Kovarik J M, Pescovitz M D, Sollinger H W, Kaplan B, Legendre C, Salmela K, Book B K, Gerbeau C, Girault D, Somberg K
Novartis Pharmaceuticals, Basel, Switzerland.
Clin Transplant. 2001 Apr;15(2):123-30. doi: 10.1034/j.1399-0012.2001.150208.x.
Pharmacokinetic sampling was performed in two multicenter trials in which basiliximab (anti-CD25 monoclonal antibody) was administered with triple immunosuppression consisting of cyclosporine microemulsion, corticosteroids, and either azathioprine or mycophenolate mofetil. Blood samples were collected over 12 wk post-transplant from 31 azathioprine-treated and 66 mycophenolate mofetil-treated patients. Empirical Bayes estimates of each patient's basiliximab disposition parameters were derived and the duration of CD25 saturation was estimated as the time over which serum concentrations exceeded 0.2 microg/mL as confirmed by flow cytometry measurements. Basiliximab clearance was 29+/-14 mL/h when coadministered with azathioprine and 18+/-8 mL/h with mycophenolate mofetil. Both were significantly lower compared with a clearance of 37+/-15 mL/h from a previous study of basiliximab with dual therapy (p<0.001). As a consequence of the lower clearance of basiliximab, the durations of CD25 saturation were prolonged in the presence of azathioprine (50+/-20 d; range, 13--84) and mycophenolate mofetil (59+/-17 d; range, 28--94) compared with dual therapy (36+/-14 d; range, 12--91). A total of 27 acute rejection episodes occurred during the first 6 months in the two studies. Durations of CD25 saturation were not different in these patients compared with those who remained rejection-free in each study. A single patient among 57 who were screened developed anti-idiotype antibodies to basiliximab. The average duration of CD25 saturation was prolonged by 39 and 64% in the presence of azathioprine and mycophenolate mofetil, respectively. This graded effect was also observed for basiliximab clearance and may be due in part to a differentially reduced humoral response to basiliximab. Nonetheless, the range of CD25 saturation durations and basiliximab clearances did not extend outside the range when basiliximab was used with dual therapy in the absence of these agents. Hence, no dosing adjustment is deemed necessary when basiliximab is used in triple immunosuppressive therapy including either azathioprine or mycophenolate mofetil.
在两项多中心试验中进行了药代动力学采样，这两项试验中，巴利昔单抗（抗CD25单克隆抗体）与由环孢素微乳剂、皮质类固醇以及硫唑嘌呤或霉酚酸酯组成的三联免疫抑制方案联合使用。在移植后12周内，从31例接受硫唑嘌呤治疗的患者和66例接受霉酚酸酯治疗的患者中采集血样。得出每位患者巴利昔单抗处置参数的经验贝叶斯估计值，并将CD25饱和度持续时间估计为血清浓度超过0.2μg/mL的时间，这通过流式细胞术测量得到确认。与硫唑嘌呤合用时，巴利昔单抗的清除率为29±14 mL/h，与霉酚酸酯合用时为18±8 mL/h。与之前巴利昔单抗双联疗法研究中37±15 mL/h的清除率相比，两者均显著降低（p<0.001）。由于巴利昔单抗清除率降低，与双联疗法（36±14天；范围12 - 91天）相比，在使用硫唑嘌呤（50±20天；范围13 - 84天）和霉酚酸酯（59±17天；范围28 - 94天）时，CD25饱和度持续时间延长。在两项研究的前6个月内共发生27次急性排斥反应。与每项研究中未发生排斥反应的患者相比，这些患者的CD25饱和度持续时间并无差异。在接受筛查的57例患者中，有1例产生了针对巴利昔单抗的抗独特型抗体。在使用硫唑嘌呤和霉酚酸酯时，CD25饱和度的平均持续时间分别延长了39%和64%。在巴利昔单抗清除率方面也观察到这种分级效应，这可能部分归因于对巴利昔单抗的体液反应差异降低。尽管如此，当在没有这些药物的情况下巴利昔单抗与双联疗法联合使用时，CD25饱和度持续时间和巴利昔单抗清除率的范围并未超出该范围。因此，当巴利昔单抗用于包括硫唑嘌呤或霉酚酸酯的三联免疫抑制疗法时，无需调整剂量。
