Grub Sibylle, Delora Patricia, Lüdin Eric, Duff Frank, Fletcher Courtney V, Brundage Richard C, Kline Mark W, Calles Nancy R, Schwarzwald Heidi, Jorga Karin
F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Clin Pharmacol Ther. 2002 Mar;71(3):122-30. doi: 10.1067/mcp.2002.121423.
Our objective was to investigate the clinical pharmacologic characteristics of saquinavir given as a soft gelatin capsule, either alone or in combination with nelfinavir, to children and adolescents with human immunodeficiency virus infection.
The pharmacokinetics of 50 mg/kg saquinavir 3 times a day (tid) alone versus 33 mg/kg saquinavir tid plus 30 mg/kg nelfinavir tid was assessed after single-dose administration and after short- and long-term administration. The single-dose pharmacokinetics of fixed (1200 mg) versus unrestricted weight-adjusted dosing (50 mg/kg) was also investigated.
Saquinavir as the sole protease inhibitor resulted in lower saquinavir exposure in children (steady-state geometric mean area under the concentration-time curve from time zero to 24 hours [AUC (0-24 h)], 5790 ng x h/ml; steady-state concentration 8 hours after drug administration [C(8h,SS)], 65 ng/ml) and adolescents [steady-state geometric mean AUC(0-24 h), 5914 ng x h/ml] than that reported in adults treated with 1200 mg tid [steady-state geometric mean AUC(0-24 h), 21,700 ng x h/ml; C(8h,SS), 223 ng/ml]. This finding appeared to be attributable to markedly higher apparent oral clearance, potentially as a result of increased systemic clearance and reduced oral bioavailability. Nelfinavir combined with saquinavir reduced apparent oral clearance, increasing saquinavir exposure in children [steady-state geometric mean AUC(0-24 h), 11,070 ng x h/ml; C(8h,SS), 380 ng/ml] to levels that approach those observed in adults. A significant correlation between average trough concentration and sustained viral load suppression was observed in children. The apparent threshold for maintaining viral load suppression was a mean trough saquinavir concentration above 200 ng/ml.
The pharmacokinetics of saquinavir in children is different from that of adults, and administration of saquinavir alone will not give consistently efficacious plasma levels. The best way of improving saquinavir exposure in children is through combination therapy with other protease inhibitors that inhibit saquinavir metabolism.
我们的目的是研究将沙奎那韦制成软胶囊单独给药或与奈非那韦联合给药，用于感染人类免疫缺陷病毒的儿童和青少年时的临床药理学特征。
评估单剂量给药后以及短期和长期给药后，每日3次（tid）服用50mg/kg沙奎那韦单独给药与每日3次服用33mg/kg沙奎那韦加每日3次服用30mg/kg奈非那韦的药代动力学。还研究了固定剂量（1200mg）与无限制的体重调整剂量（50mg/kg）的单剂量药代动力学。
沙奎那韦作为唯一的蛋白酶抑制剂，导致儿童（稳态几何平均血药浓度-时间曲线下面积从时间零点到24小时[AUC(0 - 24 h)]，5790ng·h/ml；给药后8小时的稳态浓度[C(8h,SS)]，65ng/ml）和青少年[稳态几何平均AUC(0 - 24 h)，5914ng·h/ml]的沙奎那韦暴露量低于接受每日3次1200mg治疗的成年人[稳态几何平均AUC(0 - 24 h)，21700ng·h/ml；C(8h,SS)，223ng/ml]。这一发现似乎归因于明显更高的表观口服清除率，这可能是全身清除率增加和口服生物利用度降低的结果。奈非那韦与沙奎那韦联合使用可降低表观口服清除率，使儿童的沙奎那韦暴露量增加[稳态几何平均AUC(0 - 24 h)，11070ng·h/ml；C(8h,SS)，380ng/ml]，达到接近在成年人中观察到的水平。在儿童中观察到平均谷浓度与持续病毒载量抑制之间存在显著相关性。维持病毒载量抑制的表观阈值是沙奎那韦平均谷浓度高于200ng/ml。
沙奎那韦在儿童中的药代动力学与成年人不同，单独使用沙奎那韦不会持续产生有效的血浆水平。提高儿童沙奎那韦暴露量的最佳方法是与其他抑制沙奎那韦代谢的蛋白酶抑制剂联合治疗。
