BACKGROUND Insulin therapy plays a crucial role in managing diabetes.Regulatory guidelines mandate assessing the pharmacokinetics(PK)and pharmacodynamics(PD)of new insulin formulations with euglycemic clamp techniques before entry into the market.Typically,blood glucose(BG)levels are maintained at 5%below baseline to suppress endogenous insulin secretion in healthy volunteers.However,in scenarios where BG baseline is relatively low,maintaining it at 5%below baseline can increase hypoglycemic risk.Consequently,we adjusted to maintain it at 2.5%below a baseline of<4.00 mmol/L.It remains uncertain whether this adjustment impacts endogenous insulin inhibition or the PD of study insulin.AIM To evaluate and compare the PD and C-peptide status using two different target BG setting methods.METHODS Data came from euglycemic clamp trials assessing the PK/PD of insulin aspart(IAsp)in healthy participants.Target BG was set at 2.5%below baseline for those with a basal BG of<4.00 mmol/L(group A),and at 5%below baseline for others(group B).The area under the curve(AUC)of IAsp(AUC_(IAsp,0-8 h))and GIR from 0 to 8 hours(AUCGIR,0-8 h)was used to characterize the PK and PD of IAsp,respectively.The C-peptide reduction and PK/PD of IAsp were compared between the two groups.RESULTS Out of 135 subjects,15 were assigned to group A and 120 to group B;however,group B exhibited higher basal Cpeptide(1.59±0.36 vs 1.32±0.42 ng/mL,P=0.006).Following propensity score matching to adjust for basal Cpeptide differences,71 subjects(15 in group A and 56 in group B)were analyzed.No significant differences were observed in demographics,IAsp dosage,or clamp quality.Group B showed significantly higher baseline(4.35±0.21 vs 3.91±0.09 mmol/L,P<0.001),target(4.13±0.20 vs 3.81±0.08 mmol/L,P<0.001),and clamped(4.10±0.17 vs 3.80±0.06 mmol/L,P<0.001)BG levels.Both groups exhibited comparable C-peptide suppression(32.5%±10.0%vs 35.6%±12.1%,P=0.370)and similar IAsp activity(AUCGIR,0-8 h:1433±400 vs 1440±397 mg/kg,P=0.952)under nearly equivalent IAsp
Clopidogrel effectively inhibits platelet aggregation in response to ADP by irreversibly binding to the platelet P2Y_(12) receptor through its active metabolite.However,the observed discrepancies between the pharmacokinetics(PK)and pharmacodynamics(PD)of clopidogrel present substantial challenges in individualizing of antiplatelet therapy.To address these challenges,a robust liquid chromatographyetandem mass spectrometry method has been developed to facilitate the real-time assessment of platelet P2Y_(12) receptor occupancy.This method has been validated in animal models,providing a reliable link between individual PK profiles and PD effects.Target receptor occupancy offers a comprehensive overview of interindividual variations in clopidogrel metabolism,regulation of P2Y_(12) receptor expression,and platelet turnover.Moreover,it directly correlates with the inhibitory effect on platelet aggregation.The levels of platelet P2Y_(12) occupancy accurately reflect the extent of clinical factors influencing the PD of clopidogrel,including dosage,drugedrug interactions(DDI),and type 2 diabetes mellitus(T2DM).As a normalized metric,platelet P2Y_(12) occupancy not only serves potential as a diagnostic tool for personalized clopidogrel therapy but also aids in elucidating the role of the P2Y_(12) signaling pathway in cases of abnormal on-treatment platelet reactivity.