidade Biológica , Ensaios Clínicos como Assunto , Etoricoxib , Feminino , Meia-Vida , Humanos , Falência Renal Crônica/terapia , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Ligação Proteica , Diálise RenalRESUMO
OBJECTIVE: Rofecoxib suspension is a formulation developed to increase the convenience of rofecoxib therapy for patients who have difficulty swallowing tablets. This open-label, two-part study compared the single-dose pharmacokinetics of rofecoxib tablets and rofecoxib suspension in healthy subjects. DESIGN AND STUDY PARTICIPANTS: Part I was a two-period crossover study that assessed the bioequivalence of the 12.5mg/5mL rofecoxib suspension and the 12.5mg rofecoxib tablet in 24 healthy subjects (12 men and 12 women). Part II was a crossover study in 24 additional healthy subjects (12 men and 12 women) that determined the bioequivalence of the rofecoxib 25mg/5mL suspension and the 25mg rofecoxib tablet. RESULTS: No clinically meaningful differences between rofecoxib tablet and suspension were apparent with respect to the rofecoxib area under the concentration-time curve from time zero to infinity (AUC(0-infinity)) and maximum plasma concentration (C(max)), the primary measures of bioequivalence. At the 12.5mg and 25mg doses, the 90% CI for the geometric mean ratio (suspension/tablet) of both AUC(0-infinity) and C(max) fell within the prespecified interval for bioequivalence (0.80-1.25). CONCLUSIONS: The rofecoxib suspension is bioequivalent to the rofecoxib tablet at single oral doses of 12.5mg and 25mg in healthy volunteers. The convenience and ease of administration of rofecoxib suspension may translate into increased compliance with therapy compared with a conventional solid tablet formulation, particularly for elderly patients.
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BACKGROUND: Children receiving glucocorticoids (GCs) are at an increased risk of fragility fractures. Conservative measures may be inadequate in treating low bone mass, giving rise to fractures in this population; as such, attention has turned to the use of bisphosphonates. OBJECTIVE: The goal of this study was to evaluate the bioavailability and single-dose tolerability of alendronate (ALN) in children receiving a stable dose of GCs. METHODS: Children (ages 4-17 years) receiving GC treatment for their chronic illnesses received intravenous (125 µg) and oral (35 mg) ALN in a 2-period, randomized crossover study, with doses separated by at least a 7-day washout period. Urine was collected for either 8 or 24 hours after drug administration to determine urinary excretion of ALN and bioavailability. Tolerability was assessed by continuous collection of adverse events reported during the study. The main outcome measures were total urinary excretion rates, oral bioavailability of ALN, and adverse events. RESULTS: There were 12 patients in the 4- to 11-year-old group (mean age, 8.1 years; 5 girls) and 12 patients in the 12- to 17-year-old group (mean age, 14.3 years; 5 girls). The least-squares mean bioavailability (90% CI) for children aged 4 to 11 years (n = 12) was 0.43% (0.27-0.67) and for children aged 12 to 17 years (n = 12) it was 0.39% (0.26-0.60). The least-squares mean bioavailability for all ages combined was 0.41% (0.30-0.56), with no statistical difference between the 2 age groups. The total urinary excretion of ALN after the intravenous dose was similar between groups. Fifteen patients reported a total of 36 transient clinical nonserious adverse events, all of which were mild or moderate in intensity; the most common were headache (n = 13), abdominal pain (n = 3), limb, neck, or facial pain (n = 6), and ankle or knee swelling (n = 3). CONCLUSIONS: The mean oral bioavailability of ALN was similar to previous pharmacokinetic studies in children with osteogenesis imperfecta and slightly lower than that observed in historical adult controls. Alendronate was generally well tolerated, with minor adverse events that resolved uneventfully. Elucidation of the full adverse-effect profile of this agent was limited by the single-dose nature of this study, and robust comparisons of the pharmacokinetics of ALN in different age groups may need a larger number of patients.
Assuntos
Alendronato/farmacocinética , Conservadores da Densidade Óssea/farmacocinética , Fraturas Ósseas/prevenção & controle , Glucocorticoides/uso terapêutico , Administração Oral , Adolescente , Alendronato/efeitos adversos , Alendronato/uso terapêutico , Alendronato/urina , Disponibilidade Biológica , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/efeitos adversos , Conservadores da Densidade Óssea/urina , Criança , Pré-Escolar , Estudos Cross-Over , Esquema de Medicação , Feminino , Fraturas Ósseas/induzido quimicamente , Glucocorticoides/efeitos adversos , Humanos , Injeções Intravenosas , Análise dos Mínimos Quadrados , Masculino , Pessoa de Meia-Idade , Fatores de TempoRESUMO
These studies were designed to demonstrate that the alendronate (ALN) component of an ALN/vitamin D(3) combination tablet was bioequivalent to the 70-mg ALN tablet and that the pharmacokinetic parameters of vitamin D(3) were similar with or without ALN. These were open-label, randomized, 2-part, 2-period, crossover studies. In part I, participants received either a single combination tablet or ALN 70 mg. In part II, participants received either a single combination tablet or vitamin D(3) alone. Results from part I showed that the geometric mean ratio (GMR) for total urinary excretion of ALN for both studies fell within the prespecified bioequivalence bounds. Results from part II showed that the pharmacokinetic profiles of vitamin D(3) with or without ALN were also similar. The combination tablets are bioequivalent to the ALN 70-mg tablet with respect to ALN bioavailability. The bioavailability of vitamin D(3) is similar in the combination tablets and when administered alone. No serious adverse experiences were reported.
Assuntos
Alendronato/farmacocinética , Conservadores da Densidade Óssea/farmacocinética , Colecalciferol/farmacocinética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alendronato/metabolismo , Área Sob a Curva , Disponibilidade Biológica , Conservadores da Densidade Óssea/metabolismo , Colecalciferol/metabolismo , Estudos Cross-Over , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Comprimidos , Adulto JovemRESUMO
Nonlinear mixed models are important tools for analyzing repeated measures data. In particular, these models are used for population pharmacokinetic analyses for estimating population pharmacokinetic parameters. As more clinical studies are performed for the advancement of treatment of pediatric patients, methodology is needed for comparing results from pharmacokinetic studies in pediatric patients and adult control groups. These pediatric studies introduce complexities to the design and analysis, including how analysis of sparse data affects the limitations of model selection. A case study is presented demonstrating that good communication with regulatory agencies and appropriate selection of analysis models are integral parts of completing population analyses for timely approval and labeling of drugs for treating pediatric patients.
Assuntos
Dinâmica não Linear , Farmacocinética , Adulto , Algoritmos , Área Sob a Curva , Química Farmacêutica , Pré-Escolar , Ensaios Clínicos como Assunto/estatística & dados numéricos , Humanos , Lactente , Modelos EstatísticosRESUMO
Transmittance measurements at normal incidence were carried out over the visible spectral range for metallic thin films deposited by electron beam evaporation on thick glass substrates. The presence of an inhomogeneous thin layer of Cu2O covering the deposited Cu films is required for a satisfactory model of the measurements taken from various samples with increasing thickness. A spectral projected gradient method is used to invert the transmission spectra from which the wavelength dependence of the effective dielectric function of the oxidized coating layer is obtained. Then an effective medium model is used to estimate the volume fraction of internal voids randomly distributed through the surface layer.
RESUMO
Rofecoxib (VIOXX, Merck & Co., West Point, PA) is a COX-2-selective inhibitor that combines anti-inflammatory and analgesic efficacy with improved gastrointestinal (GI) safety. The present open-label study investigated the pharmacokinetics, safety, and tolerability of a single, oral dose of rofecoxib (50 mg) in patients with end-stage renal failure (creatinine clearance <5 mL/min/1.73 m(2)) requiring hemodialysis. Rofecoxib AUC(0-48 h), AUC(0- infinity), C(max), T(max), and t(1/2) obtained from renal failure patients on hemodialysis were not significantly different from those obtained from healthy subjects. With hemodialysis initiated 48 hours postdose, rofecoxib AUC(0-48 h) adjusted mean ratio (renal failure/healthy subjects) was 0.81, with a corresponding 90% confidence interval (CI; 0.66, 1.00). Hemodialysis per se had no clinically meaningful effect on rofecoxib pharmacokinetics: plasma rofecoxib concentration-time curves were virtually superimposable when hemodialysis was initiated at 4 or 48 hours following rofecoxib dosing, although mean rofecoxib C(max) was 18% lower during the former (325 versus 395 ng/mL; P = 0.014). Overall, rofecoxib was well tolerated in end-stage renal disease patients. In this study, end-stage renal disease and hemodialysis had little effect on rofecoxib pharmacokinetics. Although there are no clinical data to support the use of rofecoxib in patients with severe renal insufficiency (creatinine clearance, 5-30 mL/min/1.73 m(2)), these data suggest that dosage adjustment of rofecoxib is not needed for patients with impaired renal function.
Assuntos
Inibidores de Ciclo-Oxigenase/farmacocinética , Falência Renal Crônica , Lactonas/farmacocinética , Diálise Renal , Adulto , Área Sob a Curva , Creatinina/metabolismo , Feminino , Meia-Vida , Humanos , Falência Renal Crônica/metabolismo , Falência Renal Crônica/terapia , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , SulfonasRESUMO
The disposition and metabolism of rofecoxib, a selective cyclooxygenase-2 inhibitor, were examined in healthy human subjects and in cholecystectomy patients. After oral administration of [(14)C]rofecoxib (125 mg, 100 micro Ci) to healthy subjects, the mean concentrations of total radioactivity and rofecoxib in plasma as a function of time indicated that the t(max) was achieved at 9 h postdose. After t(max), levels of both radioactivity and rofecoxib decreased in a parallel, exponential fashion (effective t(1/2) approximately equal 17 h). A similar result was obtained after oral administration of [(14)C]rofecoxib (142 mg, 100 micro Ci) to cholecystectomy patients equipped with an L-tube. In healthy subjects, radioactivity was recovered predominantly from the urine (71.5% of dose), with a small amount excreted in feces (14.2%). In patients with an L-tube, half the radioactive dose was recovered in feces, with a lesser amount excreted in urine (28.8%) and a negligible fraction in bile (1.8%). Rofecoxib underwent extensive metabolism in humans, and very little parent drug was recovered unchanged in urine (<1%). Products resulting from both oxidative and reductive pathways were identified by a combination of (1)H NMR and liquid chromatography-tandem mass spectrometry analyses, and included rofecoxib-3',4'-trans-dihydrodiol, 4'-hydroxyrofecoxib-O-beta-D-glucuronide, diastereomeric 5-hydroxyrofecoxib-O-beta-D-glucuronide conjugates, 5-hydroxyrofecoxib, rofecoxib-erythro-3,4-dihydrohydroxy acid, and rofecoxib-threo-3,4-dihydrohydroxy acid. Interconversion of rofecoxib and 5-hydroxyrofecoxib appeared not to be a quantitatively important pathway of rofecoxib disposition in human subjects, in contrast to previous findings in rats.