Model-Informed Precision Dosing of Levamlodipine Besylate in Smoking Patients

Abstract

Guoxing Li,1,* Ying Guan,2,* YingYing Yang,3 Qiulin Xiang,1 Song Chen,3 Jiaqi Shao,3 Yue Chen,4 Xian Yu1 1Phase I Clinical Trial Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2Joint Institute of Tobacco and Health, Kunming, Yunnan, People’s Republic of China; 3Chongqing Medical University, Chongqing, People’s Republic of China; 4Daxigou Street Health Service Center, Chongqing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xian Yu, Email [email protected]: 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

Keywords

• levamlodipine besylate
• model-informed precision dosing
• pop pk/pd model
• smoking patients.