Simultaneous oral therapeutic and intravenous <sup>14</sup>C‐microdoses to determine the absolute oral bioavailability of saxagliptin and dapagliflozin

Boulton, David W.; Kasichayanula, Sreeneeranj; Keung, Chi; Arnold, Mark E.; Christopher, Lisa J.; Xu, Xiaohui; LaCreta, Frank

doi:10.1111/j.1365-2125.2012.04391.x

Cited by 76 publications

(90 citation statements)

References 15 publications

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“…Furthermore, the plasma concentration-time terminal elimination phases for each route were parallel. Thus, this study demonstrates that the intravenous microdosing has similar pharmacokinetics to the therapeutic oral dosing [44] .…”

Section: Pharmacokineticsmentioning

confidence: 54%

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Pharmacokinetic Characteristics and Clinical Efficacy of an SGLT2 Inhibitor Plus DPP-4 Inhibitor Combination Therapy in Type 2 Diabetes

Scheen

2016

Clin Pharmacokinet

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SUMMARYType 2 diabetes (T2D) generally requires a combination of several pharmacological approaches to control hyperglycaemia. Combining a sodium-glucose cotransporter type 2 inhibitor (SGLT2i, known as gliflozin) and a dipeptidyl peptidase-4 inhibitor known as gliptin) appears to be an attractive strategy because of complementary modes of action.This narrative review analyzes the pharmacokinetics and clinical efficacy of different combined therapies with a SGLT2i (canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, tofogliflozin) and a DPP-4i (linagliptin, saxagliptin, sitagliptin, teneligliptin). Drug-drug pharmacokinetic interaction studies do not show any significant changes in peak concentrations (C max ) and total exposure (area under the curve of plasma concentrations or AUC) of either drug when they were given orally together compared to corresponding values when each of them was absorbed alone. Some fixed-dose combinations (FDC) are already available (dapagliflozin-saxagliptin, empagliflozin-linagliptin) or in development (ertugliflozin-sitagliptin), and preliminary results showed bioequivalence of the two medications given as FDC tablets when compared with co-administration of the individual tablets. Dual therapy is more potent than either monotherapy in patients treated with diet and exercise or already treated with metformin. SGLT2i and DPP-4i could be used as initial combination or in a stepwise approach. The additional glucose-lowering effect appears to be more marked when a gliflozin is added to a gliptin than when a gliptin is added to a gliflozin. Combining the two pharmacological options is safe and does not induce hypoglycaemia. Key-words : Combined therapy -DPP-4 inhibitor -Fixed-dose combination -SGLT2 inhibitor -Type 2 diabetesKey points -The combination of a sodium-glucose cotransporter type 2 inhibitor (SGLT2i), which promotes glycosuria and improves glucose tolerance independently of insulin, and a dipeptidyl peptidase-4 inhibitor (DPP-4i), an incretin-based therapy that corrects islet dysfunction, is an attractive approach for the management of type 2 diabetes.-Both dapagliflozin plus saxagliptin and empagliflozin plus linagliptin combined therapies have been tested as separate tablets (no clinically relevant pharmacokinetic drug-drug interactions) and as fixed-dose combination (FDC: bioequivalence studies); such combined therapies are more efficacious than either monotherapy to control blood glucose, without worsening of the safety profile.-Other combinations of a SGLT2i and a DPP-4i have been evaluated in studies that also showed the absence of drug-drug pharmacokinetic interactions and better glucose control compared to either therapy alone. An ertugliflozin-sitagliptin FDC is in current development.-Initial SGLT2i -DPP-4i combination may be considered or one medication may be added to the other, with apparently better results when the SGLT2i was added to the DPP-4i compared with the reverse sequence. However, which glucose-lowering agent sh...

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Section: Pharmacokineticsmentioning

confidence: 54%

“…The absolute oral bioavailability of dapagliflozin and saxagliptin was determined using simultaneous intravenous 14 C-microdose/therapeutic oral dosing in healthy volunteers [44] . The geometric mean point estimates for dapagliflozin and saxagliptin were 78% (90% confidence interval or CI: 73, 83%) and 50% (48, 53%), respectively.…”

Section: Pharmacokineticsmentioning

confidence: 99%

Pharmacokinetic Characteristics and Clinical Efficacy of an SGLT2 Inhibitor Plus DPP-4 Inhibitor Combination Therapy in Type 2 Diabetes

Scheen

2016

Clin Pharmacokinet

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“…Saxagliptin has high aqueous solubility ([17 ng/mL) relative to its usual dose of up to 5 mg. Although its in vitro permeability was indicative of poor absorption in a Caco-2 transcellular permeability assay [ [25] unpublished data 2007], the absolute oral bioavailability and recovery of total radioactivity (TRA) in human and animal urine indicated extensive oral absorption (50-75 % absorption) [25][26][27].…”

Section: Introductionmentioning

confidence: 99%

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

Boulton

2016

Clin Pharmacokinet

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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.

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“…Nucleophilic substitution is a further common type of labeling reaction. It is used for the production of radioligands such as [ 18 …”

Section: Radionuclidesmentioning

confidence: 99%

Radionuclides in drug development

Uhl

Fricker

Haberkorn

et al. 2015

Drug Discovery Today

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Simultaneous oral therapeutic and intravenous ¹⁴C‐microdoses to determine the absolute oral bioavailability of saxagliptin and dapagliflozin

Cited by 76 publications

References 15 publications

Pharmacokinetic Characteristics and Clinical Efficacy of an SGLT2 Inhibitor Plus DPP-4 Inhibitor Combination Therapy in Type 2 Diabetes

Pharmacokinetic Characteristics and Clinical Efficacy of an SGLT2 Inhibitor Plus DPP-4 Inhibitor Combination Therapy in Type 2 Diabetes

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

Radionuclides in drug development

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Simultaneous oral therapeutic and intravenous 14C‐microdoses to determine the absolute oral bioavailability of saxagliptin and dapagliflozin

Cited by 76 publications

References 15 publications

Pharmacokinetic Characteristics and Clinical Efficacy of an SGLT2 Inhibitor Plus DPP-4 Inhibitor Combination Therapy in Type 2 Diabetes

Pharmacokinetic Characteristics and Clinical Efficacy of an SGLT2 Inhibitor Plus DPP-4 Inhibitor Combination Therapy in Type 2 Diabetes

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

Radionuclides in drug development

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Product

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Simultaneous oral therapeutic and intravenous ¹⁴C‐microdoses to determine the absolute oral bioavailability of saxagliptin and dapagliflozin