临床联合用药方案的定量设计

Quantitative design of clinical scheme of combination drug therapy

目的 应用权重配方法，从多药物多剂量中优选临床联合用药方案，并以一个定量设计的范例说明其可行性。方法 根据临床实际，虚拟药1，药2和药3联用治疗儿童缺铁性贫血2wk。各药分为5-6个剂量水平，再均匀分布到6个组，每组6例，即构成6个联用方案。测定治疗2，3，4wk时的血红蛋白升高值（△Hb)，以4WK的测定值作为指标，用权重配方法进行数据分析，优化联用剂量，经确定性试验证实，从而寻找出最优化方案。结果 药1和药2都是主药，但药1对联合药效（△Hb)的贡献值最大，其次是药2，而药3作用极弱，药1与药2间有较强的协同作用，药2和药3间有微弱的协同作用，但药3对药1对有拮抗作用。重新制定联合用药方案，经确定性试验证实，将药1和药2调整到允许的最大剂量，删除药3组成新的方案，同最大效应组比较，表明此联用方案的为一优化方案。结论 权重配方法能有效地分析临床试验中各药在组方中的地位，并据此调整剂量，构成新的方案，经配方优化检验，可定量设计临床联合用药方案。

Aim To show the performance of the weighted modification method in the clinicaldesign of combination drug therapy. Methods A scheme combined by Drug1, Drug2and Drug3 was used to treat infants with iron deficiency anemia for 2 wk in a hypo-thetical clinical trial. Thirty-six infants were randomly into 6 compound groups. Threedrugs in the scheme were divided into 6 dose levels, which were evenly distributed to the6 groups according to the weighted modification method. The increased Hb (ΔHb) wasrecorded at 2, 3, 4 wk after the treatment (po ). The dose-effect data at 4 wk wereanalyzed by the method, and then the doses in scheme were modified by the analyticresult. The modified doses in the scheme would be further demonstrated. ResultsDrug1 and Drug2 were principal drugs, but Drug1 had larger contribution to the com-bined effect (△Hb) than Drug2. Drug3 had little effect. There was a strong synergismbetween Drug1 and Drug2 with the weighted coefficient (b1) = 2. 636 (P< 0. 05), and aslight synergism between Drug2 and Drug3 with b2 = 0. 460 (P< 0. 05). But there was asignificant antagonism between Drug1 and Drug3 with the weighted coefficient (b ) =-0. 829 (P< 0. 05). The doses were adjusted to form a new scheme with Drug1 60mg·kg-1 + Drug2 10 mg· kg -1 (po ) and Drug 3 was deleted from the scheme. Thescheme was an optimal one confirmed by a demonstration trial. Conclusion Thismethod is able to effectively determine important degree of drugs in combination, and tooptimize their doses for designing the scheme of combination drug therapy.