Department of Pharmacy, Radboud University Nijmegen Medical Center, Geert Grooteplein 10, Nijmegen, The Netherlands.
Department of Pharmacy, Radboud University Nijmegen Medical Center, Geert Grooteplein 10, Nijmegen, The Netherlands; Nijmegen Institute for Infection, Inflammation and Immunity (N4i), Radboud University Nijmegen Medical Center, Geert Grooteplein 10, Nijmegen, The Netherlands.
Int J Antimicrob Agents. 2014 Aug;44(2):173-7. doi: 10.1016/j.ijantimicag.2014.03.014. Epub 2014 May 23.
Psychosis and other mental illnesses are common in HIV-infected patients. Olanzapine is one of the preferred antipsychotic agents for the treatment of schizophrenia. Olanzapine is primarily metabolised by CYP1A2 and uridine diphosphate glucuronosyltransferase (UGT). High-dose ritonavir has been shown to increase olanzapine elimination through induction of CYP1A2 and/or UGT, but the effect of low-dose ritonavir on olanzapine pharmacokinetics is unknown. Fosamprenavir is an HIV protease inhibitor that is boosted by low-dose ritonavir. To compensate for the induction of olanzapine metabolism by fosamprenavir/ritonavir, we hypothesised that a dose increase of olanzapine to 15 mg with fosamprenavir/ritonavir would lead to a similar area under the concentration-time curve (AUC) compared with olanzapine 10 mg alone. An open-label, randomised, two-period, cross-over, single-centre trial was conducted in 24 healthy volunteers. Subjects were randomised to one of the following treatments: (A) fosamprenavir/ritonavir 700/100 mg twice daily (b.i.d.) for 16 days with a single dose of olanzapine 15 mg on Day 13, a wash-out period of 31 days and a single dose of olanzapine 10 mg on Day 48; or (B) the same medication in reverse order. Twenty subjects completed the trial. The geometric mean ratios (90% CI) of olanzapine AUClast, maximum drug concentration (C(max)) and apparent elimination half-life (t(1/2)) when taken with fosamprenavir/ritonavir versus olanzapine alone were 1.00 (0.93-1.08), 1.32 (1.18-1.47) and 0.68 (0.63-0.74), respectively. Fosamprenavir/ritonavir 700/100 mg b.i.d. appeared to induce olanzapine metabolism. We therefore propose a 50% dosage increase of olanzapine when combining with a ritonavir-boosted protease inhibitor.
精神分裂症患者常伴有精神疾病。奥氮平是治疗精神分裂症的首选抗精神病药物之一。奥氮平主要通过 CYP1A2 和尿苷二磷酸葡萄糖醛酸转移酶（UGT）代谢。高剂量利托那韦已被证明通过诱导 CYP1A2 和/或 UGT 增加奥氮平的消除，但低剂量利托那韦对奥氮平药代动力学的影响尚不清楚。福沙那韦是一种 HIV 蛋白酶抑制剂，与低剂量利托那韦联合使用可增强其效果。为了补偿福沙那韦/利托那韦对奥氮平代谢的诱导作用，我们假设福沙那韦/利托那韦联合使用时，奥氮平剂量增加至 15mg 与单独使用奥氮平 10mg 相比，会导致相似的浓度-时间曲线下面积（AUC）。一项在 24 名健康志愿者中进行的开放标签、随机、两周期、交叉、单中心试验。受试者随机分为以下治疗组之一：（A）福沙那韦/利托那韦 700/100mg 每日两次（b.i.d.），共 16 天，第 13 天单次服用奥氮平 15mg，洗脱期 31 天，第 48 天单次服用奥氮平 10mg；或（B）以相反的顺序服用相同的药物。20 名受试者完成了试验。当与福沙那韦/利托那韦联合使用时，奥氮平的 AUClast、最大药物浓度（C(max)）和表观消除半衰期（t(1/2)）的几何均数比值（90%CI）分别为 1.00（0.93-1.08）、1.32（1.18-1.47）和 0.68（0.63-0.74）。福沙那韦/利托那韦 700/100mg b.i.d. 似乎诱导了奥氮平的代谢。因此，当与利托那韦增强的蛋白酶抑制剂联合使用时，我们建议奥氮平的剂量增加 50%。
