Ravindran Arun, Silverstone Peter, Lacroix Denis, van Schaick Erno, Vermeulen An, Alexander Jennifer
Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
Clin Pharmacokinet. 2004;43(11):733-40. doi: 10.2165/00003088-200443110-00004.
Divalproex sodium can interact with many drugs in which combination treatments are used; it can increase plasma concentrations of some drugs by inhibiting metabolism and can increase the free fractions of other medications by displacing them from plasma proteins. The combination of risperidone and divalproex sodium is used to treat the manic phase of bipolar disorder. However, the effect of risperidone on the pharmacokinetics of valproate has not previously been systematically studied. The aims of this study were to determine the effect of repeated doses of oral risperidone on the pharmacokinetics of valproate in subjects stabilised on divalproex sodium and to document the safety of this combination.
A multicentre, observational, randomised, parallel group, single-blind, placebo-controlled drug interaction study.
Twenty-two patients with bipolar disorder, in remission, were studied.
All subjects were treated with divalproex sodium 1000 mg/day monotherapy on days 1-14. Thereafter, subjects continued to take divalproex sodium for days 15-28; they also received adjunctive treatment with either placebo (n = 11) or risperidone (n = 11) 2mg once daily on days 15 and 16, and 4 mg once daily on days 17-28. Serial blood sampling was performed throughout to determine the plasma concentrations of valproate, risperidone and 9-hydroxy-risperidone.
On analysis, steady-state pharmacokinetic parameters (peak plasma concentrations [C(max)], time to C(max,) area under the concentration-time curve) of valproate were of the same order of magnitude on day 14 (monotherapy) and day 28 (valproate plus risperidone or placebo), with no period effect. The parameters on day 28 were similar in the risperidone and placebo treatment groups, showing that risperidone, as adjunctive treatment, had no influence on the steady-state pharmacokinetics of valproate. Although there were more adverse events reported in the risperidone group compared with the placebo group (ten vs seven, respectively), none of them were serious or necessitated withdrawal. No clinically relevant changes in laboratory parameters, vital signs or ECG-tracings were observed in either group.
These results indicate that adjunctive risperidone treatment had no influence on the steady-state pharmacokinetics of valproate and this combination was safe and well tolerated.
丙戊酸钠可与多种用于联合治疗的药物相互作用；它可通过抑制代谢来提高某些药物的血浆浓度，还可通过将其他药物从血浆蛋白上置换下来来提高其游离分数。利培酮与丙戊酸钠联合使用可治疗双相情感障碍的躁狂期。然而，利培酮对丙戊酸盐药代动力学的影响此前尚未得到系统研究。本研究的目的是确定重复口服利培酮剂量对已稳定服用丙戊酸钠的受试者中丙戊酸盐药代动力学的影响，并记录这种联合用药的安全性。
一项多中心、观察性、随机、平行组、单盲、安慰剂对照的药物相互作用研究。
对22名处于缓解期的双相情感障碍患者进行了研究。
所有受试者在第1 - 14天接受丙戊酸钠1000毫克/天的单一疗法治疗。此后，受试者在第15 - 28天继续服用丙戊酸钠；他们还在第15天和16天接受安慰剂（n = 11）或利培酮（n = 11）2毫克每日一次的辅助治疗，并在第17 - 28天接受4毫克每日一次的辅助治疗。在整个过程中进行系列采血，以测定丙戊酸盐、利培酮和9 - 羟基利培酮的血浆浓度。
分析显示，丙戊酸盐的稳态药代动力学参数（血浆峰浓度[C(max)]、达峰时间、浓度 - 时间曲线下面积）在第14天（单一疗法）和第28天（丙戊酸盐加用利培酮或安慰剂）处于同一数量级，无周期效应。第28天利培酮治疗组和安慰剂治疗组的参数相似，表明利培酮作为辅助治疗对丙戊酸盐的稳态药代动力学没有影响。虽然与安慰剂组相比，利培酮组报告的不良事件更多（分别为10例和7例），但均不严重，也无需停药。两组均未观察到实验室参数、生命体征或心电图有临床相关变化。
这些结果表明，辅助使用利培酮治疗对丙戊酸盐的稳态药代动力学没有影响，且这种联合用药安全且耐受性良好。
