Sonneveld P, Marie J P, Huisman C, Vekhoff A, Schoester M, Faussat A M, van Kapel J, Groenewegen A, Charnick S, Zittoun R, Löwenberg B
University Hospital Rotterdam Dijkzigt/Erasmus University, The Netherlands.
Leukemia. 1996 Nov;10(11):1741-50.
SDZ PSC 833, a non-immunosuppressive cyclosporin analogue reverses multidrug resistance (MDR) in vitro by inhibiting P-glycoprotein (P-gp) mediated drug efflux. We performed a dose escalation study of SDZ PSC 833 combined with VAD chemotherapy in refractory multiple myeloma (MM). Twenty-two MM patients who were refractory to doxorubicin/vincristine/dexamethasone (VADr, n=11) or had failed multiple regimens (n=6) or were melphalan-refractory (MELr, n=5), were treated with one to three cycles of VAD combined with oral SDZ PSC 833, which was administered at escalating dosages starting at 5 mg/kg/day to 15 mg/kg/day for 7 days. The median trough and peak blood levels of SDZ PSC 833 ranged from 461/1134 ng/ml at 5 mg/kg/day to 821/2663 ng/ml at 15 mg/kg, respectively. With addition of SDZ PSC 833 (5 mg/kg) the mean plasma AUC 0-->96 h of doxorubicin as compared with control patients treated with VAD increased from 779 to 1510 ng/ml/h (P=0.0071), while the doxorubicin clearance was reduced from 47.6 to 27.8 l/h/m2 (P=0.0002). The clearance of doxorubicinol was reduced accordingly. Because of the increased plasma AUC, the dose of doxorubicin and vincristine had to be reduced in 13 patients to 50% (n=1) or 75% (n=12). A further dose-escalation of SDZ PSC 833 did not lead to a proportional increase of doxorubicin AUC. Toxicity WHO CTC grade 2 or 3 included hypoplasia (18/22), constipation (10/22), hyponatremia (3/22) and infections (6/22). A partial response or stable disease was achieved in eight and six patients, respectively. In 17 evaluable patients the mean percentage of pretreatment bone marrow plasma cells which expressed P-glycoprotein was 40%. The pretreatment in vitro rhodamin retention in CD38++ myeloma cells was reversible by 2 microM SDZ PSC 833 with 15-98% in 7/9 tested patients. In 4/5 responding patients analyzed before and after treatment with VAD + SDZ PSC 833, a reduction of P-gp + plasma cells was observed. It is concluded, that the blood concentrations of SDZ PSC 833 attained in MM patients increase with dose after oral administration. It can be safely combined with VAD chemotherapy. SDZ PSC 833 diminishes the clearance of doxorubicin, leading to an increase of the plasma AUC of doxorubicin. In addition, it is an effective inhibitor of P-gp mediated efflux of doxorubicin in myeloma tumor cells in vitro. Therefore, a proportional dose-reduction of doxorubicin and vincristine is warranted. Phase II/III studies in refractory MM are in progress to evaluate the therapeutic efficacy of SDZ PSC 833 with VAD.
SDZ PSC 833是一种非免疫抑制性环孢素类似物，通过抑制P-糖蛋白（P-gp）介导的药物外排，在体外逆转多药耐药（MDR）。我们开展了一项SDZ PSC 833联合VAD化疗用于难治性多发性骨髓瘤（MM）的剂量递增研究。22例对阿霉素/长春新碱/地塞米松耐药（VADr，n = 11）、或多种方案治疗失败（n = 6）、或对美法仑耐药（MELr，n = 5）的MM患者，接受1至3个周期的VAD联合口服SDZ PSC 833治疗，SDZ PSC 833起始剂量为5 mg/kg/天，以递增剂量给药至15 mg/kg/天，持续7天。SDZ PSC 833的血药谷浓度和峰浓度中位数分别从5 mg/kg/天的461/1134 ng/ml至15 mg/kg时的821/2663 ng/ml。加入SDZ PSC 833（5 mg/kg）后，与接受VAD治疗的对照患者相比，阿霉素的平均血浆AUC0→96 h从779增加至1510 ng/ml/h（P = 0.0071），而阿霉素清除率从47.6降至27.8 l/h/m2（P = 0.0002）。阿霉素醇的清除率也相应降低。由于血浆AUC增加，13例患者的阿霉素和长春新碱剂量不得不降至50%（n = 1）或75%（n = 12）。SDZ PSC 833进一步增加剂量并未导致阿霉素AUC成比例增加。世界卫生组织毒性分级2级或3级包括发育不全（18/22）、便秘（10/22）、低钠血症（3/22）和感染（6/22）。分别有8例和6例患者获得部分缓解或疾病稳定。在17例可评估患者中，表达P-糖蛋白的预处理骨髓浆细胞平均百分比为40%。在7/9例受试患者中，2 μM SDZ PSC 833可使CD38++骨髓瘤细胞中体外罗丹明保留率在预处理后出现可逆性变化，变化范围为15 - 98%。在4/5例接受VAD + SDZ PSC 833治疗前后进行分析的缓解患者中，观察到P-gp +浆细胞减少。得出结论，MM患者口服SDZ PSC 833后血药浓度随剂量增加。它可安全地与VAD化疗联合使用。SDZ PSC 833降低阿霉素清除率，导致阿霉素血浆AUC增加。此外，它在体外是骨髓瘤肿瘤细胞中P-gp介导的阿霉素外排的有效抑制剂。因此，有必要按比例减少阿霉素和长春新碱的剂量。难治性MM的II/III期研究正在进行，以评估SDZ PSC 833联合VAD的治疗效果。
