Key result
A PBPK model predicted apixaban pharmacokinetics, revealing an almost 3-fold AUC increase with ketoconazole in severe renal impairment and >2-fold higher AUC in newborns versus older children.
Why the study?
To develop a physiologically based pharmacokinetic (PBPK) model of apixaban to predict pharmacokinetic profiles and drug-drug interactions in renal impairment and paediatric populations.
A PBPK model for apixaban predicts significant exposure increases with combined renal impairment and drug interactions, and highlights age-dependent PK differences in pediatric patients.
Answers are grounded in this paper and cite their sources.
May inform apixaban dosing in renal impairment and paediatrics; leaves open prospective clinical validation.
AIMS: To develop a physiologically based pharmacokinetic (PBPK) model for apixaban, an oral anticoagulant with a narrow therapeutic index, and to predict PK profiles and potential drug-drug interactions (DDIs) in patients with renal impairment and paediatrics. METHODS: A whole-body apixaban PBPK model was developed and validated in SimCYP for healthy adults with or without interacting drugs. The model was extended to renal impairment and paediatrics. Observed PK data in adults were compared with predicted data. The effect of renal function, age and DDIs on apixaban PK was investigated. RESULTS: The PBPK model successfully predicted the PK of apixaban alone and under the influence of interacting drugs. For patients with renal impairment, the PBPK model successfully predicted the fold change in each impairment group; inhibitory DDI and renal impairment had a synergistic effect on the increase of apixaban exposure (e.g., almost 3-fold increase of AUC in ketoconazole + severe renal impairment group). For infants younger than 1 year, the exposure of apixaban decreased with increased weight-normalized clearance. For newborn infants, AUC of apixaban was >2-fold higher than that in children older than 1 year. Meanwhile, the effect of DDI seems to be weakened while the effect of renal impairment might be enhanced in infants younger than 1 year. CONCLUSION: Our study provides a reasonable approach to estimate the dose adjustment for the first use of apixaban in special populations with complex situations, which has the opportunity to make the clinical practice much safer.
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Xu et al. (2021) studied Renal impairment and pediatric populations requiring anticoagulation. Apixaban was evaluated on Pharmacokinetic profiles and potential drug-drug interactions. A PBPK model predicted apixaban pharmacokinetics, revealing an almost 3-fold AUC increase with ketoconazole in severe renal impairment and >2-fold higher AUC in newborns versus older children.
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