A model-based approach was used to integrate data from a phase II study in order to provide a quantitative rationale for selecting the apixaban dosage regimen for a phase III trial. The exposure-response models demonstrated that an increase in daily steady-state area under the plasma concentration-vs.-time curve (AUC(ss)) of 1 microg x h/ml would increase the odds ratio for major bleeding by 0.118 and decrease the odds ratio for venous thromboembolism (VTE) by 0.0499. The therapeutic utility index (TUI) was used to integrate the efficacy and safety predictions to quantify apixaban's efficacy/safety balance as a function of AUC(ss). Of the apixaban dosage regimens tested in phase II, the 2.5 mg twice-daily (b.i.d.) dosage regimen had the highest TUI (86.2%). This was also higher than the TUI for either 30 mg b.i.d. enoxaparin (82.5%) or for warfarin (71.8%). Subjects with moderate renal impairment are expected to have a 43% increase in apixaban exposure; however, apixaban's TUI suggests that dose adjustment is not needed in these subjects with renal impairment.

Dapagliflozin is a sodium–glucose co-transporter 2 inhibitor in development for the treatment of type 2 diabetes mellitus. A semi-mechanistic population pharmacokinetic (PK) model was developed for dapagliflozin and its inactive metabolite dapagliflozin 3-O-glucuronide (D3OG) with emphasis on renal and hepatic contribution to dapagliflozin metabolism. Renal and hepatic impairment decreased the clearance of dapagliflozin to D3OG and the clearance of D3OG. The fraction of D3OG formed via the renal route decreased from 40–55% in subjects with normal renal function (creatinine clearance (CLcr) > 80 ml/min) to 10% in subjects with severe renal insufficiency (CLcr = 13 ml/min). The model-based simulations suggested that the increase of systemic exposure (AUCss) of dapagliflozin and D3OG was less than twofold in subjects with mild or moderate renal impairment. This population modeling analysis presents a useful approach to evaluate the impact of renal and hepatic function on the PK of dapagliflozin.

The selective inhibition of sodium-glucose cotransporter 2 (SGLT2) has recently become a focus of potential type 2 diabetes mellitus (T2DM) therapeutics. This review describes the mechanism of SGLT2-induced urinary glucose excretion (UGE) and its effects on parameters of glycemic control in animal models, healthy humans, and patients with T2DM. Key questions on various aspects of the development of SGLT2 inhibitors are discussed, as well as insights regarding this field.