A PK/PD model of saxagliptin: to simulate its pharmacokinetics and pharmacodynamics in healthy adults and patients with impaired hepatic function

doi:10.5246/jcps.2021.02.010

Abstract

Abstract:

In this study, we aimed to develop and evaluate a whole-body physiologically based pharmacokinetic (WB-PBPK)/pharmacodynamic (PD) model for saxagliptin, simulate its pharmacokinetic and pharmacodynamic properties in healthy adults and patients with hepatic function impairment, and provide a new method for the research to the clinical pharmacy of special patients. Based on the drug-specific properties, such as logD, plasma protein binding collected by the published literature, the WB-PBPK model and the PD model were established. After comparing the simulated concentration-time profiles and the pharmacokinetic parameters with data in healthy adults from oral and intravenous clinical investigation, the WB-PBPK model could be optimized. After comparing the simulated DPP-4 inhibition profile with the observed pharmacodynamic in healthy subjects, the PD model could be optimized. The PK/PD model was utilized to predict the mean and variability of the pharmacokinetic and pharmacodynamic profiles in subjects with different hepatic impairment. All of the predicted pharmacokinetic curves were comparable to the observed curves both in healthy subjects and hepatic impairment subjects (C_max and AUC were less than 1.3-fold). The predicted pharmacodynamic curves were comparable to the observed ones in different oral dosage after optimization, and pharmacodynamics of saxagliptin in hepatic impairment subjects were predicted successfully. The WB-PBPK/PD model can accurately simulate the pharmacokinetics and pharmacodynamics of saxagliptin in normal adults and different hepatic impaired patients.

Key words: PK/PD modeling, Hepatic impairment, Saxagliptin, GastroPlus

Supporting:

Lu Shi, Feng Miao, Guopeng Wang, Wenyan Sun, Yang Liu. A PK/PD model of saxagliptin: to simulate its pharmacokinetics and pharmacodynamics in healthy adults and patients with impaired hepatic function[J]. Journal of Chinese Pharmaceutical Sciences, 2021, 30(2): 119-132.

Figures/Tables 23

Table 1. The mean physiological parameters used in the WB-PBPK absorption models.

Table 2. Physicochemical properties and in vitro data used in the simulations.

Table 3. Predicted and observed parameters of saxagliptin after intravenous administration in healthy adults.

Table 4. Predicted and observed parameters of saxagliptin after 5 mg oral administration in healthy adults.

Table 5. Observed and predicted pharmacokinetic parameters of saxagliptin after oral administration in healthy adults.

Table 6. Observed and predicted pharmacokinetic parameters of saxagliptin between different patients with hepatic impairment after oral 10 mg administration.

Table 7. Pharmacokinetic parameters of healthy subjects and patients with hepatic impairment after oral 10 mg administration.

Table 8. The fitting data of all the models.

Table 9. The fitting parameters after optimized.

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