(1) Purpose: To develop a mathematical model combining
physiologically
based pharmacokinetic and urinary glucose excretion (PBPK-UGE) to
simultaneously predict pharmacokinetic (PK) and UGE changes of luseogliflozin
(LUS) as well as to explore the role of sodium-glucose cotransporters
(SGLT1 and SGLT2) in renal glucose reabsorption (RGR) in humans. (2)
Methods: The PBPK-UGE model was built using physicochemical and biochemical
properties, binding kinetics data, affinity to SGLTs for glucose,
and physiological parameters of renal tubules. (3) Results: The simulations
using this model clarified that SGLT1/2 contributed 15 and 85%, respectively,
to RGR in the absence of LUS. However, in the presence of LUS, the
contribution proportion of SGLT1 rose to 52–76% in healthy
individuals and 55–83% in T2DM patients, and that of SGLT2
reduced to 24–48 and 17–45%, respectively. Furthermore,
this model supported the underlying mechanism that only 23–40%
inhibition of the total RGR with 5 mg of LUS is resulted from SGLT1’s
compensatory effect and the reabsorption activity of unbound SGLT2.
(4) Conclusion: This PBPK-UGE model can predict PK and UGE in healthy
individuals and T2DM patients and can also analyze the contribution
of SGLT1/2 to RGR with and without LUS.
This study aimed to develop a physiologically based pharmacokinetic (PBPK) model to predict the maximum plasma concentration (Cmax) and trough concentration (Ctrough) at steady-state of olaparib (OLA) in Caucasian, Japanese and Chinese. On top of that, the PBPK model was then combined with the mean and 95% confidence interval to predict optimal dosing regimens of OLA when co-administered with CYP3A4 modulators and administered in patients with hepatic impairment based on safety and efficacy PK threshold Cmax (< 12500 ng/mL) and Ctrough (772–2500 ng/mL). Here, the population PBPK model of OLA has been successfully developed and validated based on the prediction good consistent with the clinically observed data. The ratio of prediction to observation for Cmax and Ctrough was between 0.5 and 2.0. The dosing regimens of OLA should be reduced to 100 mg BID and 150 BID, respectively, when dosed with a strong or moderate CYP3A4 inhibitor. Additionally, the PBPK model also suggested that OLA should be permitted with CYP3A4 inducer (strong or moderate).The PBPK model also suggested that dosing regimens of OLA should be reduced to 200 mg BID and 150 mg BID in patients with moderate hepatic and renal impairment. In addition, in patients with severe hepatic and renal impairment, dosing regimens of OLA were suggested to be reduced to 100 mg BID by the PBPK model. Overall, the present PBPK model can identify the optimal dosing regimens in multiple clinical situations.
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