RESUMEN
Tigecycline, a novel glycylcycline, possesses broad-spectrum antimicrobial activity. A structural population pharmacokinetic model for tigecycline was developed based on data pooled from 5 phase I studies. Intravenous tigecycline was administered as single (12.5-300 mg) or multiple (25-100 mg) doses every 12 hours for up to 10 days. Three-compartment models with zero-order input and first-order elimination separately described the single- or multiple-dose full-profile data. Additional models were evaluated using a subset of the phase I data mimicking the phase II/III trial sparse-sampling scheme and dosage. A 2-compartment model best described the reduced phase I data following single or multiple doses and provided reliably accurate estimates of tigecycline AUC(0-12). This modeling supported phase II/III population pharmacokinetic model development to further determine individual patient tigecycline exposures for safety and efficacy analyses.
Asunto(s)
Antibacterianos/farmacocinética , Minociclina/análogos & derivados , Adolescente , Adulto , Anciano , Antibacterianos/sangre , Área Bajo la Curva , Ensayos Clínicos Fase I como Asunto , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Minociclina/sangre , Minociclina/farmacocinética , Modelos Biológicos , Estudios Multicéntricos como Asunto , TigeciclinaRESUMEN
Tigecycline, a first-in-class expanded glycylcycline antimicrobial agent, has demonstrated efficacy in the treatment of complicated skin and skin structure infections (cSSSI) and complicated intra-abdominal (cIAI) infections. A population pharmacokinetic (PK) model for tigecycline was developed for patients with cSSSI or cIAI enrolled in two phase 2 clinical trials, and the influence of selected demographic factors and clinical laboratory measures was investigated. Tigecycline was administered as an intravenous loading dose followed by a 0.5- or 1-h infusion every 12 h for up to 14 days. Blood samples were collected the day before or the day of hospital discharge for the determination of serum tigecycline concentrations. Patient covariates were evaluated using stepwise forward (alpha = 0.05) and backward (alpha = 0.001) procedures. The predictive performance of the model was assessed separately using pooled data from either two phase 3 studies for patients with cSSSI or two phase 3 studies for patients with cIAI. A two-compartment model with zero-order input and first-order elimination adequately described the steady-state tigecycline concentration-time data. Tigecycline clearance was shown to increase with increasing weight, increasing creatinine clearance, and male gender (P < 0.001). The final model provided a relatively unbiased fit to each data set. Individual predicted values of the area under the concentration-time curve from 0 to 12 h (AUC(0-12)) were generally unbiased (median prediction error, -1.60% to -3.78%) and were similarly precise (median absolute prediction error, <4%) when compared across data sets. The population PK model provided the basis to obtain individual estimates of steady-state AUC(0-12) in later exposure-response analyses of tigecycline safety and efficacy in patients with cSSSI or cIAI.
Asunto(s)
Abdomen , Antibacterianos/farmacocinética , Infecciones Bacterianas/metabolismo , Minociclina/análogos & derivados , Enfermedades Cutáneas Infecciosas/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Área Bajo la Curva , Femenino , Humanos , Masculino , Persona de Mediana Edad , Minociclina/farmacocinética , Modelos Estadísticos , Población , TigeciclinaRESUMEN
BACKGROUND: Pharmacokinetic (PK) and pharmacodynamic (PD) models for azimilide were developed and validated with sparse blood sampling and QTc interval data obtained during three clinical trials of azimilide for prevention of supraventricular arrhythmia recurrence. METHODS: Patients were orally administered placebo or azimilide dihydrochloride, 35, 50, 75, 100, or 125 mg/d, for 6 to 9 months. NONMEM was used for data fitting and assessment of selected patient covariates and concomitant medication classes for PK/PD relationships. RESULTS: Results indicate that azimilide clearance (CL) was dependent on body weight (WTKG), gender, and current tobacco use, where CL (L/h) = 3.92 x (WTKG - 43)(0.208), with a 17% increase for male subjects and a 15.5% increase for current tobacco use. Volume of distribution (V) was also dependent on WTKG and total bilirubin (BIL), where V (L) = 9.88 x (WTKG - 43) + 717 x (BIL)(0.348). The PK/PD analysis indicated that the baseline QTc interval was dependent on gender, New York Heart Association Class, digoxin, and paced artificial pacemaker spike, whereas the 50% effective concentration (EC(50)) was dependent on the serum potassium (K) level, where EC(50) = 107 x K. The change in EC(50) was not clinically significant within the normal range for potassium. The mean E(max) (maximum increase in the QTc interval for the E(max) models) was a 61.7 ms increase from baseline. At 125 mg/d the predicted percent increase in the QTc interval at the maximum plasma drug concentration at steady state was 9% and 10% for male and female patients, respectively. The values of the median prediction error were -3% and -0.4% for the PK and PK/PD models, respectively, and the values of the absolute prediction error were 21% and 4% for the PK and PK/PD models, respectively, indicating that both models are essentially unbiased and acceptably accurate. CONCLUSIONS: Azimilide PK parameters are dependent on body weight, gender, smoking status, and bilirubin and are independent of the coadministration of digoxin, warfarin, and cytochrome P4503A4 inhibitors and inducers. The relationship between azimilide concentration and change in QTc is primarily dependent on serum potassium.
Asunto(s)
Antiarrítmicos/farmacología , Antiarrítmicos/farmacocinética , Imidazoles/farmacología , Imidazoles/farmacocinética , Imidazolidinas , Piperazinas/farmacología , Piperazinas/farmacocinética , Taquicardia Supraventricular/tratamiento farmacológico , Análisis de Varianza , Bilirrubina/sangre , Peso Corporal , Ensayos Clínicos Fase III como Asunto , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Electrocardiografía/efectos de los fármacos , Etnicidad , Femenino , Humanos , Hidantoínas , Masculino , Persona de Mediana Edad , Modelos Estadísticos , Potasio/sangre , Reproducibilidad de los Resultados , Factores Sexuales , Fumar , Taquicardia Supraventricular/sangre , Taquicardia Supraventricular/prevención & controlRESUMEN
OBJECTIVE: Oral contraceptive (OC) steroids alter the disposition of numerous drugs, including corticosteroids. We investigated the pharmacokinetics and pharmacodynamics of methylprednisolone. METHODS: Twelve women (six women used OC steroids and six women did not) received intravenous methylprednisolone (0.6 mg/kg ideal body weight). Methylprednisolone disposition was assessed from plasma concentrations. Pharmacodynamic parameters measured were plasma cortisol, whole blood histamine (reflecting basophils), and blood helper T lymphocytes. RESULTS: Methylprednisolone clearance was significantly decreased in the women who used OC steroids (0.298 versus 0.447 L/hr/kg), resulting in a longer elimination half-life (2.20 versus 1.72 hours). With use of indirect response models, significant differences were observed with the cortisol and basophil responses. A larger value for the concentration that inhibits the zero-order production rate by 50% (0.37 versus 0.11 ng/ml) was observed in the women who used OC steroids for suppression of cortisol secretion, indicating less sensitivity to the suppressive effects of methylprednisolone. Greater net suppression of basophils was observed in the users of OC steroids (area under the response curve, 694 versus 401 ng x hr/ml). No differences were observed for helper T-cell responses. CONCLUSION: OC steroids appear to inhibit methylprednisolone metabolism. However, mixed changes in several responses occur, indicating that women can probably receive similar doses of methylprednisolone irrespective of OC steroid use.
PIP: At the Buffalo General Hospital in New York, researchers randomly assigned 6 healthy, nonobese women, 30-36 years old and using a triphasic oral contraceptive (OC) (Triphasil 28, Wyeth-Ayerst Laboratories), to either the baseline phase group or the group receiving an intravenous bolus of methylprednisolone sodium succinate at a dose of 0.6 mg/kg ideal body weight during the 2-week period after ovulation (i.e., luteal phase). These women were compared with 6 other women who did not use OCs but did receive the same dose of methylprednisolone. The purpose was to determine whether the adrenosuppressive, anti-inflammatory, and immunosuppressive effects of methylprednisolone differ in OC users. OC users experienced slower clearance of methylprednisolone (33% slower) than controls. This slower clearance rate contributed to a longer elimination half-life for methylprednisolone (2.2 vs. 1.72 hours; p 0.05). OC users also had a rate of slower elimination of cortisol than controls (0.180 vs. 0.276 hr-1; p 0.05). They had higher mean cortisol levels than controls (136 vs. 65 ng/ml). Women who used OCs for suppression of cortisol secretion had a larger value for the concentration of cortisol that suppresses the zero-order production rate by 50% (0.37 vs. 0.11 ng/ml; p 0.05), suggesting a decreased sensitivity to the effects of methylprednisolone on cortisol suppression. OC users experienced a greater net suppression of basophils at drug effect than at baseline. Methylprednisolone appeared to have no effect on helper T-cell responses. These findings suggest that OCs inhibit methylprednisolone metabolism. Since there were inconsistent changes in several responses, women can likely receive similar doses of methylprednisolone irrespective of OC use.
Asunto(s)
Antiinflamatorios/farmacocinética , Anticonceptivos Hormonales Orales/farmacología , Inmunosupresores/farmacocinética , Metilprednisolona/farmacocinética , Adulto , Estudios Cruzados , Femenino , Histamina/sangre , Humanos , Hidrocortisona/sangre , Recuento de Linfocitos , Valores de ReferenciaRESUMEN
Methylprednisolone (MP) pharmacokinetics and its directly suppressive effects on cortisol secretion and cell trafficking were compared in 6 chronic renal failure (CRF) subjects and 6 healthy controls. After IV administration of MP 0.6 mg/kg as Solu-Medrol, the pharmacokinetics of methylprednisolone were similar. The clearance was about 280 ml/hr/kg, volume of distribution was 1.1 l/kg, t1/2 was 2.7 hr, and fraction unbound was 0.2. Physiologic pharmacodynamics models were applied for the suppression of cortisol secretion and recirculation of basophils, T-helper cells, and T-suppressor cells. The net response (area under the curve) and inhibitory concentrations (IC50) of methylprednisolone for each pharmacodynamic parameter were similar in both groups. As the pharmacokinetics of other corticosteroids are altered in CRF, the lack of pharmacokinetic/dynamic changes of methylprednisolone may offer a therapeutic advantage for CRF patients.
Asunto(s)
Fallo Renal Crónico/metabolismo , Metilprednisolona/farmacología , Metilprednisolona/farmacocinética , Adulto , Basófilos/efectos de los fármacos , Humanos , Hidrocortisona/sangre , Fallo Renal Crónico/sangre , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , Diálisis Renal , Linfocitos T Colaboradores-Inductores/efectos de los fármacos , Linfocitos T Reguladores/efectos de los fármacosRESUMEN
The circadian pattern of the immune system correlates with that of circulating T-helper cells and inversely with cortisol concentrations. Corticosteroids, both endogenous and exogenous, cause lymphocyte dimunition in blood by retention of cells in the lymphatic circulation. A physiologic pharmacodynamic model was developed to describe changes in circulating lymphocytes as a function of both endogenous cortisol and methylprednisolone concentrations. The model was applied to T-helper and T-suppressor cell data collected from six asthmatic men during baseline, after single-dose, and after 6 days of 20 mg daily methylprednisolone. The model described all phases of the study well. Baseline circadian rhythm of lymphocytes was related to cortisol concentrations. Multiple-dosing of methylprednisolone caused apparent tolerance and decreased the sensitivity of lymphocytes to corticosteroids by 116% and markedly reduced endogenous cortisol concentrations. A 60% increase in circulating T-helper cells was observed which could be accounted for by dual changes in receptor sensitivity and endogenous cortisol.
Asunto(s)
Corticoesteroides/farmacología , Corticoesteroides/fisiología , Linfocitos/efectos de los fármacos , Linfocitos/fisiología , Adulto , Asma/sangre , Relación CD4-CD8 , Ritmo Circadiano/fisiología , Glucocorticoides/farmacología , Humanos , Hidrocortisona/farmacología , Recuento de Linfocitos/efectos de los fármacos , Masculino , Metilprednisolona/farmacología , Modelos Biológicos , Linfocitos T Colaboradores-Inductores/efectos de los fármacos , Linfocitos T Colaboradores-Inductores/fisiologíaRESUMEN
The pharmacokinetics and selected pharmacodynamic responses to methylprednisolone were investigated in six men and six premenopausal women after a dose of 0.6 mg/kg ideal body weight. Women (luteal phase) exhibited a greater methylprednisolone clearance (0.45 versus 0.29 L/hr/kg) and shorter elimination half-life (1.7 versus 2.6 hours) than men. The volume of distribution of methylprednisolone was similar when normalized for ideal body weight. Pharmacodynamic models were used to examine the methylprednisolone suppressive effects on cortisol secretion and basophil and helper T lymphocyte trafficking. A significantly smaller 50% inhibitory concentration (IC50) value (0.1 versus 1.7 ng/ml) was seen in the women for suppression of cortisol secretion, indicating increased sensitivity. However, the area under the concentration-time curve of effect was similar for both groups. The IC50 values for effects of methylprednisolone on basophil trafficking related to estradiol concentrations in a log-linear fashion in women, with increased sensitivity found at higher estradiol concentrations. Men displayed a greater 24-hour net suppression in blood basophil numbers, but no difference was observed in net cortisol and helper T lymphocyte suppression between the sexes. These findings suggest that methylprednisolone dosages should be based on ideal body weight. Although women are more sensitive to methylprednisolone as measured by cortisol suppression, they eliminate the drug more quickly, generally producing a similar net response.
Asunto(s)
Metilprednisolona/farmacología , Caracteres Sexuales , Adulto , Basófilos/efectos de los fármacos , Femenino , Semivida , Histamina/sangre , Humanos , Hidrocortisona/sangre , Recuento de Leucocitos/efectos de los fármacos , Masculino , Ciclo Menstrual/metabolismo , Metilprednisolona/sangre , Metilprednisolona/farmacocinética , Persona de Mediana Edad , Modelos Biológicos , Valores de Referencia , Linfocitos T Colaboradores-Inductores/efectos de los fármacosRESUMEN
The disposition of methylprednisolone (MP) and its prodrug hemisuccinate (MPHS) was assessed in six middle-aged patients with chronic liver disease (CLD) and compared with six younger, healthy subjects after a single IV dose of 25.4 mg of MPHS. Blood and urine samples were collected over 12 hours. Plasma and urine concentrations of MPHS and MP and plasma cortisol were measured by HPLC. MPHS clearance (CL) was significantly reduced in the CLD group (495 vs. 1389 mL/hr/kg) whereas volume of distribution (Vss) of MPHS (about 0.35 1/kg) did not differ. The elimination half-life, t1/2 beta, was significantly longer in CLD (0.61 vs. 0.32 hr). The percent recovery of unchanged MPHS in urine was similar (about 9%) in both groups. The kinetic parameters of MP did not differ between the two groups for: clearance (about 370 L/hr/kg IBW), Vss (about 1.3 L/kg), and t1/2 beta (about 3.0 hr). The suppression t1/2 of cortisol after MPHS was longer (3.9 vs. 1.9 hr) indicating metabolic pathways for cortisol and MP are affected differently in CLD. Reduction in MPHS CL may reflect altered hepatic blood flow due to both cirrhosis and age effects. However, good availability of MP from MPHS and lack of perturbation of MP pharmacokinetics in CLD patients may provide therapeutic advantages in selection of this glucocorticoid. This is the first study that characterizes the disposition of the prodrug MPHS and the formation of MP simultaneously in CLD patients.
Asunto(s)
Cirrosis Hepática Alcohólica/metabolismo , Hemisuccinato de Metilprednisolona/farmacocinética , Metilprednisolona/farmacocinética , Adulto , Enfermedad Crónica , Semivida , Humanos , Hidrocortisona/sangre , Hipertensión Portal/metabolismo , Cirrosis Hepática Alcohólica/enzimología , Masculino , Metilprednisolona/sangre , Metilprednisolona/orina , Hemisuccinato de Metilprednisolona/sangre , Hemisuccinato de Metilprednisolona/orina , Persona de Mediana EdadRESUMEN
The pharmacokinetics and pharmacodynamics of prednisolone were evaluated in normal male volunteers. Seven subjects completed 3 phases: 16.4- and 49.2-mg iv prednisolone, and a phase with no drug to assess baseline responses. Plasma concentrations of prednisolone and urine concentrations of prednisolone and 5 metabolites were assayed by HPLC. Protein binding of prednisolone was measured by ultrafiltration. The polyexponential disposition of free and total plasma prednisolone were evaluated and apparent parameters were compared between doses. Suppression of plasma cortisol and alterations in blood basophil and helper-T cell trafficking were used as pharmacodynamic indices. Pharmacodynamic models were used to relate total or free plasma prednisolone concentrations to each of these effects generating response parameters and IC50 (50% inhibitory) concentrations common to both doses. The pharmacokinetics of total drug were comparable to previous findings with CL and Vss increasing with dose. Free prednisolone exhibited slight capacity-limited elimination and distribution as CL and Vss decreased with the larger dose. Pharmacodynamic models jointly fitting all three phases characterized the suppression/trafficking phenomena equally well with use of total or free drug concentrations. In each case the models provided realistic values of parameters relating to steroid sensitivity--in particular IC50--and to the underlying physiology of the affected systems. This study comprehensively elucidates the complexities of prednisolone pharmacokinetics and demonstrates how plasma concentration--time profiles of total or free prednisolone can be utilized for evaluation of prednisolone pharmacodynamics.
Asunto(s)
Prednisolona/farmacocinética , Adulto , Basófilos/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Relación Dosis-Respuesta a Droga , Humanos , Hidrocortisona/sangre , Masculino , Modelos Biológicos , Prednisolona/administración & dosificación , Prednisolona/farmacología , Unión Proteica , Linfocitos T Colaboradores-Inductores/efectos de los fármacosRESUMEN
A two-compartment closed model was used to characterize the cell trafficking behavior of helper T cells in response to various single doses of methylprednisolone. Steroids are assumed to inhibit the circadian-determined cell return from extravascular sites to blood in a classic inhibitory pattern reflected by an IC50. The rate of cell efflux from tissues is modeled with a cosine function having a period of 24 hr and a maximum at about 1 AM. Nonlinear least-squares regression employing differential equations was used to analyze helper T-cell data from three human studies from our laboratory. The IC50 value of methylprednisolone of 12-19 ng/ml approximates receptor KD values. Simulations were performed to demonstrate the log-linear role of steroid dose or AUC on the integral of effect of helper T cells over a wide range of methylprednisolone doses. This pharmacodynamic model allows flexibility for characterizing any type of steroid dosing regimen and is relevant in describing complex response data for corticosteroid immunosuppressive effects in man.
Asunto(s)
Ritmo Circadiano/efectos de los fármacos , Metilprednisolona/farmacología , Linfocitos T Colaboradores-Inductores/efectos de los fármacos , Humanos , Masculino , Modelos Biológicos , Modelos Estadísticos , Linfocitos T Colaboradores-Inductores/inmunologíaRESUMEN
The temporal variations in the pharmacokinetics and pharmacodynamics of methylprednisolone at 8 AM versus 4 PM were investigated in six healthy male volunteers. Subjects completed three phases: no drug administration, 20 mg intravenous methylprednisolone at 8 AM, and the same dose at 4 PM. Methylprednisolone clearance was 28% greater in the afternoon. The suppressive effects of methylprednisolone on basophils (measured as whole blood histamine), helper T lymphocytes, and cortisol concentrations, assessed by the ratio of the area under the curve (AUC) after methylprednisolone to the baseline AUC, were not different between the phases. The 50% inhibitory concentration values for methylprednisolone derived from pharmacodynamic models were also similar, indicating no difference in intrinsic responsiveness. However, cortisol concentrations returned to baseline about 4 hours earlier after the 4 PM compared with the 8 AM dose because of the enhanced afternoon methylprednisolone clearance. These findings are in agreement with other studies that suggest adequate clinical effects and less disturbance of cortisol circadian behavior when methylprednisolone is administered as a single dose in the morning.
Asunto(s)
Ritmo Circadiano/fisiología , Metilprednisolona/farmacología , Adulto , Basófilos/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Humanos , Hidrocortisona/sangre , Masculino , Metilprednisolona/sangre , Metilprednisolona/farmacocinética , Modelos Biológicos , Linfocitos T Colaboradores-Inductores/efectos de los fármacosRESUMEN
Methylprednisolone pharmacokinetics and its directly suppressive effects on plasma cortisol, blood histamine (basophils), and circulating helper T cells were evaluated in six obese (at least 35% above ideal body weight) men and six nonobese male volunteers. Methylprednisolone doses of 0.6 mg/kg total body weight were administered as the 21-succinate sodium salt. Absolute clearance (in liters per hour) of methylprednisolone was 40% less in the obese subjects. Total volume of distribution (Vss) of methylprednisolone was unchanged (about 120 L), but when normalized for total body weight, Vss per kilogram was less in obesity. The patterns of cortisol, blood histamine, and helper T cell responses after methylprednisolone administration were similar in both groups, but more profound effects were observed in the obese subjects. Pharmacodynamic models were applied for these immediate effects of methylprednisolone based on the premise that receptor interactions of steroids are followed by rapid suppression of the circadian rhythm of cortisol and recirculation of basophils and helper T cells, which persist until inhibitory concentrations (IC50) of methylprednisolone disappear. Similar IC50 values for the three effects were obtained in both groups, indicating no intrinsic pharmacodynamic differences in sensitivity to these methylprednisolone effects in obesity. However, methylprednisolone should be administered on the basis of ideal body weight, and the dosing interval should be potentially lengthened because of decreased methylprednisolone clearance in obesity.
Asunto(s)
Hemisuccinato de Metilprednisolona/farmacocinética , Metilprednisolona/farmacocinética , Obesidad/metabolismo , Adulto , Basófilos/metabolismo , Ritmo Circadiano , Evaluación de Medicamentos , Histamina/sangre , Humanos , Hidrocortisona/sangre , Recuento de Leucocitos , Masculino , Hemisuccinato de Metilprednisolona/sangre , Hemisuccinato de Metilprednisolona/orina , Análisis de Regresión , Linfocitos T Colaboradores-Inductores/efectos de los fármacosRESUMEN
The effects of ketoconazole on the pharmacokinetics and pharmacodynamics of intravenous prednisolone (14.8 mg) were assessed in six healthy volunteers. Subjects were studied with and without receiving ketoconazole, 200 mg orally for 6 days. The addition of ketoconazole did not significantly change the clearance (96 +/- 11 versus 90 +/- 11 ml/hr/kg), mean residence time (4.29 +/- 0.43 versus 4.45 +/- 0.59 hours), volume of distribution (0.41 +/- 0.02 versus 0.40 +/- 0.02 L/kg), or plasma protein binding characteristics of prednisolone. The suppressive effects of prednisolone on serum cortisol, blood basophil, and helper T lymphocyte values, assessed by the ratio of the area under the curve (AUC) after prednisolone administration to the baseline AUC, was not altered significantly by ketoconazole. The 50% inhibitory concentration values derived from pharmacodynamic models developed to describe the direct suppressive effects of corticosteroids indicated no alteration in intrinsic sensitivity in the presence of ketoconazole. Ketoconazole does not appear to alter the pharmacokinetics or the pharmacodynamic response patterns of selected direct suppression effects of single low doses of prednisolone.
Asunto(s)
Cetoconazol/farmacocinética , Prednisolona/farmacocinética , Adulto , Análisis de Varianza , Basófilos/metabolismo , Proteínas Sanguíneas/metabolismo , Ritmo Circadiano , Evaluación de Medicamentos , Interacciones Farmacológicas , Histamina/sangre , Humanos , Hidrocortisona/sangre , Cetoconazol/sangre , Cetoconazol/farmacología , Recuento de Leucocitos , Masculino , Prednisolona/sangre , Prednisolona/farmacología , Unión Proteica , Linfocitos T Colaboradores-Inductores/citologíaRESUMEN
Inhibitory drug interactions affecting the metabolism of methylprednisolone (MP) may produce either steroid sparing or adverse effects partly by increasing the exposure time to the steroid. This phenomenon can be mimicked by administering MP in divided doses. Two types of responses were compared after a single MP dose (40 mg bolus) and a divided regimen (20 mg bolus and a 5 mg bolus 8 hours later) in six healthy male volunteers. The suppression of basophils measured as whole blood histamine and plasma cortisol concentrations was assessed during 32 hours. The 37.5% reduction in dose produced a 23% overall decreased blood histamine response. A pharmacodynamic model for basophil cell distribution to and from an extravascular compartment describes the effects of MP after both regimens. A slower initial decline in blood histamine after the divided regimen may be related to incomplete suppression of basophil cell return to blood. The 50% inhibitory concentrations of MP of about 5 ng/ml were similar for both regimens. The decline and return of cortisol concentrations were similar between MP treatments with suppression continuing for 24 hours. The 50% inhibitory concentrations of MP values for adrenal suppression were about 1 ng/ml. Pharmacodynamic modeling is useful in quantitating corticosteroid responses and generally predicted the "dose-sparing" effects that were achieved by prolonging MP plasma concentrations. This study supports previous clinical observations that patients may require morning through evening exposure to MP to optimize efficacy while adrenal suppression is being minimized.
Asunto(s)
Metilprednisolona/farmacología , Adulto , Basófilos/citología , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Histamina/sangre , Humanos , Hidrocortisona/sangre , Recuento de Leucocitos , Masculino , Metilprednisolona/administración & dosificación , Ensayos Clínicos Controlados Aleatorios como Asunto , Receptores de Glucocorticoides/fisiologíaRESUMEN
Pharmacodynamic models for "directly suppressive" effects of methylprednisolone are based on the premise that receptor interactions of steroids are followed by immediate suppression of either the circadian secretion of cortisol or the constant rate recirculation of histamine-containing basophils that persists until inhibitory concentrations of methylprednisolone disappear. Methylprednisolone doses of 0, 10, 20, and 40 mg were given as the 21-succinate sodium salt in a balanced crossover study to six normal men. Plasma steroid concentrations and blood histamine were measured simultaneously. Both forms of methylprednisolone exhibited linear kinetic parameters. One dynamic model quantitates the baseline circadian pattern and the decline and return of cortisol with similar parameter estimates for all three dose levels. A similar model describes the monoexponential decline and the log-linear return to steady-state baseline of blood histamine. Similar inhibitory concentration values for both effects approximated the equilibrium dissociation constant of in vitro steroid receptor binding. The new models are more physiologically appropriate for these steroid effects than three other models that are commonly employed in pharmacodynamics. Steroid effects generally appear to be receptor mediated with either nongene immediate responses or gene-mediated delayed effects. These models allow quantitation of the rapid effects of steroids with simple equations and common fitted parameters for all steroid dose levels.
Asunto(s)
Histamina/sangre , Hidrocortisona/sangre , Hemisuccinato de Metilprednisolona/farmacocinética , Metilprednisolona/análogos & derivados , Metilprednisolona/farmacocinética , Modelos Biológicos , Adulto , Análisis de Varianza , Basófilos/análisis , Basófilos/metabolismo , Proteínas Sanguíneas/metabolismo , Cromatografía Líquida de Alta Presión , Ritmo Circadiano , Humanos , Análisis de los Mínimos Cuadrados , Masculino , Metilprednisolona/farmacología , Hemisuccinato de Metilprednisolona/farmacología , Unión Proteica , RadioinmunoensayoRESUMEN
Ketoconazole inhibits the clearance of methylprednisolone by 60 percent and extends cortisol suppression beyond that produced by methylprednisolone alone. This study examined prednisolone pharmacokinetics and cortisol suppression in four healthy male volunteers following administration of prednisone 20 mg. Studies were performed with and without ketoconazole 200 mg po for six days. Blood samples were obtained serially over 24 hours and serum prednisone, prednisolone, and cortisol concentrations were determined by HPLC. Prednisolone clearance before and after ketoconazole therapy was not significantly different (160 +/- 38 vs. 148 +/- 23 mL/h/kg). In addition, no significant differences were found in mean residence time (5.03 +/- 0.69 vs. 6.18 +/- 1.77 h), terminal slope (0.23 +/- 0.03 vs. 0.19 +/- 0.05 h-1), or volume of distribution (0.79 +/- 0.11 vs. 0.84 +/- 0.12 L/kg). The ratio of cortisol area under the concentration versus time curve (AUC) 0-24 hours after prednisone administration to the AUC under baseline conditions was used as a measure of adrenal suppression. This ratio was not significantly different after prednisolone with and without ketoconazole (0.40 +/- 0.10 vs. 0.45 +/- 0.03). Renal excretion of prednisone and prednisolone was not significantly changed with ketoconazole. Based on this preliminary study, ketoconazole minimally alters prednisolone clearance in contrast to the significant ketoconazole-methylprednisolone interaction previously reported.
Asunto(s)
Corticoesteroides/farmacocinética , Cetoconazol/farmacología , Prednisolona/orina , Administración Oral , Adulto , Ritmo Circadiano , Humanos , Masculino , Prednisolona/farmacocinética , Prednisona/farmacocinéticaRESUMEN
The effects of 3 days of pretreatment with cardioselective doses of atenolol on theophylline pharmacokinetics were determined. Nine healthy nonsmoking male volunteers received 6 mg kg-1 i.v. aminophylline under baseline conditions and after both 50 mg day-1 and 100 mg day-1 atenolol. Theophylline clearance, volume of distribution and half-life were not influenced by atenolol pretreatment. These data indicate that cardioselective doses of atenolol do not alter the pharmacokinetics of theophylline.