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Observational Study
. 2025 Apr 24:19:3193-3207.
doi: 10.2147/DDDT.S501762. eCollection 2025.

Model-Informed Precision Dosing of Levamlodipine Besylate in Smoking Patients

Guoxing Li #  1 , Ying Guan #  2 , YingYing Yang  3 , Qiulin Xiang  1 , Song Chen  3 , Jiaqi Shao  3 , Yue Chen  4 , Xian Yu  1
Affiliations
Observational Study

Model-Informed Precision Dosing of Levamlodipine Besylate in Smoking Patients

Guoxing Li et al. Drug Des Devel Ther. .

Abstract

Object: To quantitatively investigate the influence of various factors, including nicotine, demographics, biochemical index, and genetic polymorphisms of PAHs and drug metabolising enzymes, on the steady-state trough concentrations of levamlodipine besylate and its therapeutic effects in smokers. Using models to promote rational and accurate medication dosing in smoking patients when administered as initial monotherapy.

Methods: A prospective study (NCT05126381) enrolled 43 patients receiving levamlodipine monotherapy. Pop PK/PD model of levamlodipine besylate was established to investigate the effects of nicotine concentration, demographics (age, sex, height, weight, BMI), biochemical index (ALT, AST, ALB, UA, eGFR), and the genetic polymorphisms (rs4646903, rs1048943, rs762551, rs12459249, rs776746, rs2740574) on the patients' steady state trough concentrations and the antihypertensive efficacy (ΔSBP) of levamlodipine besylate after dosing.

Results: The Pop PK/PD model was conducted using the study data of 43 patients. One-compartment model was used to describe the PK characteristics, and the direct effect model was used to describe the antihypertensive effect of levamlodipine besylate. The final Pop PK/PD model showed that the typical value of V = 3521L, CL = 62.6L·h-1, E0 = 168mmHg, Imax = 31mmHg, IC50 = 1.71ng·mL-1; eGFR and UA were found in the model had significant effect on the CL of levamlodipine besylate.

Conclusion: Patients with lower eGFR and UA levels exhibited lower CL levels, higher dosages may be considered for initial monotherapy in such patients. The current study tentatively do not show that nicotine concentration and PAHs metabolizing enzymes have significant effect on PK and PD in patients taking the drug. More data may be needed in the future to refine the effects of the above covariates on the PK and PD parameters of the levamlodipine besylate.

Keywords: Levamlodipine besylate; model-informed precision dosing; pop PK/PD model; smoking patients.

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Conflict of interest statement

The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Recruitment flow of study. The figure illustrates the recruitment process and the number of patients included/excluded in the study and the number of research samples collected of the study.
Figure 2
Figure 2
Pop DV vs IPRED of the final Pop PK model. The figure illustrates the comparison of population observed values and individual predicted values of the final Pop PK model.
Figure 3
Figure 3
Pop IWRES vs IPRED of the final Pop PK model. The figure illustrates the comparison of individual weighted residuals values and individual predicted values of the final Pop PK model.
Figure 4
Figure 4
Pop CWERS - QQ of the final Pop PK model. The figure illustrates the quantiles of conditional weighted residuals to the quantiles of a standard normal distribution of the final Pop PK model.
Figure 5
Figure 5
Pop DV vs IPRED of the final Pop PD model. The figure illustrates the comparison of population observed values and individual predicted values of the final Pop PD model.
Figure 6
Figure 6
Pop IWRES vs IPRED of the final Pop PD model. The figure illustrates the comparison of individual weighted residuals values and individual predicted values of the final Pop PD model.
Figure 7
Figure 7
Pop CWERS - QQ of the final Pop PD model. The figure illustrates the quantiles of conditional weighted residuals to the quantiles of a standard normal distribution of the final Pop PD model.
Figure 8
Figure 8
VPC of the final Pop PK model. The figure illustrates the visual predictive check of the final Pop PK model.
Figure 9
Figure 9
VPC of the final Pop PD model. The figure illustrates the visual predictive check of the final Pop PD model.
See this image and copyright information in PMC

References

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