Frank LaCreta

Differential Effects of Omeprazole and Pantoprazole on the Pharmacodynamics and Pharmacokinetics of Clopidogrel in Healthy Subjects: Randomized, Placebo-Controlled, Crossover Comparison Studies

Four randomized, placebo‐controlled, crossover studies were conducted among 282 healthy subjects to investigate whether an interaction exists between clopidogrel (300‐mg loading dose/75‐mg/day maintenance dose) and the proton‐pump inhibitor (PPI) omeprazole (80 mg) when they are administered simultaneously (study 1); whether the interaction, if any, can be mitigated by administering clopidogrel and omeprazole 12 h apart (study 2) or by increasing clopidogrel to 600‐mg loading/150‐mg/day maintenance dosing (study 3); and whether the interaction applies equally to the PPI pantoprazole (80 mg) (study 4). Relative to levels after administration of clopidogrel alone in studies 1,2,3, and 4, coadministration of PPI decreased the AUC0–24 of the clopidogrel active metabolite H4 by 40, 47, 41, and 14% (P ≤ 0.002), respectively; increased maximal platelet aggregation (MPA) induced by 5 µmol/l adenosine diphosphate (ADP) by 8.0, 5.6, 8.1, and 4.3% (P ≤ 0.014), respectively; and increased the vasodilator‐stimulated phosphoprotein phosphorylation‐platelet reactivity index (VASP‐PRI) by 20.7, 27.1, 19.0 (P < 0.0001), and 3.9% (P = 0.3319), respectively. The results suggest that a metabolic drug–drug interaction exists between clopidogrel and omeprazole but not between clopidogrel and pantoprazole.

Apixaban, an oral, direct factor Xa inhibitor: single dose safety, pharmacokinetics, pharmacodynamics and food effect in healthy subjects

To evaluate apixaban single dose safety, tolerability, pharmacokinetics and pharmacodynamics and assess the effect of food on apixaban pharmacokinetics.

Safety, pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban, a factor Xa inhibitor, in healthy subjects.

AIM Apixaban is an oral factor Xa inhibitor approved for stroke prevention in atrial fibrillation and thromboprophylaxis in patients who have undergone elective hip or knee replacement surgery and under development for treatment of venous thromboembolism. This study examined the safety, pharmacokinetics and pharmacodynamics of multiple dose apixaban. METHOD This double-blind, randomized, placebo-controlled, parallel group, multiple dose escalation study was conducted in six sequential dose panels - apixaban 2.5, 5, 10 and 25 mg twice daily and 10 and 25 mg once daily- with eight healthy subjects per panel. Within each panel, subjects were randomized (3:1) to oral apixaban or placebo for 7 days. Subjects underwent safety assessments and were monitored for adverse events (AEs). Blood samples were taken to measure apixaban plasma concentration, international normalized ratio (INR), activated partial thromboplastin time (aPTT) and modified prothrombin time (mPT). RESULTS Forty-eight subjects were randomized and treated (apixaban, n = 36; placebo, n = 12); one subject receiving 2.5 mg twice daily discontinued due to AEs (headache and nausea). No dose limiting AEs were observed. Apixaban maximum plasma concentration was achieved ~3 h post-dose. Exposure increased approximately in proportion to dose. Apixaban steady-state concentrations were reached by day 3, with an accumulation index of 1.3-1.9. Peak : trough ratios were lower for twice daily vs. once daily regimens. Clotting times showed dose-related increases tracking the plasma concentration-time profile. CONCLUSION Multiple oral doses of apixaban were safe and well tolerated over a 10-fold dose range, with pharmacokinetics with low variability and concentration-related increases in clotting time measures.

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.

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.

Lack of pharmacokinetic interaction between dapagliflozin, a novel sodium–glucose transporter 2 inhibitor, and metformin, pioglitazone, glimepiride or sitagliptin in healthy subjects

Aims: Dapagliflozin increases urinary glucose excretion by selectively inhibiting renal sodium–glucose transporter 2, an insulin‐independent mechanism of action that may be complementary to that of other oral antidiabetes drugs. The current studies assessed the potential for pharmacokinetic (PK) interaction between dapagliflozin and pioglitazone, metformin, glimepiride or sitagliptin in healthy subjects following single‐dose administration.

Pharmacokinetics and pharmacodynamics of dapagliflozin, a novel selective inhibitor of sodium–glucose co-transporter type 2, in Japanese subjects without and with type 2 diabetes mellitus

Aims: Dapagliflozin, a selective, orally active inhibitor of the renal sodium–glucose co‐transporter type 2 (SGLT2) is in development for the treatment of type 2 diabetes mellitus (T2DM). Here, the pharmacokinetics (PK) and pharmacodynamics (PD) of dapagliflozin were evaluated in healthy Japanese subjects and in Japanese subjects with T2DM.

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.

A Dose‐Escalation Study of the Safety, Tolerability, and Pharmacokinetics of Intravenous Gatifloxacin in Healthy Adult Men

Study Objectives. To examine single‐ and multiple‐dose safety, tolerability and pharmacokinetics of gatifloxacin administered as daily 1‐hour intravenous infusions for 14 days, and to determine the effect of gatifloxacin on glucose tolerance, pancreatic β‐cell function, and electrocardiogram (ECG).

Effect of multiple-dose gatifloxacin or ciprofloxacin on glucose homeostasis and insulin production in patients with noninsulin-dependent diabetes mellitus maintained with diet and exercise.

Study Objectives. To compare the effects of gatifloxacin and ciprofloxacin on glucose homeostasis, including glucose tolerance test (GTT), pancreatic β‐cell function, and insulin production and secretion in patients with noninsulin‐dependent (type 2) diabetes mellitus (NIDDM) maintained with diet and exercise; and to evaluate the pharmacokinetics, safety, and tolerability of gatifloxacin.