Drug–drug interaction comparison between tacrolimus and phenobarbital in different formulations for paediatrics and adults

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.

Keywords:

• Tacrolimus
• phenobarbital
• pharmacokinetics
• drug-drug interaction
• PBPK model

Acknowledgements

Certara UK (Simcyp Division) granted free access to the Simcyp Simulators through an academic licence (subject to conditions).

Disclosure statement

The authors declare that they have no conflict of interest.

Author contributions

All authors read and approved the final manuscript. All authors were involved in the study. Xianmei Zhao, Xiaoqing Lu, Liqin Zhu and Wei Liu mainly contributed to study conception and design. Meiling Zuo and Jingtao Chen were involved in the operation of simulations. Xianmei Zhao and Yuan Zhang were involved in acquisition, analysis and interpretation of data. The first draft of the manuscript was written by Xianmei Zhao. Nan Wang revised the grammar and content of the article. All authors participated in critical revision of the manuscript, contributed comments and approved the final version.

Additional information

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.