Evaluation of the Pharmacokinetics of Dapagliflozin in Patients With Chronic Kidney Disease With or Without Type 2 Diabetes Mellitus.

Evidence shows that sodium-glucose cotransporter 2 inhibitors, such as dapagliflozin, can delay the progressive decline of kidney function in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). We used a population pharmacokinetics (popPK) model to characterize the pharmacokinetics of dapagliflozin in patients with CKD and compare dapagliflozin systemic exposure in different populations, such as CKD with or without T2DM and T2DM without CKD. A 2-compartmental popPK model was developed from a previous popPK model. The final popPK model was based on 9715 dapagliflozin plasma concentrations from 3055 patients included in clinical studies involving adults with CKD with or without T2DM, adults with T2DM, healthy subjects, and pediatric patients with T2DM. Overall, the apparent clearance for patients treated with dapagliflozin was 21.6 L/h, similar to previous estimates in adults with T2DM and healthy subjects (22.9 L/h). Model-derived area under the plasma concentration-time curve (AUC) was not meaningfully different between patients with CKD with and without T2DM. Median AUC was 1.6-fold higher in adult patients with CKD with T2DM compared with adult patients with T2DM without CKD. Compared with patients with normal kidney function (estimated glomerular filtration rate ≥90 mL/min/1.73 m2 ), median AUC was 2.4-fold higher in patients with CKD (with/without T2DM) with estimated glomerular filtration rate 15-29 mL/min/1.73 m2 owing to decreased renal clearance of dapagliflozin. A higher AUC was observed in patients with a higher age or lower body weight but was not considered clinically relevant. This popPK model adequately described dapagliflozin pharmacokinetics and found that systemic exposure in patients with CKD was consistent, irrespective of T2DM status.

Effects of exenatide and open-label SGLT2 inhibitor treatment, given in parallel or sequentially, on mortality and cardiovascular and renal outcomes in type 2 diabetes: insights from the EXSCEL trial.

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) improve cardiovascular and renal outcomes in patients with type 2 diabetes through distinct mechanisms. However, evidence on clinical outcomes in patients treated with both GLP-1 RA and SGLT2i is lacking. We aim to provide insight into the effects of open-label SGLT2i use in parallel with or shortly after once-weekly GLP-1 RA exenatide (EQW) on cardiorenal outcomes. METHODS: In the EXSCEL cardiovascular outcomes trial EQW arm, SGLT2i drop-in occurred in 8.7% of participants. These EQW+SGLT2i users were propensity-matched to: (1) placebo-arm participants not taking SGLT2i (n = 572 per group); and to (2) EQW-arm participants not taking SGLT2i (n = 575), based on their last measured characteristics before SGLT2i initiation, and equivalent study visit in comparator groups. Time-to-first major adverse cardiovascular event (MACE) and all-cause mortality (ACM) were compared using Cox regression analyses. eGFR slopes were quantified using mixed model repeated measurement analyses. RESULTS: In adjusted analyses, the risk for MACE with combination EQW+SGLT2i use was numerically lower compared with both placebo (adjusted hazard ratio 0.68, 95% CI 0.39-1.17) and EQW alone (0.85, 0.48-1.49). Risk of ACM was nominally significantly reduced compared with placebo (0.38, 0.16-0.90) and compared with EQW (0.41, 0.17-0.95). Combination EQW+SGLT2i use also nominally significantly improved estimated eGFR slope compared with placebo (+ 1.94, 95% CI 0.94-2.94 mL/min/1.73 m2/year) and EQW alone (+ 2.38, 1.40-3.35 mL/min/1.73 m2/year). CONCLUSIONS: This post hoc analysis supports the hypothesis that combinatorial EQW and SGLT2i therapy may provide benefit on cardiovascular outcomes and mortality. Trial registration Clinicaltrials.gov, Identifying number: NCT01144338, Date of registration: June 15, 2010.

Quantitative Systems Pharmacology: An Exemplar Model-Building Workflow With Applications in Cardiovascular, Metabolic, and Oncology Drug Development.

Quantitative systems pharmacology (QSP), a mechanistically oriented form of drug and disease modeling, seeks to address a diverse set of problems in the discovery and development of therapies. These problems bring a considerable amount of variability and uncertainty inherent in the nonclinical and clinical data. Likewise, the available modeling techniques and related software tools are manifold. Appropriately, the development, qualification, application, and impact of QSP models have been similarly varied. In this review, we describe the progressive maturation of a QSP modeling workflow: a necessary step for the efficient, reproducible development and qualification of QSP models, which themselves are highly iterative and evolutive. Furthermore, we describe three applications of QSP to impact drug development; one supporting new indications for an approved antidiabetic clinical asset through mechanistic hypothesis generation, one highlighting efficacy and safety differentiation within the sodium-glucose cotransporter-2 inhibitor drug class, and one enabling rational selection of immuno-oncology drug combinations.

Pharmacokinetic Interaction Study Between Saxagliptin and Omeprazole, Famotidine, or Magnesium and Aluminum Hydroxides Plus Simethicone in Healthy Subjects: An Open-Label Randomized Crossover Study.

Saxagliptin is an orally administered, highly potent, and selective dipeptidyl peptidase-4 inhibitor for the management of type 2 diabetes mellitus. This study was conducted to determine the effect of magnesium and aluminum hydroxides plus simethicone, famotidine, and omeprazole on the pharmacokinetics of saxagliptin and its active metabolite, 5-hydroxy saxagliptin. This was an open-label, randomized, 5-treatment, 5-period, 3-way crossover study in 15 healthy subjects. Mean Cmax of saxagliptin was 26% lower, but AUC was almost unchanged when saxagliptin was coadministered with Maalox Max. Mean Cmax was 14% higher, but AUC was almost unchanged when saxagliptin was coadministered with famotidine. Changes in pharmacokinetics of 5-hydroxy saxagliptin generally paralleled the changes in saxagliptin. These pharmacokinetic changes were unlikely to be clinically meaningful. Coadministration of omeprazole did not affect saxagliptin Cmax or AUC. Saxagliptin in combination with these medicines resulted in no unexpected safety or tolerability findings in these healthy subjects. No dose adjustment of saxagliptin or separation in the time of saxagliptin dosing is necessary with medicines that raise gastric pH when coadministered with saxagliptin.

Clinical Pharmacokinetics and Pharmacodynamics of Saxagliptin, a Dipeptidyl Peptidase-4 Inhibitor.

Saxagliptin is an orally active, highly potent, selective and competitive dipeptidyl peptidase (DPP)-4 inhibitor used in the treatment of type 2 diabetes mellitus at doses of 2.5 or 5 mg once daily. DPP-4 is responsible for degrading the intestinally derived hormones glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP). Inhibition of DPP-4 increases intact plasma GLP-1 and GIP concentrations, augmenting glucose-dependent insulin secretion. Both saxagliptin and its major active metabolite, 5-hydroxy saxagliptin, demonstrate high degrees of selectivity for DPP-4 compared with other DPP enzymes. Saxagliptin is orally absorbed and can be administered with or without food. The half-life of plasma DPP-4 inhibition with saxagliptin 5 mg is ~27 h, which supports a once-daily dosing regimen. Saxagliptin is metabolized by cytochrome P450 (CYP) 3A4/5 and is eliminated by a combination of renal and hepatic clearance. No clinically meaningful differences in saxagliptin or 5-hydroxy saxagliptin pharmacokinetics have been detected in patients with hepatic impairment. No clinically meaningful differences in saxagliptin or 5-hydroxy saxagliptin pharmacokinetics have been detected in patients with mild renal impairment, whereas dose reduction is recommended in patients with moderate or severe renal impairment because of greater systemic exposure [the area under the plasma concentration-time curve (AUC)] to saxagliptin total active moieties. Clinically relevant drug-drug interactions have not been detected; however, limiting the dose to 2.5 mg once daily is recommended in the USA when saxagliptin is coadministered with strong CYP inhibitors, because of increased saxagliptin exposure. In summary, saxagliptin has a predictable pharmacokinetic and pharmacodynamic profile.

Use of low-dose clinical pharmacodynamic and pharmacokinetic data to establish an occupational exposure limit for dapagliflozin, a potent inhibitor of the renal sodium glucose co-transporter 2.

Classical risk assessment models for setting safe occupational exposure limits (OEL) have used multiple uncertainty factors (UF) applied to a point of departure (POD), e.g., a No Observed Effect Level (NOEL), which in some cases is the pharmacological effect. Dapagliflozin promotes glucosuria by inhibiting the renal sodium-glucose cotransporter-2 transporter. The initial OEL for dapagliflozin (0.002mg/m(3)) was calculated when low dose clinical data was not available to identify a NOEL resulting in the need to use excessive UFs. To reduce the UFs from the OEL, a clinical pharmacodynamic [glucosuria and urinary glucose dipstick (UGD)] and pharmacokinetic study was conducted with single oral doses of 0.001, 0.01, 0.1, 0.3, 1.0 or 2.5mg administered to 36 healthy subjects. Dose-related dapagliflozin systemic exposures were observed at doses ⩾0.1mg and glucosuria was observed at doses ⩾0.3mg and corroborated by UGD. The NOEL was therefore 0.1mg for glucosuria. For setting the new OEL, no UFs were required. Dividing the POD by 10m(3) (the volume of air an adult inhales in a workday), the resulting OEL was 0.01mg/m(3). In conclusion, low-dose clinical pharmacodynamic and pharmacokinetic data can allow the OEL to be adjusted to the highest safe level.

Influence of hepatic impairment on the pharmacokinetics and safety profile of dapagliflozin: an open-label, parallel-group, single-dose study.

BACKGROUND: Dapagliflozin, a selective inhibitor of renal sodium glucose co-transporter 2, is under development for the treatment of type 2 diabetes mellitus. Dapagliflozin elimination is primarily via glucuronidation to an inactive metabolite, dapagliflozin 3-O-glucuronide. Pharmacokinetic studies are recommended in subjects with impaired hepatic function if hepatic metabolism accounts for a substantial portion of the absorbed drug. OBJECTIVE: The purpose of our study was to compare the pharmacokinetics of dapagliflozin in patients with mild, moderate, or severe hepatic impairment (HI) with healthy subjects. METHODS: This was an open-label, parallel-group study in male or female patients with mild, moderate, or severe HI (6 per group according to Child-Pugh classification) and in 6 healthy control subjects. The control subjects were matched to the combined HI group for age (±10 years), weight (±20%), sex, and smoking status, with no deviations from normal in medical history, physical examination, ECG, or laboratory determinations. All participants received a single 10-mg oral dose of dapagliflozin, and the pharmacokinetics of dapagliflozin and dapagliflozin 3-O-glucuronide were characterized. Dapagliflozin tolerability was also assessed throughout the study. RESULTS: Demographic characteristics and baseline physical measurements (weight, height, and body mass index) were similar among the 18 patients in the HI groups (58-126 kg; 151.2-190.0 cm, and 31.5-37.7 kg/m(2), respectively) and the healthy subject group (65.0-102.6 kg; 166.0-184.0 cm, and 23.3-34.3 kg/m(2), respectively). In those with mild, moderate, or severe HI, dapagliflozin mean C(max) values were 12% lower and 12% and 40% higher than healthy subjects, respectively. Mean dapagliflozin AUC(0-∞) values were 3%, 36%, and 67% higher compared with healthy subjects, respectively. Dapagliflozin 3-O-glucuronide mean C(max) values were 4% and 58% higher and 14% lower in those with mild, moderate, or severe HI compared with healthy subjects, respectively, and mean dapagliflozin 3-O-glucuronide AUC(0-∞) values were 6%, 100%, and 30% higher compared with healthy subjects, respectively. These values were highly dependent on the calculated creatinine clearance of each group. All adverse events were mild or moderate, with no imbalance in frequency between groups. CONCLUSIONS: Compared with healthy subjects, systemic exposure to dapagliflozin in subjects with HI was correlated with the degree of HI. Single 10-mg doses of dapagliflozin were generally well tolerated by participants in this study. Due to the higher dapagliflozin exposures in patients with severe HI, the benefit:risk ratio should be individually assessed because the long-term safety profile and efficacy of dapagliflozin have not been specifically studied in this population.

Influence of renal or hepatic impairment on the pharmacokinetics of saxagliptin.

BACKGROUND AND OBJECTIVE: Patients with type 2 diabetes mellitus often have impaired renal function or may have impaired hepatic function, which can pose significant safety and tolerability issues for antihyperglycaemic pharmacotherapies. Therefore, the pharmacokinetics and tolerability of saxagliptin and its pharmacologically active metabolite, 5-hydroxy saxagliptin, in nondiabetic subjects with mild, moderate or severe renal or hepatic impairment, or end-stage renal disease (ESRD) were compared with saxagliptin and metabolite pharmacokinetics and tolerability in healthy adult subjects. METHODS: Two open-label, parallel-group, single-dose studies were conducted. Subjects received a single oral dose of saxagliptin 10 mg (Onglyza™). RESULTS: Compared with healthy subjects, the geometric mean area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC∞) for saxagliptin was 16%, 41% and 108% (2.1-fold) higher in subjects with mild, moderate or severe renal impairment, respectively. AUC∞ values for 5-hydroxy saxagliptin were 67%, 192% (2.9-fold) and 347% (4.5-fold) higher in subjects with mild, moderate or severe renal impairment, respectively. As creatinine clearance (CLCR) values decreased, saxagliptin and 5-hydroxy saxagliptin AUC∞ generally increased or became more variable. Twenty-three percent of the saxagliptin dose (measured as the sum of saxagliptin and 5-hydroxy saxagliptin) was cleared by haemodialysis in a 4-hour dialysis session. In the hepatic impairment study, the differences in exposure to saxagliptin and 5-hydroxy saxagliptin were less than 2-fold across all groups. As compared with healthy subjects matched for age, bodyweight, sex and smoking status, the AUC∞ values for saxagliptin were 10%, 38% and 77% higher in subjects with mild, moderate or severe hepatic impairment, respectively. These values were 22%, 7% and 33% lower, respectively, for 5-hydroxy saxagliptin compared with matched healthy subjects. CONCLUSIONS: One-half the usual dose of saxagliptin 5 mg (i.e. 2.5 mg orally once daily) is recommended for patients with moderate (CLCR 30-50 mL/min) or severe (CLCR<30 mL/min not on dialysis) renal impairment or ESRD, but no dose adjustment is recommended for those with mild renal impairment or any degree of hepatic impairment.