Abstract

1. To compare drug–drug interaction (DDI) between tacrolimus and different formulations of phenobarbital in paediatrics and adults.

2. Physiologically based pharmacokinetics (PBPK) models were used to evaluate DDI between phenobarbital (oral (p.o.) and intravenous (i.v.) formulations) and tacrolimus in paediatrics and adults. All dosing regimens were maintained for 7 days.

3. Compared to i.v. phenobarbital, p.o. phenobarbital could decrease pharmacokinetic (PK) parameters of tacrolimus much more in both paediatrics and adults. On day 7, the results showed that the ratio of C_max for tacrolimus in the presence and absence of phenobarbital were 0.13 (p.o.) and 0.48 (i.v.), respectively, in paediatrics, while 0.54 (p.o.) and 0.73 (i.v.) in adults, respectively. The ratios of the area under the concentration–time curve (AUC) were 0.06 (p.o.) and 0.18 (i.v.) in paediatrics, while 0.46 (p.o.) and 0.53 (i.v.) in adults, respectively. PK parameters of tacrolimus decreased more significantly in paediatrics compared to adults.

4. In paediatric, phenobarbital had a greater impact on PK of tacrolimus than that in adults. P.o. phenobarbital reduced PK parameters of tacrolimus even more than i.v. administration. In clinical practice, the concentration monitoring and dosage adjustment of tacrolimus should be emphasised when co-administrated with phenobarbital, especially in paediatric or in p.o. formulation.

• Key points

• The results indicated that p.o. and i.v. phenobarbital both had a significant DDI with tacrolimus in paediatrics and adults.

• Phenobarbital had a greater impact on the PK of tacrolimus over time in paediatrics.

• P.o. administration of phenobarbital can reduce the PK parameters of tacrolimus more.

摘要

1. 比较他克莫司与不同剂型苯巴比妥在儿科和成人中的药物相互作用 (DDI)。

2. 基于生理学的药代动力学 (PBPK) 模型用于评估苯巴比妥（口服 (po) 和静脉内 (iv) 制剂）和他克莫司在儿科和成人中的 DDI。所有给药方案维持7天。

3. 与 iv 苯巴比妥相比，po 苯巴比妥可以在儿科和成人中更多地降低他克莫司的药代动力学 (PK) 参数。在第 7 天，结果显示，在存在和不存在苯巴比妥的情况下，他克莫司的 C _max比值在儿科中分别为 0.13 (po) 和 0.48 (iv)，而在成人中为 0.54 (po) 和 0.73 (iv) ， 分别。浓度-时间曲线下面积 (AUC) 的比率在儿科中分别为 0.06 (po) 和 0.18 (iv)，而在成人中分别为 0.46 (po) 和 0.53 (iv)。与成人相比，他克莫司的 PK 参数在儿科中下降更显着。

4. 在儿科中，苯巴比妥对他克莫司 PK 的影响大于成人。Po 苯巴比妥降低他克莫司的 PK 参数甚至比静脉注射给药还要多。在临床实践中，当他克莫司与苯巴比妥合用时，尤其是在儿科或口服制剂中，应强调他克莫司的浓度监测和剂量调整。

• 关键点

• 结果表明，po 和 iv 苯巴比妥在儿科和成人中均与他克莫司有显着的 DDI。

• 随着时间的推移，苯巴比妥对儿科他克莫司的 PK 影响更大。

• 苯巴比妥的口服给药更能降低他克莫司的PK参数。