RESUMEN
Thalidomide is approved in the United States for treating erythema nodosum leprosum, a complication of leprosy. The present study determined the single-dose oral pharmacokinetics and dose proportionality from 50 to 400 mg of Celgene's commercial Thalomid thalidomide formulation in an open-label, single-dose, three-way crossover study. Fifteen healthy subjects were given 50, 200, and 400 mg of thalidomide on three occasions, and blood samples were collected over 48 hours. Pharmacokinetic parameters were determined using noncompartmental methods, and dose proportionality was assessed by linear regression of dose-normalized Cmax and AUC0-infinity. No serious or unexpected adverse events occurred. The most common adverse events were dizziness, somnolence, headache, and nausea. One patient was discontinued because of pharyngitis. There was a significant deviation from proportionality for Cmax with increases being less than proportional than changes in dose. AUC0-infinity increased proportionally with dose, suggesting that the overall amount of thalidomide absorbed, as well as its clearance, is independent of dose over the range used. V/F was found to increase with dose. This was most likely due to the terminal rate constant, which is used to calculate V/F, actually representing the absorption process rather than elimination (i.e., flip-flop phenomenon). The terminal rate constant (absorption rate constant) for the highest dose was 50% less than for the other two lower doses. The less than proportional increases in Cmax were most likely due to thalidomide's low aqueous solubility. Thalidomide shows reasonable dose proportionality with respect to AUC from 50 to 400 mg.
Asunto(s)
Leprostáticos/farmacocinética , Talidomida/farmacocinética , Adulto , Área Bajo la Curva , Peso Corporal , Femenino , Humanos , Leprostáticos/administración & dosificación , Leprostáticos/efectos adversos , Leprostáticos/sangre , Masculino , Persona de Mediana Edad , Talidomida/administración & dosificación , Talidomida/efectos adversos , Talidomida/sangreRESUMEN
Clinical management of ductal carcinoma in situ (DCIS) remains a challenge because significant proportions of patients experience recurrence after conservative surgical treatment. Unfortunately, it is difficult to prospectively identify, using objective criteria, patients who are at high risk of recurrence and might benefit from additional treatment. We conducted a multi-institutional, collaborative case-control study to identify nuclear morphometric features that would be useful for identifying women with DCIS at the highest risk of recurrence. Tissue sections of archival breast tissue of 29 women with recurrent and 73 matched women with nonrecurrent DCIS were stained for DNA, and nuclei in the DCIS lesions were evaluated by image analysis. A clear correlation between mean fractal2_area (FA2) and nuclear grade was observed (P < 0.001), allowing an objective determination of nuclear grade. Several nuclear morphometric features, including mean and variance of variation of radius, mean area, mean and variance of frequency of high boundary harmonics (FQH), and variance in sphericity, were found to be useful in discriminating recurrent from nonrecurrent DCIS subjects. However, the nuclear features associated with recurrence differed between high- and low-grade lesions. For lesions with high FA2 (nuclear grade 3), mean variation of radius, mean FQH, and mean area alone yielded recurrence odds ratios of 4.55 [95% confidence interval (CI) 0.45-45.96], 3.86 (95% CI, 0.88-16.98), 2.90 (95% CI, 0.31-27.2), respectively. Using a summed feature model, high-FA2 lesions showing three poor prognostic features had an odds ratio of 15.63 (95% CI, 1.22-200), compared with those with zero or one poor prognostic feature. Lesions with low mean FA2 (nuclear grade 1 or 2) showing high variances in sphericity and FQH had an odds ratio of 7.71 (95% CI, 1.77-33.60). Addition of other features did not enhance the odds ratio or its significance. These results suggest that nuclear image analysis of DCIS lesions may provide an adjunctive tool to conventional pathological analysis, both for the objective assessment of nuclear grade and for the identification of features that predict patient outcome.
Asunto(s)
Neoplasias de la Mama/patología , Carcinoma Intraductal no Infiltrante/patología , ADN de Neoplasias/análisis , Procesamiento de Imagen Asistido por Computador , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/patología , Matriz Nuclear/patología , Adulto , Anciano , Anciano de 80 o más Años , Biopsia con Aguja , Neoplasias de la Mama/epidemiología , Carcinoma Intraductal no Infiltrante/epidemiología , Estudios de Casos y Controles , Estudios de Cohortes , Intervalos de Confianza , Femenino , Humanos , Incidencia , Persona de Mediana Edad , Oportunidad Relativa , Valor Predictivo de las Pruebas , Probabilidad , Valores de Referencia , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Sensibilidad y Especificidad , Estadísticas no ParamétricasRESUMEN
UNLABELLED: Diaspirin cross-linked hemoglobin (DCLHb) solution is a purified human hemoglobin product chemically stabilized to deliver oxygen to tissues. We determined the peak plasma hemoglobin concentration and assessed changes in methemoglobin concentration after the infusion of 1 g/kg DCLHb in large blood loss surgical patients. This prospective, randomized study included 26 surgical patients who were either infused with up to three 250-mL units of 10% DCLHb or transfused with up to three units of packed red blood cells during the study infusion period. Serial plasma hemoglobin, plasma methemoglobin, and whole blood methemoglobin levels were measured before and at intervals up to 48 h after the study infusion period. Plasma hemoglobin and blood methemoglobin concentrations increased during the infusion of DCLHb. The plasma hemoglobin values in the DCLHb group continued to increase during each of the infusion periods to reach a peak plasma concentration of 1450 +/- 176 mg/dL. The fraction of whole blood methemoglobin increased from 0.84 +/- 0.77% at baseline to 4.08 +/- 1.36%. With a median DCLHb dose of 936 mg/kg (range 658-1500 mg/kg), the harmonic mean half-life was 10 h, and the increased whole blood methemoglobin reached a range not associated with complications. IMPLICATIONS: The dose of diaspirin cross-linked hemoglobin (DCLHb) (936 +/- 276 mg/kg) used in this study was one of the largest reported in humans to date. The DCLHb mean half-life was 10 h. The half-life observed was 2-4 times that found at smaller doses in previous studies. Whole blood methemoglobin fraction increased during DCLHb infusion but did not reach a range associated with complications.
Asunto(s)
Aspirina/análogos & derivados , Aspirina/uso terapéutico , Sustitutos Sanguíneos/uso terapéutico , Hemoglobinas/metabolismo , Hemoglobinas/uso terapéutico , Metahemoglobina/metabolismo , Pérdida de Sangre Quirúrgica/prevención & control , Relación Dosis-Respuesta a Droga , Transfusión de Eritrocitos , Humanos , Infusiones Intravenosas , Estudios ProspectivosRESUMEN
The effect of food on the oral pharmacokinetics of thalidomide and the relative bioavailability of two oral thalidomide formulations were determined in an open label, single dose, randomized, three-way crossover study. Five male and eight female healthy volunteers received a single oral dose of 200 mg Celgene thalidomide capsules under fasted and non-fasted conditions, and a single dose of 200 mg tablets of Serral thalidomide under fasted conditions. The high-fat meal resulted in a 0.5-1.5 h absorption lag time, an increased mean C(max), a decreased mean AUC and a delay in mean T(max). The Serral tablet formulation resulted in a lower mean C(max), and slower terminal decline in plasma thalidomide concentrations compared with both Celgene treatments. Mean C(max) concentrations were 1.99+/-0.41 microg/mL (range 1.28-2.76) within 4.00+/-1.13 h (2-5) for the Celgene formulation fasted, 2.17+/-0.51 microg/mL (1.43-3.01) within 6.08+/-2.33 h (3-12) for the Celgene formulation with food, and 1. 05+/-0.31 microg/mL (0.62-1.65) within 6.23+/-1.88 h (5-10) for the Serral formulation fasted. Mean terminal half-lives were 13.50+/-6. 77 h for the Serral product, compared with 5.80+/-1.72 h and 5. 09+/-1.03 h for Celgene fasted and fed, respectively. Celgene's formulation exhibited slightly greater bioavailability than Serral's formulation, with mean ratios of 122% and 110% for Ln-transformed AUC(0-t) and AUC(0-infinity), respectively. The mean C(max) for the Celgene formulation was approximately two times greater than Serral's. Food delayed the onset of absorption of by 0.5-1.5 h, but had little effect on the extent of absorption from the Celgene capsule. Under fasted conditions, the Celgene thalidomide resulted in a two-fold greater C(max) and 10% greater AUC(0-infinity) than the Serral formulation.
Asunto(s)
Grasas de la Dieta/farmacología , Hipnóticos y Sedantes/farmacocinética , Absorción Intestinal/efectos de los fármacos , Talidomida/farmacocinética , Administración Oral , Adulto , Análisis de Varianza , Área Bajo la Curva , Disponibilidad Biológica , Cápsulas , Química Farmacéutica , Ayuno , Femenino , Semivida , Humanos , Hipnóticos y Sedantes/sangre , Masculino , Persona de Mediana Edad , Talidomida/sangreRESUMEN
The current state of clinical pharmacology and drug development did not just happen. Clinical pharmacology and the drug development process were born, evolved, and have come to the fore during the past 100 years. The past century has been one of accelerating progress in science and medicine. The progress has not been a straight line but rather more like a sidewinder moving across the desert. Drug development has moved from small experiments with concoctions, extracts, and potions along with the manufacturing and promotion of the purported remedies to processes that exploited unknowing patients to a process that now requires concept generation, discovery, research, planning, and development with many checks and balances for the protection of human subjects. The factors that contributed to this progression from inappropriate use of potions, concoctions, and snake oil to the highly regulated drug development process of today is described in some detail.
Asunto(s)
Farmacología Clínica/historia , Diseño de Fármacos , Predicción , Historia del Siglo XX , Humanos , Farmacología Clínica/organización & administraciónRESUMEN
AIMS: To compare the pharmacokinetics of ziprasidone in healthy young (18-45 years) men and women, and healthy elderly (> or = 65 years) men and women. METHODS: Eight young men, 11 young women, 8 elderly men and 8 elderly women were given oral ziprasidone 40 mg day(-1), in two evenly divided daily doses, for 7 days, followed by a single 20 mg dose on day 8. Serum samples were collected immediately before the morning dose on days 1-8, for up to 12 h after dosing on day 1 and for up to 96 h after dosing on day 8. The resulting data were used to derive pharmacokinetic parameters of ziprasidone in each age and gender group. RESULTS: Steady-state serum concentrations of ziprasidone were achieved within 2-3 days. The steady-state pharmacokinetics of ziprasidone, determined 8 days after the initiation of treatment, were similar in the young men, elderly men and young women. Assessment of gender effects by analysis of variance revealed statistically significant differences in Cmax (85 vs. 69 ng ml(-1) and tmax (3.19 vs. 4.81 h) but no differences in AUC(0,12 h) or lambda(z). Assessment of age effects by analysis of variance revealed statistically significant differences in AUC(0,12 h) (560 vs. 465 ng ml(-1) h), Cmax (85 vs. 69 ng ml(-1) and lambda(z) (0.126 vs. 0.197 l h(-1) but no difference in tmax. Assessment of age and gender effects by analysis of covariance, with body weight as the covariate, did not reveal any significant differences. The mean t(1/2), z in the young men, young women, elderly men and elderly women were 3.1, 4.1, 5.7 and 5.3 h, respectively. Standard deviations of the means for the pharmacokinetic parameters for the elderly women tended to be large. CONCLUSIONS: The influence of age and gender on the pharmacokinetics of ziprasidone is not clinically significant.
Asunto(s)
Envejecimiento/metabolismo , Antipsicóticos/farmacocinética , Piperazinas/farmacocinética , Tiazoles/farmacocinética , Adolescente , Adulto , Anciano , Antipsicóticos/administración & dosificación , Antipsicóticos/sangre , Área Bajo la Curva , Femenino , Humanos , Masculino , Persona de Mediana Edad , Piperazinas/administración & dosificación , Piperazinas/sangre , Tiazoles/administración & dosificación , Tiazoles/sangreRESUMEN
The two domains in clinical pharmacology dealing with optimizing dosing recommendations are pharmacokinetics and pharmacodynamics. However, the usefulness of these disciplines is limited if viewed in isolation. Pharmacokinetic/pharmacodynamic (PK/PD) relationships and modeling builds the bridge between these two classical disciplines of clinical pharmacology. It links the concentration-time profile as assessed by pharmacokinetics to the intensity of observed response as quantified by pharmacodynamics. Thus, the resulting so-called integrated PK/PD-models allow the description of the complete time course of the desired and/or undesired effects in response to a drug therapy. PK/PD-modeling can elucidate the causative relationship between drug exposure and response and provide a better understanding of the sequence of events that result in the observed drug effect. This information can then be used to streamline the drug development process and dose optimization. This consensus paper presents an update on the current state of PK/PD-modeling from an academic, industrial and regulatory perspective.
Asunto(s)
Diseño de Fármacos , Farmacocinética , Quimioterapia , Humanos , Modelos Biológicos , Farmacología Clínica , Unión Proteica , Tasa de Supervivencia , Factores de Tiempo , Resultado del TratamientoRESUMEN
Biomarkers and surrogate endpoints are critical to the future of efficient drug development. Definitions, a conceptual model, and a conceptual framework for validating and bridging biomarkers to clinical endpoints are provided in this presentation. In addition, a few examples are provided to support the development concept. Poor correlation between a biomarker and its clinical endpoint may result from (1) poor measurement of one or both, (2) selection of an inappropriate biomarker, or, more important, (3) use of an inappropriate clinical endpoint. Pharmacokinetic/pharmacodynamic (PK/PD) modeling output can be no better than biomarkers or surrogate endpoints used for the modeling. As we increase our understanding of biomarkers, surrogate markers, and the mechanistic basis for the processes of interest, biomarker and surrogate endpoint predictive power will no longer be an issue and PK/PD modeling inputs and outputs will improve.
Asunto(s)
Biomarcadores/análisis , Diseño de Fármacos , Relación Dosis-Respuesta a Droga , Quimioterapia , Predicción , Humanos , Farmacocinética , Reproducibilidad de los Resultados , Factores de TiempoRESUMEN
Thalidomide was recently approved in the United States for the treatment of erythema nodosum leprosum, a complication of leprosy. The present study determined the bioequivalence and pharmacokinetics of Celgene's commercial and clinical trial thalidomide formulations and the Brazilian Tortuga formulation in an open-label, single-dose, three-way crossover design. Seventeen healthy subjects were given 200 mg of thalidomide on three occasions, and blood samples were collected over 48 hours. Pharmacokinetic parameters were determined using compartmental methods for the two Celgene formulations and using noncompartmental methods for all three formulations. All subjects reported adverse events, none of which was serious or unexpected. Celgene formulations were bioequivalent when comparing Cmax, tmax, and AUC. There was significant variability in plasma levels from the Tortuga formulation, giving a mean profile that was distinctly different from the two Celgene formulations with a lower Cmax value and a longer terminal phase. The lower Cmax was probably due to slower absorption. The terminal rate constant for the Tortuga formulation was significantly less, giving rise to a terminal half-life of 15 hours compared to about 5 to 6 hours for the Celgene formulations. Confidence intervals for Cmax between the Tortuga and the Celgene formulations were outside the 80% to 125% range, indicating a lack of bioequivalence. Extent of absorption, as measured by AUC0-infinity, was approximately equal for all three formulations. Terminal half-life for Tortuga was two to three times longer compared to the Celgene formulations and is clear evidence for absorption rate limitations. The two Celgene formulations showed similar pharmacokinetic parameters with profiles that were best described by a one-compartment model with first-order absorption and elimination. The authors conclude that Celgene's clinical trial and commercial thalidomide formulations are similar to each other and distinctly different from the Tortuga formulation and that all three formulations exhibited absorption rate-limited elimination.
Asunto(s)
Leprostáticos/farmacocinética , Talidomida/farmacocinética , Adulto , Estudios Cruzados , Ayuno , Humanos , Leprostáticos/efectos adversos , Leprostáticos/sangre , Masculino , Modelos Biológicos , Talidomida/efectos adversos , Talidomida/sangre , Equivalencia Terapéutica , Factores de TiempoRESUMEN
Tacrolimus (FK506, Prograf) is marketed for the prophylaxis of organ rejection following allogenic liver or kidney transplantation. A previously conducted, randomized, 24-subject, crossover bioavailability study of 1 and 5 mg capsules (one period each) failed to demonstrate bioequivalence. A single-dose, four-period, four-sequence, randomized, crossover, replicate study (N = 32) was therefore used to evaluate the bioequivalence of the marketed 1 and 5 mg capsules in healthy volunteers. Tacrolimus blood concentrations were measured serially over 72 hours using a commercially available ELISA assay. Noncompartmental pharmacokinetic parameters were determined. Ninety percent CIs of log-transformed parameter ratios were 90.5-101.9, 87.1-101.7, and 89.7-103.8 for Cmax, AUC0-t, and AUC0-infinity, respectively. Since all values were within 80% to 125%, the capsules are bioequivalent. Based on %CVs, intersubject variability was approximately two to three times greater than intrasubject variability. The safety of single 5 mg oral tacrolimus doses administered to healthy volunteers at 7-day intervals was also ascertained.
Asunto(s)
Inmunosupresores/farmacocinética , Tacrolimus/farmacocinética , Dolor Abdominal/inducido químicamente , Adulto , Área Bajo la Curva , Artralgia/inducido químicamente , Cápsulas , Estudios Cruzados , Diarrea/inducido químicamente , Relación Dosis-Respuesta a Droga , Femenino , Cefalea/inducido químicamente , Humanos , Inmunosupresores/efectos adversos , Articulación de la Rodilla , Masculino , Púrpura/inducido químicamente , Tacrolimus/efectos adversos , Tacrolimus/sangre , Equivalencia TerapéuticaRESUMEN
BACKGROUND: Ductal carcinoma in situ is a non-invasive carcinoma that is unlikely to recur if completely excised. Margin width, the distance between the boundary of the lesion and the edge of the excised specimen, may be an important determinant of local recurrence. METHODS: Margin widths, determined by direct measurement or ocular micrometry, and standardized evaluation of the tumor for nuclear grade, comedonecrosis, and size were performed on 469 specimens of ductal carcinoma in situ from patients who had been treated with breast-conserving surgery with or without postoperative radiation therapy, according to the choice of the patient or her physician. We analyzed the results in relation to margin width and whether the patient received postoperative radiation therapy. RESULTS: The mean (+/-SE) estimated probability of recurrence at eight years was 0.04+/-0.02 among 133 patients whose excised lesions had margin widths of 10 mm or more in every direction. Among these patients there was no benefit from postoperative radiation therapy. There was also no statistically significant benefit from postoperative radiation therapy among patients with margin widths of 1 to <10 mm. In contrast, there was a statistically significant benefit from radiation among patients in whom margin widths were less than 1 mm. CONCLUSIONS: Postoperative radiation therapy did not lower the recurrence rate among patients with ductal carcinoma in situ that was excised with margins of 10 mm or more. Patients in whom the margin width is less than 1 mm can benefit from postoperative radiation therapy.
Asunto(s)
Neoplasias de la Mama/cirugía , Carcinoma in Situ/cirugía , Carcinoma Ductal de Mama/cirugía , Mastectomía Segmentaria , Recurrencia Local de Neoplasia , Neoplasias de la Mama/patología , Neoplasias de la Mama/radioterapia , Carcinoma in Situ/patología , Carcinoma in Situ/radioterapia , Carcinoma Ductal de Mama/patología , Carcinoma Ductal de Mama/radioterapia , Supervivencia sin Enfermedad , Femenino , Humanos , Mastectomía Segmentaria/métodos , Recurrencia Local de Neoplasia/prevención & control , Periodo Posoperatorio , Radioterapia Adyuvante , Estudios RetrospectivosRESUMEN
OBJECTIVES: To determine the single- and multiple-dose pharmacokinetics of oral thalidomide (200 mg/day, administered for 21 days) and to assess the effects of steady-state plasma concentrations of thalidomide on the single-dose pharmacokinetics of ethinyl estradiol (INN, ethinylestradiol) and norethindrone (INN, norethisterone). METHODS: A randomized, 2-period crossover study was performed in 10 healthy premenopausal female volunteers. The pharmacokinetic profiles of plasma concentrations of thalidomide were evaluated with both noncompartmental and compartmental methods, whereas those of ethinyl estradiol and norethindrone were calculated with noncompartmental methods. The effects of steady-state plasma thalidomide concentrations on the pharmacokinetics of ethinyl estradiol and norethindrone were determined with use of an ANOVA model that included treatment sequence, subject within sequence, period, and treatment as factors. RESULTS: Thalidomide plasma concentrations were best predicted by a 1-compartment model with first-order absorption and elimination and an absorption time-lag. There were no significant differences between pharmacokinetic parameters for thalidomide after 1 dose and those after 18 consecutive doses. Except for a minor decrease of the elimination rate constant (k(e)) for ethinyl estradiol, coadministration of thalidomide had no significant effects on the pharmacokinetic profiles for either ethinyl estradiol or norethindrone. The change in k(e) for ethinyl estradiol during thalidomide administration was not associated with any alteration in the clearance or elimination half-life for this hormone. CONCLUSIONS: Multiple-dose pharmacokinetics of thalidomide is similar to the single-dose profile. This study did not investigate the efficacy of the 21-day fixed ethinyl estradiol-norethindrone regimen, but the results suggest that thalidomide is unlikely to affect the pharmacokinetics of orally administered hormonal contraceptives.
Asunto(s)
Antineoplásicos Hormonales/farmacocinética , Anticonceptivos Sintéticos Orales/farmacocinética , Etinilestradiol/farmacocinética , Noretindrona/farmacocinética , Talidomida/farmacología , Talidomida/farmacocinética , Administración Oral , Adulto , Área Bajo la Curva , Estudios Cruzados , Fármacos Dermatológicos/farmacocinética , Fármacos Dermatológicos/farmacología , Esquema de Medicación , Femenino , Semivida , Humanos , Hipnóticos y Sedantes/farmacocinética , Hipnóticos y Sedantes/farmacología , Leprostáticos/farmacocinética , Leprostáticos/farmacología , Valores de Referencia , Talidomida/administración & dosificación , Talidomida/sangreRESUMEN
Several studies have shown an association between high nuclear grade or necrosis of ductal carcinoma in situ (DCIS) lesions and the risk of local disease recurrence in patients with DCIS treated surgically with less than mastectomy. Although criteria for separating low from high nuclear grade lesions have been published, no information exists regarding interobserver reproducibility (IR). To assess IR in the classification of DCIS, six surgical pathologists from four institutions used the Lagios grading system to grade 125 DCIS lesions. Before meeting to evaluate the cases, a training set of 12 glass slides, including cases chosen to present conflicting cues for classification, was mailed to the participants with a written criteria summary. This was followed by a working session in which criteria were reviewed and agreed on. The pathologists then graded the lesions independently. The area of interest was marked on each slide before grading. After initial grading, the pathologists met again to resolve discrepant lesion classifications. A complete agreement among raters was achieved in 43 (35%) cases, with five of six raters agreeing in another 45 (36%) cases. In no case did two raters differ by more than one grade. The pairwise kappa agreement values ranged from fair to substantial (0.30 to 0.61). Generalized kappa value indicated moderate agreement (0.46, standard error = 0.02). Kappa statistics for the distinction between grades 1 and 2 and 2 and 3 were 0.29 and 0.48, respectively, (standard error = 0.02). Only one of the six raters differed significantly in scoring. With adherence to specific criteria, IR in the classification of DCIS cases can be obtained in most cases. Although these pathologists made a few grading system modifications, further refinements are needed, especially if grading will influence future therapy.
Asunto(s)
Neoplasias de la Mama/clasificación , Neoplasias de la Mama/patología , Carcinoma Intraductal no Infiltrante/clasificación , Carcinoma Intraductal no Infiltrante/patología , Núcleo Celular/patología , Femenino , Humanos , Variaciones Dependientes del Observador , Reproducibilidad de los ResultadosRESUMEN
This study was designed to determine the steady-state relative bioavailability of ganciclovir after three dosage regimens designed to deliver 6,000 mg/day. The study design was an open-label, randomized, three-treatment crossover design in which 22 human immunodeficiency virus (HIV) and cytomegalovirus (CMV) seropositive patients received in random order multiple oral doses of ganciclovir 1,000 mg six times a day, 1,500 mg four times a day, and 2,000 mg three times a day. Blood samples were obtained on day 3 of each oral regimen over a 24-hour time interval. Mean steady-state average serum concentrations of ganciclovir were greater than 1.0 microgram/mL, which exceeds the median in vitro inhibitory concentration (IC50) of most CMV isolates (0.5-1.0 microgram/mL). All three regimens resulted in values for area under the concentration-time curve from 0 to 24 hours (AUC0-24) that were comparable to those seen after maintenance ganciclovir intravenous infusions of 5 mg/kg/day. The 1,000 mg six times daily regimen resulted in an AUC0-24 that was significantly higher than that of the 1,500 mg four times daily or the 2,000 mg three times daily regimens, although the differences were less than 12.5%.
Asunto(s)
Antivirales/farmacocinética , Ganciclovir/farmacocinética , Seropositividad para VIH/tratamiento farmacológico , VIH/efectos de los fármacos , Administración Oral , Adulto , Antivirales/administración & dosificación , Antivirales/efectos adversos , Área Bajo la Curva , Disponibilidad Biológica , Estudios Cruzados , Citomegalovirus/efectos de los fármacos , Infecciones por Citomegalovirus/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Ganciclovir/administración & dosificación , Ganciclovir/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Vómitos/inducido químicamenteRESUMEN
This study was designed to determine the bioavailability and dose linearity and proportionality of ganciclovir after multiple oral administrations of 3,000 mg to 6,000 mg per day. In an open-label, randomized, four-treatment crossover design, 24 patients seropositive for human immunodeficiency virus (HIV) and cytomegalovirus (CMV) received in random order multiple oral doses of ganciclovir 1,000 mg every 3 hours (six times a day), 1,000 mg four times a day, and 1,000 mg three times a day and a single 5-mg/kg intravenous infusion (over 1 hour) of ganciclovir. Blood samples for pharmacokinetic determinations were obtained on day 3 of each oral regimen and on the day of the intravenous infusion over a 24-hour time interval. Mean steady-state average serum concentrations of ganciclovir were 0.54, 0.79, and 0.99 microgram/mL, respectively, with the 3, 4, and 6 g/day oral regimens. The steady-state area under the concentration-time curve (AUC0-24) for the 6,000 mg/day oral regimen approached that of the single-dose intravenous regimen. There was a proportional increase in AUC0-24 between the 3 and 4 g/day dosage regimens, but not between the 4 and 6 g/day regimens. This suggests nonlinear absorption of ganciclovir at higher dosages, although the departure from proportionality was less than 11%.
Asunto(s)
Antivirales/farmacocinética , Ganciclovir/farmacocinética , Seropositividad para VIH/metabolismo , Adulto , Área Bajo la Curva , Disponibilidad Biológica , Estudios Cruzados , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Biochemical and clinical markers are critical for efficient development of new molecular entities. Biologic markers of drug effect, sometimes referred to as "surrogate" markers, are used when such clinical outcome measures as survival are substantially delayed relative to predictive biochemical changes or clinical effects of the new molecular entity. Biologic markers have generally been used for early-phase decision-making studies and accelerated regulatory approvals for much-needed drugs to treat cancer and acquired immune deficiency syndrome (AIDS). The rationale for these two uses of biologic markers is different and therefore the foundation required for establishing and validating each may be different. The theoretical foundation required for a marker that will be used to justify the regulatory approval of a treatment for a life-threatening disease should be greater than the required for an early decision-making study with an angiotensin II antagonist that will be used to treat mild to moderate hypertension. Use of CD4 counts as "surrogate markers" for prolonged survival was inappropriate. In contrast, changes in angiotensin-II concentrations and other renin-angiotensin system biochemical markers, observed for the first time in a study in humans, with a purported angiotensin-II receptor antagonist indicate that the new molecular entity is working as hoped. This is a good decision-making tool, because theory indicates that these changes should lead to reduced blood pressure, which is a predictive "surrogate" for reduction in subsequent cardiovascular events. Surrogate, biologic markers should be used only if they have a rational theoretical basis, are proven in preclinical or clinical experience, and are measured with validated methods. Different validation-acceptance criteria for decision-making markers compared with markers used for regulatory approval must be prospectively acknowledged and delineated.