Hsu Ann, Isaacson Jeffrey, Brun Scott, Bernstein Barry, Lam Wayne, Bertz Richard, Foit Cheryl, Rynkiewicz Karen, Richards Bruce, King Martin, Rode Richard, Kempf Dale J, Granneman G Richard, Sun Eugene
Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
Antimicrob Agents Chemother. 2003 Jan;47(1):350-9. doi: 10.1128/AAC.47.1.350-359.2003.
The steady-state pharmacokinetics and pharmacodynamics of two oral doses of lopinavir-ritonavir (lopinavir/r; 400/100 and 533/133 mg) twice daily (BID) when dosed in combination with efavirenz, plus two nucleoside reverse transcriptase inhibitors, were assessed in a phase II, open-label, randomized, parallel arm study in 57 multiple protease inhibitor-experienced but non-nucleoside reverse transcriptase inhibitor-naive human immunodeficiency virus (HIV)-infected subjects. All subjects began dosing of lopinavir/r at 400/100 mg BID; subjects in one arm increased the lopinavir/r dose to 533/133 mg BID on day 14. When codosed with efavirenz, the lopinavir/r 400/100 mg BID regimen resulted in lower lopinavir concentrations in plasma, particularly C(min), than were observed in previous studies of lopinavir/r administered without efavirenz. Increasing the lopinavir/r dose to 533/133 mg increased the lopinavir area under the concentration-time curve over a 12-h dosing interval (AUC(12)), C(predose), and C(min) by 46, 70, and 141%, respectively. The increase in lopinavir C(max) (33%,) did not reach statistical significance. Ritonavir AUC(12), C(max), C(predose), and C(min) values were increased 46 to 63%. The lopinavir predose concentrations achieved with the 533/133-mg BID dose were similar to those observed with lopinavir/r 400/100 mg BID in the absence of efavirenz. Results from univariate logistic regression analyses identified lopinavir and efavirenz inhibitory quotient (IQ) parameters, as well as the baseline lopinavir phenotypic susceptibility, as predictors of antiviral response (HIV RNA < 400 copies/ml at week 24); however, no lopinavir or efavirenz concentration parameter was identified as a predictor. Multiple stepwise logistic regressions confirmed the significance of the IQ parameters, as well as other baseline characteristics, in predicting virologic response at 24 weeks in this patient population.
在一项II期、开放标签、随机、平行组研究中，对57名有多种蛋白酶抑制剂使用经验但未使用过非核苷类逆转录酶抑制剂的人类免疫缺陷病毒（HIV）感染受试者，评估了每日两次（BID）联合使用依非韦伦以及两种核苷类逆转录酶抑制剂时，口服两剂洛匹那韦-利托那韦（洛匹那韦/利托那韦；400/100和533/133毫克）的稳态药代动力学和药效学。所有受试者开始以400/100毫克BID的剂量服用洛匹那韦/利托那韦；其中一组受试者在第14天将洛匹那韦/利托那韦剂量增加至533/133毫克BID。与依非韦伦合用时，洛匹那韦/利托那韦400/100毫克BID方案导致血浆中洛匹那韦浓度较低，尤其是C(min)，低于先前未使用依非韦伦的洛匹那韦/利托那韦研究中观察到的浓度。将洛匹那韦/利托那韦剂量增加至533/133毫克，使12小时给药间隔内洛匹那韦的浓度-时间曲线下面积（AUC(12)）、给药前浓度（C(predose)）和C(min)分别增加了46%、70%和141%。洛匹那韦C(max)的增加（33%）未达到统计学显著性。利托那韦的AUC(12)、C(max)、C(predose)和C(min)值增加了46%至63%。533/133毫克BID剂量达到的洛匹那韦给药前浓度与在无依非韦伦情况下洛匹那韦/利托那韦400/100毫克BID观察到的浓度相似。单因素逻辑回归分析结果确定洛匹那韦和依非韦伦抑制商（IQ）参数以及基线洛匹那韦表型敏感性是抗病毒反应（第24周时HIV RNA < 400拷贝/毫升）的预测指标；然而，未确定任何洛匹那韦或依非韦伦浓度参数为预测指标。多步逻辑回归证实了IQ参数以及其他基线特征在预测该患者群体24周病毒学反应中的显著性。
