Dominici C, Petrucci F, Caroli S, Alimonti A, Clerico A, Castello M A
Department of Pediatrics, University La Sapienza, Rome, Italy.
J Clin Oncol. 1989 Jan;7(1):100-7. doi: 10.1200/JCO.1989.7.1.100.
The pharmacokinetics of cisplatin were investigated in 14 patients, aged 10 months through 13 years who were affected by solid malignant tumors. High-dose cisplatin (40 mg/m2/d) was administered with repeated courses for five days as a continuous intravenous (IV) infusion. Total platinum (Pt) levels in plasma and urine and free (protein-unbound) Pt levels in plasma ultrafiltrate were determined by inductively coupled plasma atomic emission spectrometry (ICP-AES). Areas under the concentration v time curve (AUCs) for mean total and free Pt levels were calculated for the 120-hour period of infusion and for the 384 and 120 hours following its completion, respectively. Half-lives of total and free Pt in plasma were calculated for the 216 hours following completion of infusion in five patients at their first course. The fraction of the administered Pt dose excreted in urine as Pt was determined for the five-day period of infusion and seven-day period after its completion. A total of 36 courses were studied. Maximum average Pt levels were reached after 120 hours of infusion: at the first course, 3.22 and 0.17 micrograms/mL for total and free Pt, respectively. Platinum levels declined according to a biexponential model, with initial half-lives of 18.3 and 16.9 minutes, and terminal half-lives of 81.9 and 59.0 hours as determined for total and free Pt, respectively. In the second and third courses studied there was a progressive increase in mean Pt plasma levels. Consequently, the free drug exposure as measured by AUC increased in all patients with repeated courses: 47.7% for the second and 124.4% for the third course, when compared with the first. At the same time, the mean fraction of the dose excreted in the urine for the 12-day period considered, was 44.1% for the first course, 36.2% for the second, and 28.4% for the third. The progressive enhancement of tissue exposure to the free cytotoxic drug, resulting from a reduced renal clearance of Pt with sequential courses of cisplatin, produced mainly increased toxicity while therapeutic effect progressively diminished.
对14例年龄在10个月至13岁之间的实体恶性肿瘤患者进行了顺铂的药代动力学研究。高剂量顺铂（40mg/m²/d）以连续静脉输注的方式重复给药5天。通过电感耦合等离子体原子发射光谱法（ICP-AES）测定血浆和尿液中的总铂（Pt）水平以及血浆超滤液中的游离（未与蛋白质结合）Pt水平。分别计算了输注120小时期间以及输注结束后384小时和120小时内平均总Pt水平和游离Pt水平的浓度-时间曲线下面积（AUC）。在5例患者首次疗程输注结束后的216小时内计算了血浆中总Pt和游离Pt的半衰期。确定了输注5天期间及输注结束后7天内以Pt形式经尿液排泄的给药Pt剂量的比例。共研究了36个疗程。输注120小时后达到最大平均Pt水平：在首次疗程时，总Pt和游离Pt分别为3.22和0.17μg/mL。铂水平根据双指数模型下降，总Pt和游离Pt的初始半衰期分别为18.3和16.9分钟，终末半衰期分别为81.9和59.0小时。在研究的第二个和第三个疗程中，平均血浆Pt水平逐渐升高。因此，所有患者重复疗程后，以AUC衡量的游离药物暴露增加：与首次疗程相比，第二个疗程增加47.7%，第三个疗程增加124.4%。同时，在所考虑的12天期间，首次疗程经尿液排泄的剂量平均比例为44.1%，第二个疗程为36.2%，第三个疗程为28.4%。顺铂连续疗程导致Pt肾清除率降低，从而使组织对游离细胞毒性药物的暴露逐渐增加，这主要导致毒性增加，而治疗效果逐渐减弱。
