Application of pharmacometric approaches to evaluate effect of weight and renal function on pharmacokinetics of alogliptin

Abstract

AIMSThe aims of the study were to characterize the pharmacokinetics (PK) of alogliptin in healthy and type 2 diabetes mellitus (T2DM) subjects using a population PK approach and to assess the influence of various covariates on alogliptin exposure. METHODSPlasma concentration data collected from two phase 1 studies and one phase 3 study following administration of alogliptin (12.5-400 mg) were used for the PK model development. One-and two-compartment models were evaluated as base structural PK models. The impact of selected covariates was assessed using stepwise forward selection and backward elimination procedures. The predictability and robustness of the final model was evaluated using visual predictive check and bootstrap analyses. The final model was used to perform simulations and guide appropriate dose adjustments. RESULTSA two-compartment model with first-order absorption and elimination best described the alogliptin concentration vs. time profiles. Creatinine clearance and weight had a statistically significant effect on the oral clearance (CL/F) of alogliptin. The model predicted a lower CL/F (17%, 35%, 80%) and a higher systemic exposure (56%, 89%, 339%) for subjects with mild, moderate and severe renal impairment, respectively, compared with healthy subjects. Effect of weight on CL/F was not considered clinically relevant. Simulations at different doses of alogliptin support the approved doses of 12.5 mg and 6.25 mg for patients with moderate and severe renal impairment, respectively. CONCLUSIONSThe PK of alogliptin was well characterized by the model. The analysis suggested an alogliptin dose adjustment for subjects with moderate-to-severe renal impairment and no dose adjustments based on weight. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Alogliptin produces rapid and sustained DPP-4 inhibition and controls both post prandial/fasting plasma glucose and HbA 1c levels in patients with type 2 diabetes mellitus (T2DM).• The influence of renal impairment on the pharmacokinetic parameters of alogliptin has not been evaluated in subjects with T2DM. WHAT THIS STUDY ADDS• This population pharmacokinetic model accounts for clinically relevant covariates and can be used for simulations of alogliptin exposure in healthy subjects and T2DM patients with varying renal function.• The model provides a quantitative rationale for alogliptin dose adjustments in T2DM patients with moderate-to-severe renal impairment and no weight-based dose adjustments.

Diabetes mellitus and DPP IV/CD26 Inhibitors

“…Djelovanjem citokromnih enzima CYP3A4 i CYP2C8, sitagliptin se metabolizira u šest metabolita u tragovima od kojih su samo tri aktivna (M1, M2, M5) 84 . S druge strane, alogliptin se metabolizira pomoću citokromnih enzima CYP2D6 i CYP3A4 u dva manja metabolita u tragovima: N-demetilirani (aktivni) i N-acetilirani (neaktivni) alogliptin 85 . Za razliku od njih, vildagliptin i saxagliptin prolaze opsežan metabolički put kod ljudi.…”

Prusogliptin (DBPR108) monotherapy in treatment‐naïve patients with type 2 diabetes: A randomized, double‐blind, active and placebo‐controlled, phase 3 study

“…Notably, saxagliptin has been associated with an elevated risk of hospitalization for heart failure 12 . Among these inhibitors, only linagliptin stands out as it can be administered to patients with renal impairment without necessitating dose adjustments or renal function monitoring 13–17 . This highlights the potential for further development of DPP‐4 inhibitors in the treatment of type 2 diabetes.…”

“…12 Among these inhibitors, only linagliptin stands out as it can be administered to patients with renal impairment without necessitating dose adjustments or renal function monitoring. [13][14][15][16][17] This highlights the potential for further development of DPP-4 inhibitors in the treatment of type 2 diabetes. Prusogliptin (DBPR108) is a novel, highly selective DPP-4 inhibitor with specific inhibitory activity against DPP-4, not DPP-8 or DPP-9, 18 developed by CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd.…”