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

Li, Jianke; Klemm, Kirsti; O'Farrell, A. Marie; Guler, Hans‐Peter; Cherrington, Julie M.; Schwartz, Sherwyn; Boyea, Teresa

doi:10.1185/03007995.2010.491266

Cited by 4 publications

(2 citation statements)

References 28 publications

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“…Based on previous studies, dutogliptin was minimally metabolized and excreted as the parent compound in urine. Apparent clearance dutogliptin was similar to glomerular filtration rate, suggesting that passive renal clearance is the primary mechanism for the elimination of dutogliptin . Consistent with the pathway of elimination of dutogliptin, CrCL was identified as the most significant covariate explaining the CL/F of dutogliptin.…”

Section: Resultsmentioning

confidence: 57%

“…Apparent clearance dutogliptin was similar to glomerular filtration rate, suggesting that passive renal clearance is the primary mechanism for the elimination of dutogliptin. 15 Consistent with the pathway of elimination of dutogliptin, CrCL was identified as the most significant covariate explaining the CL/F of dutogliptin. Mean CL/F of dutogliptin in patients with mild and moderate renal impairment were 121 and 79 L/h, respectively.…”

Section: Model Evaluation/qualificationmentioning

confidence: 65%

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Population pharmacokinetic analysis of dutogliptin, a selective dipeptidyl peptidase‐4 inhibitor

Marier¹,

Mouksassi²,

Gosselin³

et al. 2014

Clinical Pharm in Drug Dev

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Dutogliptin is a selective dipeptidyl peptidase-4 inhibitor shown to be efficacious and safe in patients with type 2 diabetes mellitus (T2DM). Population pharmacokinetic (PK) analysis of dutogliptin was performed based on data collected in 561 healthy subjects and patients with T2DM enrolled in Phase I and II studies to assess sources of variability and support dosing rationale. The effect of extrinsic (formulations, fed/fasting conditions, potential drug-drug interaction with metformin) and intrinsic (baseline characteristics, markers of renal function, renal impairment category, and disease status) covariates was evaluated using non-linear mixed effect modeling. Plasma concentrations of dutogliptin were best fitted with a two-compartment model with a first-order rate constant of absorption (Ka) and a lag time. No differences were observed between healthy subjects and patients with T2DM. Apparent clearance (CL/F) and terminal elimination half-life of dutogliptin were 176 L/h and 12.2 hours, respectively. Typical CL/F values in patients with mild and moderate renal impairment were 121 and 79 L/h, respectively. No drug-drug interaction was observed with metformin. These results suggest that a reduction in dosing from 400 to 200 mg daily is warranted in T2DM patients with moderate renal impairment. No dose adjustments were deemed necessary for other evaluated patient characteristics and coadministration with metformin.

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Section: Resultsmentioning

confidence: 57%

Section: Model Evaluation/qualificationmentioning

confidence: 65%

Population pharmacokinetic analysis of dutogliptin, a selective dipeptidyl peptidase‐4 inhibitor

Marier¹,

Mouksassi²,

Gosselin³

et al. 2014

Clinical Pharm in Drug Dev

Self Cite

View full text Add to dashboard Cite

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Understanding the Molecular Dynamics of Type-2 Diabetes Drug Target DPP-4 and its Interaction with Sitagliptin and Inhibitor Diprotin-A

Chakraborty

Hsu

Agoramoorthy

2014

Cell Biochem Biophys

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The occurrence of type 2 diabetes (T2D) accounts for 90-95 % of all diabetes. Intestine hormone glucagon-like peptide-1 (GLP-1) has an antidiabetic role that enhances insulin secretion and pancreatic β-cell proliferation. GLP-1 is degraded by the enzyme dipeptidyl peptidase-4 (DPP-4) rapidly. Hence, the DPP-4 inhibition has been preferred not only for the treatment but also as a major drug target. Sitagliptin and Diprotin-A are antihyperglycemic agents for the treatment of T2D. However, little is known on the molecular dynamics of DPP-4 and the interaction properties with its ligands, namely Sitagliptin and Diprotin-A. This study has used the latest bioinformatic tools to understand the molecular dynamics and its interaction properties of DPP-4. This study has explored the number of α helices, β strands, β hairpins, Ψ loop, β bulges, β turns, and ϒ turns and they were 19, 46, 25, 1, 14, 70, and 4, respectively. The highest number of H-bonds was recorded in α helix of domain-1, and the lowest number H-bonds were noted in α helix of domain-2. During interaction between residues, in A- and B-chain, 47 and 48 residues are involved for interaction, and interaction interface area was more in A-Chain (2176 Å(2)). From DPP-4 and Sitagliptin interaction, three residues in active sites such as Try226, Glu205, and Glu206 were involved in three H-bond formation, while 10 other amino acids (Try547, Try667, Asn710, Val711, His740, Ser630, Ser209, Arg358, Phe357, and Val207) were involved in hydrophobic interactions. In this review, we have shown the importance of bioinformatics as an excellent tool for a rapid method to assess the molecular dynamics and its interaction properties of DPP-4. Our predictions highlighted in this review will help researchers to understand the interaction properties and recognition of interactive sites to design more DPP-4 inhibitors for the treatment of T2D and drug discovery.

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A Comprehensive Review of Drug–Drug Interactions with Metformin

2015

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Metformin is the world's most commonly used oral glucose-lowering drug for type 2 diabetes, and this is mainly because it protects against diabetes-related mortality and all-cause mortality. Although it is an old drug, its mechanism of action has not yet been clarified and its pharmacokinetic pathway is still not fully understood. There is considerable inter-individual variability in the response to metformin, and this has led to many drug-drug interaction (DDI) studies of metformin. In this review, we describe both in vitro and human interaction studies of metformin both as a victim and as a perpetrator. We also clarify the importance of including pharmacodynamic end points in DDI studies of metformin and taking pharmacogenetic variation into account when performing these studies to avoid hidden pitfalls in the interpretation of DDIs with metformin. This evaluation of the literature has revealed holes in our knowledge and given clues as to where future DDI studies should be focused and performed.

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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

Cited by 4 publications

References 28 publications

Population pharmacokinetic analysis of dutogliptin, a selective dipeptidyl peptidase‐4 inhibitor

Population pharmacokinetic analysis of dutogliptin, a selective dipeptidyl peptidase‐4 inhibitor

Understanding the Molecular Dynamics of Type-2 Diabetes Drug Target DPP-4 and its Interaction with Sitagliptin and Inhibitor Diprotin-A

A Comprehensive Review of Drug–Drug Interactions with Metformin

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