First-in-human study to assess the safety, pharmacokinetics and pharmacodynamics of BMS-962212, a direct, reversible, small molecule factor XIa inhibitor in non-Japanese and Japanese healthy subjects.

AIMS: The aims of the present study were to assess the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of BMS-962212, a first-in-class factor XIa inhibitor, in Japanese and non-Japanese healthy subjects. METHODS: This was a randomized, placebo-controlled, double-blind, sequential, ascending-dose study of 2-h (part A) and 5-day (part B) intravenous (IV) infusions of BMS-962212. Part A used four doses (1.5, 4, 10 and 25 mg h-1 ) of BMS-962212 or placebo in a 6:2 ratio per dose. Part B used four doses (1, 3, 9 and 20 mg h-1 ) enrolling Japanese (n = 4 active, n = 1 placebo) and non-Japanese (n = 4 active, n = 1 placebo) subjects per dose. The PK, PD, safety and tolerability were assessed throughout the study. RESULTS: BMS-962212 was well tolerated; there were no signs of bleeding, and adverse events were mild. In parts A and B, BMS-962212 demonstrated dose proportionality. The mean half-life in parts A and B ranged from 2.04 to 4.94 h and 6.22 to 8.65 h, respectively. Exposure-dependent changes were observed in the PD parameters, activated partial thromboplastin time (aPTT) and factor XI clotting activity (FXI:C). The maximum mean aPTT and FXI:C change from baseline at 20 mg h-1 in part B was 92% and 90%, respectively. No difference was observed in weight-corrected steady-state concentrations, aPTT or FXI:C between Japanese and non-Japanese subjects (P > 0.05). CONCLUSION: BMS-962212 has tolerability, PK and PD properties suitable for investigational use as an acute antithrombotic agent in Japanese or non-Japanese subjects.

Effect of extremes of body weight on the pharmacokinetics, pharmacodynamics, safety and tolerability of apixaban in healthy subjects.

AIM: Apixaban is an oral, direct, factor-Xa inhibitor approved for thromboprophylaxis in patients who have undergone elective hip or knee replacement surgery and for prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. This open label, parallel group study investigated effects of extremes of body weight on apixaban pharmacokinetics, pharmacodynamics, safety and tolerability. METHOD: Fifty-four healthy subjects were enrolled [18 each into low (≤50 kg), reference (65-85 kg) and high (≥120 kg) body weight groups]. Following administration of a single oral dose of 10 mg apixaban, plasma and urine samples were collected for determination of apixaban pharmacokinetics and anti-factor Xa activity. Adverse events, vital signs and laboratory assessments were monitored. RESULTS: Compared with the reference body weight group, low body weight had approximately 27% [90% confidence interval (CI): 8-51%] and 20% (90% CI: 11-42%) higher apixaban maximum observed plasma concentration (Cmax) and area under the concentration-time curve extrapolated to infinity (AUC(0,∞)), respectively, and high body weight had approximately 31% (90% CI: 18-41%) and 23% (90% CI: 9-35%) lower apixaban Cmax and AUC(0,∞) , respectively. Apixaban renal clearance was similar across the weight groups. Plasma anti-factor Xa activity showed a direct, linear relationship with apixaban plasma concentration, regardless of body weight group. Apixaban was well tolerated in this study. CONCLUSION: The modest change in apixaban exposure is unlikely to require dose adjustment for apixaban based on body weight alone. However, caution is warranted in the presence of additional factors (such as severe renal impairment) that could increase apixaban exposure.

The influence of kidney function on dapagliflozin exposure, metabolism and pharmacodynamics in healthy subjects and in patients with type 2 diabetes mellitus.

AIM(S): This study assessed the effect of differences in renal function on the pharmacokinetics and pharmacodynamics of dapagliflozin, a renal sodium glucose co-transporter-2 (SGLT2) inhibitor for the treatment of type 2 diabetes mellitus (T2DM). METHODS: A single 50 mg dose of dapagliflozin was used to assess pharmacokinetics and pharmacodynamics in five groups: healthy non-diabetic subjects; patients with T2DM and normal kidney function and patients with T2DM and mild, moderate or severe renal impairment based on estimated creatinine clearance. Subsequently, 20 mg once daily multiple doses of dapagliflozin were evaluated in the patients with T2DM. Formation rates of dapagliflozin 3-O-glucuronide (D3OG), an inactive metabolite, were evaluated using human isolated kidney and liver microsomes. RESULTS: Plasma concentrations of dapagliflozin and D3OG were incrementally increased with declining kidney function. Steady-state Cmax for dapagliflozin were 4%, 6% and 9% higher and for D3OG were 20%, 37% and 52% higher in patients with mild, moderate and severe renal impairment, respectively, compared with normal function. AUC(0,τ) was likewise higher. D3OG formation in kidney microsomes was three-fold higher than in liver microsomes and 109-fold higher than in intestine microsomes. Compared with patients with normal renal function, pharmacodynamic effects were attenuated with renal impairment. Steady-state renal glucose clearance was reduced by 42%, 83% and 84% in patients with mild, moderate or severe renal impairment, respectively. CONCLUSIONS: These results indicate that both kidney and liver significantly contribute to dapagliflozin metabolism, resulting in higher systemic exposure with declining kidney function. Dapagliflozin pharmacodynamics in diabetic subjects with moderate to severe renal impairment are consistent with the observation of reduced efficacy in this patient population.

Effect of rifampicin on the pharmacokinetics and pharmacodynamics of saxagliptin, a dipeptidyl peptidase-4 inhibitor, in healthy subjects.

AIM: To investigate the effect of co-administration of rifampicin, a potent inducer of cytochrome P450 (CYP) 3A4 enzymes, on the pharmacokinetics (PK) and pharmacodynamics (PD) of saxagliptin and 5-hydroxy saxagliptin in healthy subjects. Saxagliptin is metabolized by CYP3A4/3A5 to 5-hydroxy saxagliptin, its major pharmacologically active metabolite. METHODS: In a non-randomized, open label, single sequence design, 14 healthy subjects received single oral doses of saxagliptin 5 mg with and without steady-state rifampicin (600 mg once daily for 6 days). PK (saxagliptin and 5-hydroxy saxagliptin) and PD (plasma DPP-4 activity) were measured for up to 24 h on days 1 and 7. RESULTS: Concomitant administration with rifampicin resulted in 53% (point estimate 0.47, 90% CI 0.38, 0.57) and 76% (point estimate 0.24, 90% CI 0.21, 0.27) decreases in the geometric mean C(max) and AUC values of saxagliptin, respectively, with a 39% (point estimate 1.39, 90% CI 1.23, 1.56) increase in the geometric mean C(max) and no change (point estimate 1.03, 90% CI 0.97, 1.09) in the AUC of 5-hydroxy saxagliptin. Similar maximum % inhibition and area under the % inhibition-time effect curve over 24 h for DPP-4 activity were observed when saxagliptin was administered alone or with rifampicin. The saxagliptin total active moieties exposure (AUC) decreased by 27% (point estimate 0.73, 90% CI 0.66, 0.81). Saxagliptin with or without rifampicin in this study was generally well tolerated. CONCLUSIONS: Lack of change of PD effect of saxagliptin is consistent with the observed 27% reduction in systemic exposure to the total active moieties, which is not considered clinically meaningful. Based on these findings, it is not necessary to adjust the saxagliptin dose when co-administered with rifampicin.

Pharmacokinetic and pharmacodynamic properties of single- and multiple-dose of dapagliflozin, a selective inhibitor of SGLT2, in healthy Chinese subjects.

BACKGROUND: Dapagliflozin, a selective, orally active, renal sodium glucose cotransporter 2 (SGLT2) 2 inhibitor, is under investigation as a treatment of type 2 diabetes mellitus (T2DM). Dapagliflozin reduces hyperglycemia by inhibiting renal glucose reabsorption and dose-dependently increasing urinary glucose excretion, independent of insulin secretion or action. OBJECTIVES: These studies assessed the single- and multiple-dose pharmacokinetic and pharmaco dynamic properties of dapagliflozin and its major inactive metabolite, dapagliflozin 3-O-glucuronide (D3OG), in healthy subjects residing in China. METHODS: In 2 identically designed, open-label, single- and multiple-dose studies (n = 14 for both studies), healthy Chinese subjects were administered oral dapagliflozin 5 or 10 mg. In both studies, subjects received a single dose on day 1 (single-dose administration period) followed by 6 once-daily doses on days 5 to 10 (multiple-dose administration period). Pharmacokinetic parameters (plasma and urinary dapagliflozin and D3OG), pharmacodynamic response (urinary glucose excretion), and tolerability were assessed. RESULTS: Fourteen subjects completed the dapagliflozin 5-mg study, and 13 completed the dapagliflozin 10-mg study. Baseline characteristics were balanced across the two studies: 9 versus 10 men; mean age, 27.1 versus 28.9 years; mean weight, 62.8 versus 62.2 kg; and mean body mass index, 23.0 versus 22.2 kg/m(2) in the dapagliflozin 5- and 10-mg studies, respectively. In both doses, dapagliflozin was rapidly absorbed (T(max), ≤1.5 h), accumulation (defined as the geometric mean ratio of AUC(τ) at day 10 to AUC(τ) at day 1) after multiple dosing was minimal (<1.13 fold), and elimination half-life was 10 to 12 h. D3OG showed a slightly longer median Tmax (≤2 h) but a similar plasma concentration-time profile and half-life compared with dapagliflozin. The majority of D3OG (up to 69.7% of the dapagliflozin dose) was excreted in urine, while ≤1.9% of dapagliflozin was excreted unchanged in urine. Over a 24-hour period and at steady state (day 10), urinary glucose excretion values were 28.1 and 41.1 g with dapagliflozin 5 and 10 mg, respectively. Dapagliflozin was generally well tolerated; one dapagliflozin 10 mg-treated subject discontinued the study because of a serious adverse event (bronchitis) considered by the investigator as unrelated to dapagliflozin dosing. CONCLUSIONS: Pharmacokinetic and pharmacodynamic characteristics following single- and multiple-dose dapagliflozin 5 and 10 mg oral administration in healthy Chinese subjects were as predicted from previous studies and were similar to findings observed in non-Chinese healthy subjects. Dapagliflozin dosing was well tolerated. The clinically recommended dapagliflozin dose of 10 mg once daily is expected to be appropriate in patients of Chinese ethnicity; results from an efficacy and tolerability study in Chinese patients with T2DM are awaited.

Bioequivalence of saxagliptin/metformin immediate release (IR) fixed-dose combination tablets and single-component saxagliptin and metformin IR tablets in healthy adult subjects.

BACKGROUND: As compared with individual tablets, saxagliptin/metformin immediate release (IR) fixed-dose combination (FDC) tablets offer the potential for increased convenience, compliance, and adherence for patients requiring combination therapy. OBJECTIVES: Two bioequivalence studies assessed the fed-state and the fasted-state bioequivalence of saxagliptin/metformin IR 2.5 mg/500 mg FDC (study 1) and saxagliptin/metformin IR 2.5 mg/1,000 mg FDC (study 2) relative to the same dosage strengths of the individual component tablets [saxagliptin (Onglyza™) and metformin IR (Glucophage(®))] administered concurrently. STUDY DESIGNS: These were randomized, open-label, single-dose, four-period, four-treatment, crossover studies in healthy subjects (n = 24 in each study). The treatments in study 1 were a saxagliptin/metformin IR 2.5 mg/500 mg FDC tablet in the fed and fasted states on separate occasions, and saxagliptin 2.5 mg and metformin IR 500 mg tablets co-administered in the fed state and fasted states on separate occasions. The treatments in study 2 were a saxagliptin/metformin IR 2.5 mg/1,000 mg FDC tablet in the fed and fasted states on separate occasions, and saxagliptin 2.5 mg and metformin IR 1,000 mg co-administered in the fed state and fasted states on separate occasions. The pharmacokinetics, safety, and tolerability of each treatment were evaluated. RESULTS: For both studies, saxagliptin and metformin in the FDCs were bioequivalent to the individual components in both the fed and the fasted states as the limits of the 90 % confidence interval of the ratio of adjusted geometric means for all key pharmacokinetic parameters were contained within the predefined 0.800 to 1.250 bioequivalence criteria. Co-administration of saxagliptin and metformin IR was generally safe and well tolerated as the FDCs or as individual tablets. CONCLUSIONS: Saxagliptin/metformin IR 2.5 mg/500 mg and saxagliptin/metformin IR 2.5 mg/1,000 mg FDCs were bioequivalent to individual tablets of saxagliptin and metformin of the same strengths in both the fed and the fasted states. No unexpected safety findings were observed with saxagliptin/metformin IR administration. The tolerability of the FDC of saxagliptin/metformin IR was comparable to that of the co-administered individual components. These results indicate that the safety and efficacy profile of co-administration of saxagliptin and metformin can be extended to the saxagliptin/metformin IR FDC tablets.

Characterization of renal glucose reabsorption in response to dapagliflozin in healthy subjects and subjects with type 2 diabetes.

OBJECTIVE: To examine the effect of dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on the major components of renal glucose reabsorption (decreased maximum renal glucose reabsorptive capacity [TmG], increased splay, and reduced threshold), using the pancreatic/stepped hyperglycemic clamp (SHC) technique. RESEARCH DESIGN AND METHODS: Subjects with type 2 diabetes (n=12) and matched healthy subjects (n=12) underwent pancreatic/SHC (plasma glucose range 5.5-30.5 mmol/L) at baseline and after 7 days of dapagliflozin treatment. A pharmacodynamic model was developed to describe the major components of renal glucose reabsorption for both groups and then used to estimate these parameters from individual glucose titration curves. RESULTS: At baseline, type 2 diabetic subjects had elevated TmG, splay, and threshold compared with controls. Dapagliflozin treatment reduced the TmG and splay in both groups. However, the most significant effect of dapagliflozin was a reduction of the renal threshold for glucose excretion in type 2 diabetic and control subjects. CONCLUSIONS: The SGLT2 inhibitor dapagliflozin improves glycemic control in diabetic patients by reducing the TmG and threshold at which glucose is excreted in the urine.

Lack of pharmacokinetic interactions between dapagliflozin and simvastatin, valsartan, warfarin, or digoxin.

INTRODUCTION: Coronary heart disease, stroke, and peripheral vascular disease are the most common causes of mortality in patients with type 2 diabetes mellitus (T2DM). The aim of these studies was to assess the potential for pharmacokinetic interaction between dapagliflozin, a sodium glucose co-transporter-2 inhibitor being developed for the treatment of T2DM, and four medications commonly prescribed in patients with T2DM and cardiovascular disease: simvastatin, valsartan, warfarin, and digoxin. METHODS: Potential pharmacokinetic interactions between 20 mg dapagliflozin, 40 mg simvastatin, or 320 mg valsartan were assessed in an open-label, randomized, five-period, five-treatment, unbalanced crossover study in 24 healthy subjects. In a second study, the effects of steady-state dapagliflozin on the pharmacokinetics of 25 mg warfarin or 0.25 mg digoxin were assessed in an open-label, randomized, two-period, two-treatment crossover study in 30 healthy subjects divided into two cohorts. The potential pharmacodynamic interaction between dapagliflozin and warfarin was also evaluated. RESULTS: All treatments were well tolerated. Neither simvastatin nor valsartan had any clinically meaningful effect on the pharmacokinetics of dapagliflozin. Dapagliflozin increased the area under the curve for simvastatin, simvastatin acid, and valsartan by approximately 19%, 30%, and 6%, respectively, and decreased the maximum observed plasma concentration of valsartan by approximately 6%. These effects were not considered clinically meaningful. In addition, dapagliflozin had no effect on the pharmacokinetics of either digoxin or warfarin. The pharmacodynamics of warfarin were also unaffected by dapagliflozin. CONCLUSION: In these studies the co-administration of dapagliflozin and simvastatin, valsartan, warfarin, or digoxin was well tolerated without clinically meaningful drug-drug interaction.

Bioequivalence of saxagliptin/metformin extended-release (XR) fixed-dose combination tablets and single-component saxagliptin and metformin XR tablets in healthy adult subjects.

BACKGROUND AND OBJECTIVES: As compared with individual tablets, saxagliptin/metformin extended-release (XR) fixed-dose combination (FDC) tablets offer potential for increased patient compliance with the convenience of once-daily dosing. Two bioequivalence studies assessed the fed-state bioequivalence of saxagliptin/metformin XR 5 mg/500 mg FDC (study 1) and saxagliptin/metformin XR 5 mg/1000 mg FDC (study 2) relative to the same dosage strengths of individual component tablets administered concurrently. The effect of food on saxagliptin and metformin pharmacokinetics from the saxagliptin/metformin XR 5 mg/500 mg FDC and their steady-state pharmacokinetics from the saxagliptin/metformin XR 5 mg/1000 mg were also investigated. METHODS: These were randomized, open-label, single-dose, three-period, three-treatment, crossover studies in healthy subjects (n = 30 in each study). The treatments in study 1 were a saxagliptin/metformin XR 5 mg/500 mg FDC tablet in the fed and fasted states on separate occasions, and saxagliptin 5 mg and metformin XR 500 mg co-administered in the fed state. The treatments in study 2 were a saxagliptin/metformin XR 5 mg/1000 mg FDC tablet in the fed state, saxagliptin 5 mg and 2 × metformin XR 500 mg co-administered in the fed state, and saxagliptin/metformin XR 5 mg/1000 mg FDC once daily for 4 days in the fed state to assess steady-state pharmacokinetics. The safety and tolerability of each treatment were also evaluated. RESULTS: For both studies, saxagliptin and metformin in the FDCs were bioequivalent to the individual components as the limits of the 90% confidence interval of the ratio of adjusted geometric means for all key pharmacokinetic parameters were contained within 0.800 to 1.250. Compared with the fasted state, food did not have a meaningful effect on the pharmacokinetics of saxagliptin and metformin when administered as the saxagliptin/metformin XR 5 mg/500 mg FDC. The saxagliptin/metformin XR 5 mg/1000 mg FDC showed consistent pharmacokinetics at steady state without evidence of dose dumping. Co-administration of saxagliptin and metformin XR was generally safe and well tolerated as the FDCs or as individual tablets. CONCLUSION: Saxagliptin/metformin XR 5 mg/500 mg and saxagliptin/metformin XR 5 mg/1000 mg FDCs were bioequivalent to individual tablets of saxagliptin and metformin of the same strengths. Additionally, food had little effect on the pharmacokinetics of saxagliptin and metformin administered in the saxagliptin/metformin XR 5 mg/500 mg FDC and the steady-state pharmacokinetics of the saxagliptin/metformin XR 5 mg/1000 mg FDC was consistent over time. No unexpected safety findings were observed with saxagliptin/metformin XR administration. The tolerability of the FDC of saxagliptin/metformin XR was comparable to that of the co-administered individual components. These results indicate that the safety and efficacy profile of co-administration of saxagliptin and metformin can be extended to the saxagliptin/metformin XR FDC tablets. TRIALS REGISTRATION: ClinicalTrials.gov Identifiers: NCT01192139 and NCT01192152.

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.