RESUMO
This Phase I study of 1alpha-hydroxyvitamin D(2), an p.o. administered vitamin D analogue, in patients with advanced hormone-refractory prostate cancer was designed to assess the toxicity, pharmacokinetic and biological markers of drug activity, and lastly tumor response data to recommend a dose for Phase II studies. 1alpha-Hydroxyvitamin D(2) was administered daily at doses ranging from 5 to 15 microg/day. Patients were monitored for toxicity and tumor response, and blood and urine samples were collected for pharmacokinetics (1alpha,25-dihydroxyvitamin D(2) levels) and other parameters of biological activity (bone markers, parathyroid hormone, urine calcium, and serum phosphorus levels). Twenty-five patients were enrolled. Main toxicities were hypercalcemia with associated renal insufficiency. No other significant toxicity was seen. Pharmacokinetics showed an increase in the active metabolite 1alpha,25-dihydroxyvitamin D(2) that reached a plateau by week 4 despite continuous drug dosing. Elevation in daily urinary calcium excretion and serum phosphorus levels was seen, whereas a decrease in serum parathyroid hormone was evident. Two patients showed evidence of a partial response, whereas 5 others achieved disease stabilization for > or =6 months. 1alpha-Hydroxyvitamin D(2) was well tolerated with main toxicities being hypercalcemia and renal insufficiency. All of the toxicity was reversible with drug discontinuation. Evidence for drug activity was seen in surrogate markers, and pharmacokinetic analysis showed substantial increases in vitamin D metabolite levels among the various cohorts. Whereas the defined maximum tolerated dose was not reached, the recommended Phase II dose was 12.5 microg/day given continuously.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos Hormonais/uso terapêutico , Ergocalciferóis/uso terapêutico , Pró-Fármacos/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Terapia de Salvação , Adenocarcinoma/sangue , Adenocarcinoma/urina , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/sangue , Antineoplásicos Hormonais/efeitos adversos , Antineoplásicos Hormonais/sangue , Antineoplásicos Hormonais/farmacocinética , Antineoplásicos Hormonais/urina , Biomarcadores Tumorais/sangue , Cálcio/urina , Estudos de Coortes , Resistencia a Medicamentos Antineoplásicos , Ergocalciferóis/efeitos adversos , Ergocalciferóis/sangue , Ergocalciferóis/farmacocinética , Ergocalciferóis/urina , Humanos , Hipercalcemia/induzido quimicamente , Falência Renal Crônica/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/sangue , Osteocalcina/sangue , Hormônio Paratireóideo/sangue , Fósforo/sangue , Pró-Fármacos/efeitos adversos , Pró-Fármacos/farmacocinética , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/urina , Resultado do TratamentoRESUMO
Patients with the nephrotic syndrome may exhibit low serum 25-OH-D concentrations. We developed a method for isolation of 25-OH-D from urine, with measurement by competitive binding assay. Daily urinary 25-OH-D excretion in healthy subjects averaged 0.17 +/- 0.15 nmol/day. Among nephrotic patients, urinary 25-OH-D excretion ranged from 0.27 to 10 nmol/day, in direct relation to the severity of proteinuria (r=0.76) and averaged 3.7 +/- 3.5 nmol/day. The 25-OH-D in the urine of nephrotic patients was unconjugated, implying that it was excreted with the serum VDBG, which has been shown to have a molecular weight and isoelectric point similar to that of albumin. We conclude that low serum 25-OH-D concentrations among nephrotic patients are principally the result or urinary losses of steroid. (J Lab Clin Med 99:325, 1982.)
