First dose in neonates: pharmacokinetic bridging study from juvenile mice to neonates for drugs metabolized by CYP3A

Abstract

1. First dose prediction is challenging in neonates. Our objective in this proof-of-concept study was to perform a pharmacokinetic (PK) bridging study from juvenile mice to neonates for drugs metabolized by CYP3A.

2. We selected midazolam and clindamycin as model drugs. We developed juvenile mice population PK models using NONMEM. The PK parameters of these two drugs in juvenile mice were used to bridge PK parameters in neonates using different correction methods. The bridging results were evaluated by the fold-error of 0.5- to 1.5-fold.

3. Simple allometry with and without a correction factor for maximum lifespan potential could be used for a bridging of clearance (CL) and volume of distribution (V_d), respectively, from juvenile mice to neonates. Simulation results demonstrated that for midazolam, 100% of clinical studies for which both the predictive CL and V_d were within 0.5- to 1.5-fold of the observed. For clindamycin, 75% and 100% of clinical studies for which the predictive CL and V_d were within 0.5- to 1.5-fold of the observed.

4. A PK bridging of drugs metabolized by CYP3A is feasible from juvenile mice to neonates. It could be a complement to the ADE and PBPK models to support the first dose in neonates.

Keywords:

• Bridging study
• pharmacokinetics
• juvenile mice
• neonates
• midazolam
• clindamycin

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

Pan-Pan Ye and Yi Zheng contributed equally to this work and should be considered co-first authors. Wei Zhao, Feng Yu, Pan-Pan Ye and Yi Zheng designed the research. Pan-Pan Ye, Bin Du, Xi-Ting Liu and Min Kan provided pharmacokinetic data in juvenile mice and neonates. Pan-Pan Ye and Bo-Hao Tang performed data analysis. All authors contributed to the discussion and interpretation of the results. Pan-Pan Ye wrote the manuscript and, which was critically reviewed by all authors.

Additional information

Funding

This study was supported by the Key Technologies R & D Program of Shandong Province (Grant No.2018GSF118053), National Science and Technology Major Project for Major New Drugs Innovation and Development (2017ZX09304029-002), Young Taishan Scholars Program of Shandong Province, and Qilu Young Scholars Program of Shandong University.