Pharmacokinetic and Pharmacodynamic Assessments of the Dipeptidyl Peptidase-4 Inhibitor PHX1149: Double-Blind, Placebo-Controlled, Single- and Multiple-Dose Studies in Healthy Subjects

O'Farrell, A. Marie; Vliet, André van; Farha, Khalid Abou; Cherrington, Julie M.; Campbell, David A.; Li, Xin-Qiang; Hanway, Denise; Li, Jianke; Guler, Hans‐Peter

doi:10.1016/j.clinthera.2007.08.005

Cited by 27 publications

(27 citation statements)

References 19 publications

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“…Very recently, clinical trial results of Gly-boroPro derivative DPP4 inhibitor PHX1149 (47) were reported [55][56][57]104]. PHX1149 was given orally at the doses of 200 or 400 mg.…”

Section: Boron-containing Dipeptidyl Peptidase 4 Inhibitorsmentioning

confidence: 99%

Therapeutic Potential of Boron-Containing Compounds

Baker¹,

Ding²,

Akama³

et al. 2009

Future Med. Chem.

299

214

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Relative to carbon, hydrogen, nitrogen and oxygen, very little is currently known about boron in therapeutics. In addition, there are very few boron-containing natural products identified to date to serve as leads for medicinal chemists. Perceived risks of using boron and lack of synthetic methods to handle boron-containing compounds have caused the medicinal chemistry community to shy away from using the atom. However, physical, chemical and biological properties of boron offer medicinal chemists a rare opportunity to explore and pioneer new areas of drug discovery. Boron therapeutics are emerging that show different modes of inhibition against a variety of biological targets. With one boron-containing therapeutic agent on the market and several more in various stages of clinical trials, the occurrence of this class of compound is likely to grow over the next decade and boron could become widely accepted as a useful element in future drug discovery.

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“…Very recently, clinical trial results of Gly-boroPro derivative DPP4 inhibitor PHX1149 (47) were reported [55][56][57]104]. PHX1149 was given orally at the doses of 200 or 400 mg.…”

Section: Boron-containing Dipeptidyl Peptidase 4 Inhibitorsmentioning

confidence: 99%

Therapeutic Potential of Boron-Containing Compounds

Baker¹,

Ding²,

Akama³

et al. 2009

Future Med. Chem.

299

214

View full text Add to dashboard Cite

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“…In order to confirm steady state conditions, additional blood samples were collected prior to the morning dose on Days 3,4,8,9,13, and 14. All samples were drawn into the appropriate anticoagulant.…”

Section: Collection and Preparation Of Pharmacokinetic And Pharmacodymentioning

confidence: 99%

“…These are desirable properties as they retain dutogliptin in the extracellular compartment where DPP4, the regulator of GLP-1 degradation, is located. Studies in normal volunteers and in diabetic patients have shown a dose-dependent increase of plasma dutogliptin concentrations which correlate with ex vivo DPP4 inhibition [12][13] . Furthermore, a dosedependent increase of intact GLP-1 concentrations, reduced postprandial glucose excursion, and improved glycemic control have been demonstrated in patients with T2DM 12 .…”

Section: Introductionmentioning

confidence: 97%

“…Furthermore, a dosedependent increase of intact GLP-1 concentrations, reduced postprandial glucose excursion, and improved glycemic control have been demonstrated in patients with T2DM 12 . The terminal elimination half life (t 1/2 ) for dutogliptin is 10 to 13 hours at steady state, which is reached within 5 days of administration 13 . In humans, dutogliptin appears to be minimally metabolized and absorbed dutogliptin is primarily eliminated unchanged by the renal route 14 .…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of the potential for pharmacokinetic and pharmacodynamic interactions between dutogliptin, a novel DPP4 inhibitor, and metformin, in type 2 diabetic patients

Li¹,

Klemm²,

O'Farrell³

et al. 2010

Current Medical Research and Opinion

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In this small, multiple dose study, the steady state pharmacokinetics of either dutogliptin or metformin were not altered by co-administration of the two agents. Dutogliptin and metformin were well tolerated either alone or in combination and co-administered metformin did not alter the ex vivo DPP4 inhibition by dutogliptin. There is no need to consider pharmacokinetic and pharmacodynamic interactions when determining the dosage of either agent for co-administration. A phase 3 clinical trial is underway to provide more definitive data on the safety and efficacy of dutogliptin administered on a background of metformin treatment.

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“…A reduction in the dose of sulfonylureas is usually recommended (risk of hypoglycemia) when DPP-4 inhibitors are added (pharmacodynamic rather than a pharmacokinetic interaction) (Scheen, 2010a). (Garcia-Soria et al, 2008;Pattzi et al, 2010); efficacy and tolerability are positive (O'Farrell et al, 2007;GarciaSoria et al, 2008;Rosenberg et al, 2010). Dutogliptin is highly water soluble (Ͼ2000 mg/ml), has low cellular permeability, is rapidly absorbed (with a T max of 3 to 4 h), has a half-life of 10 to 13 h, exhibits low plasma protein binding (11%) (Pattzi et al, 2010), is not metabolized (Pattzi et al, 2010), and is excreted renally.…”

Section: Alogliptin (Syr-322)mentioning

confidence: 99%

Novel Pharmacological Approaches to the Treatment of Type 2 Diabetes

Verspohl

2012

Pharmacol Rev

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Pharmacokinetic and Pharmacodynamic Assessments of the Dipeptidyl Peptidase-4 Inhibitor PHX1149: Double-Blind, Placebo-Controlled, Single- and Multiple-Dose Studies in Healthy Subjects

Cited by 27 publications

References 19 publications

Therapeutic Potential of Boron-Containing Compounds

Therapeutic Potential of Boron-Containing Compounds

Evaluation of the potential for pharmacokinetic and pharmacodynamic interactions between dutogliptin, a novel DPP4 inhibitor, and metformin, in type 2 diabetic patients

Novel Pharmacological Approaches to the Treatment of Type 2 Diabetes

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