Pharmacokinetic and pharmacodynamic properties of multiple oral doses of sitagliptin, a dipeptidyl peptidase-IV inhibitor: A double-blind, randomized, placebo-controlled study in healthy male volunteers
Dipeptidyl peptidase-IV (DPP-IV) inhibitorsrepresent a new class of oral antihyperglycemic agents. Sitagliptin is an orally active and selective DPP-IV inhibitor currently in Phase III development for the treatment of type 2 diabetes mellitus. The aim of this study was to assess the pharmacokinetic...
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| Veröffentlicht in: | Clinical therapeutics 2006, Vol.28 (1), p.55-72 |
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| creator | Bergman, Arthur J. Stevens, Catherine Zhou, YanYan Yi, Bingming Laethem, Martine De Smet, Marina Snyder, Karen Hilliard, Deborah Tanaka, Wesley Zeng, Wei Tanen, Michael Wang, Amy Q. Chen, Li Winchell, Gregory Davies, Michael J. Ramael, Steven Wagner, John A. Herman, Gary A. |
| description | Dipeptidyl peptidase-IV (DPP-IV) inhibitorsrepresent a new class of oral antihyperglycemic agents. Sitagliptin is an orally active and selective DPP-IV inhibitor currently in Phase III development for the treatment of type 2 diabetes mellitus.
The aim of this study was to assess the pharmacokinetic and pharmacodynamic (PK/PD) properties and tolerability of multiple oral once-daily or twice-daily doses of sitagliptin.
This double-blind, randomized, placebo-controlled,incremental oral-dose study was conducted at SGS Biopharma, Antwerp, Belgium. Healthy, nonsmoking male volunteers aged 18 to 45 years with a creatinine clearance rate of >80 mL/min and normoglycemia and weighing within 15% of their ideal height/weight range were randomly assigned to 1 of 8 treatment groups: sitagliptin 25, 50, 100, 200, or 400 mg or placebo, QD for 10 days; a single dose of sitagliptin 800 mg administered on day 1 followed by 600 mg QD on days 3 to 10; or sitagliptin 300 mg BID for 10 days. For analysis of PK properties, plasma and urine samples were obtained before study drug administration on day 1 and at 0.5, 1, 2, 4, 6, 8, 10, 12, and 16 hours after study drug administration on day 1; before study drug administration on days 2 to 9; and every 24 hours for 96 hours after the last dose on day 10, and analyzed for sitagliptin concentrations. Assays were used to measure inhibition of plasma DPP-IV activity and plasma concentrations of active and total glucagon-like peptide-1 (GLP-1), glucose, and glucagon, and serum concentrations of insulin, C-peptide, insulin-like growth factor-1, and insulin like growth factor binding protein-3. Tolerability was assessed throughout the study using physical examination, including vital sign measurements; 12-lead electrocardiography; and laboratory analysis, including hematology, biochemistry (hepatic aminotransferase and creatine phosphokinase), and urinalysis.
Seventy subjects were enrolled (mean age, 32.9 years [range, 18–45 years]; mean weight, 79.7 kg [range, 63.4–97.7 kg]; 8 patients per sitagliptin study group and 14 patients in the control group). In the sitagliptin groups, the plasma concentration-time profiles and principal PK parameters (T
max, C
max, and t
½) were statistically similar at days 1 (single dose) and 10 (steady state). In the groups receiving sitagliptin QD doses, accumulation of sitagliptin was modest (AUC accumulation ratio [day 10/day 1] range, 1.05–1.29), and the apparent terminal elimination t
½ was 11.8 to 14.4 h |
| doi_str_mv | 10.1016/j.clinthera.2006.01.015 |
| format | Article |
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The aim of this study was to assess the pharmacokinetic and pharmacodynamic (PK/PD) properties and tolerability of multiple oral once-daily or twice-daily doses of sitagliptin.
This double-blind, randomized, placebo-controlled,incremental oral-dose study was conducted at SGS Biopharma, Antwerp, Belgium. Healthy, nonsmoking male volunteers aged 18 to 45 years with a creatinine clearance rate of >80 mL/min and normoglycemia and weighing within 15% of their ideal height/weight range were randomly assigned to 1 of 8 treatment groups: sitagliptin 25, 50, 100, 200, or 400 mg or placebo, QD for 10 days; a single dose of sitagliptin 800 mg administered on day 1 followed by 600 mg QD on days 3 to 10; or sitagliptin 300 mg BID for 10 days. For analysis of PK properties, plasma and urine samples were obtained before study drug administration on day 1 and at 0.5, 1, 2, 4, 6, 8, 10, 12, and 16 hours after study drug administration on day 1; before study drug administration on days 2 to 9; and every 24 hours for 96 hours after the last dose on day 10, and analyzed for sitagliptin concentrations. Assays were used to measure inhibition of plasma DPP-IV activity and plasma concentrations of active and total glucagon-like peptide-1 (GLP-1), glucose, and glucagon, and serum concentrations of insulin, C-peptide, insulin-like growth factor-1, and insulin like growth factor binding protein-3. Tolerability was assessed throughout the study using physical examination, including vital sign measurements; 12-lead electrocardiography; and laboratory analysis, including hematology, biochemistry (hepatic aminotransferase and creatine phosphokinase), and urinalysis.
Seventy subjects were enrolled (mean age, 32.9 years [range, 18–45 years]; mean weight, 79.7 kg [range, 63.4–97.7 kg]; 8 patients per sitagliptin study group and 14 patients in the control group). In the sitagliptin groups, the plasma concentration-time profiles and principal PK parameters (T
max, C
max, and t
½) were statistically similar at days 1 (single dose) and 10 (steady state). In the groups receiving sitagliptin QD doses, accumulation of sitagliptin was modest (AUC accumulation ratio [day 10/day 1] range, 1.05–1.29), and the apparent terminal elimination t
½ was 11.8 to 14.4 hours. At steady state in the sitagliptin QD groups, the mean proportion of drug excreted unchanged in the urine was ∼70.6%. Dose-dependent inhibition of plasma DPP-IV activity was apparent, and the pattern of inhibition at steady state (day 10) was statistically similar to that observed on day 1. Day-10 weighted mean inhibition of plasma DPP-IV activity over 24 hours was ≥ 80% for doses of ≥ 50 mg QD. After a standard meal, active GLP-1 concentrations were significantly increased in the sitagliptin groups by ∼2-fold compared with that in the control group, a finding consistent with near-maximal acute glucose lowering in preclinical studies. Across doses, no apparent adverse effects, including hypoglycemia, were found or reported.
The results from this study in a select population of healthy male volunteers suggest that multiple oral doses of sitagliptin inhibited plasma DPP-IV activity and affected active GLP-1 concentrations in a dose-dependent manner, without producing hypoglycemia. Multiple dosing of sitagliptin exhibited a PK/PD profile consistent with that of a QD regimen and was well tolerated.</description><identifier>ISSN: 0149-2918</identifier><identifier>EISSN: 1879-114X</identifier><identifier>DOI: 10.1016/j.clinthera.2006.01.015</identifier><identifier>PMID: 16490580</identifier><language>eng</language><publisher>Belle Mead, NJ: EM Inc USA</publisher><subject>Administration, Oral ; Adolescent ; Adult ; antihyperglycemic agents ; Biological and medical sciences ; Blood Glucose - drug effects ; Blood Glucose - metabolism ; Diabetes ; Diabetes Mellitus, Type 2 - blood ; Diabetes Mellitus, Type 2 - drug therapy ; Diabetes. Impaired glucose tolerance ; Dipeptidyl Peptidase 4 - blood ; Dipeptidyl Peptidase 4 - drug effects ; dipeptidyl peptidase-IVinhibitor ; Dose-Response Relationship, Drug ; Double-Blind Method ; DPP-IV ; Drug dosages ; Endocrine pancreas. Apud cells (diseases) ; Endocrinopathies ; Enzyme-Linked Immunosorbent Assay ; Etiopathogenesis. Screening. Investigations. Target tissue resistance ; Follow-Up Studies ; Glucagon ; Glucagon-Like Peptide 1 - blood ; Glucose ; Humans ; incretins ; Insulin-Like Growth Factor Binding Protein 3 - blood ; Insulin-Like Growth Factor I - metabolism ; Male ; Medical sciences ; Metabolism ; Metabolites ; Middle Aged ; MK-0431 ; Pharmacokinetics ; Pharmacology. Drug treatments ; Polypeptides ; Pyrazines - administration & dosage ; Pyrazines - pharmacokinetics ; Reference Values ; sitagliptin ; Sitagliptin Phosphate ; Triazoles - administration & dosage ; Triazoles - pharmacokinetics ; type 2 diabetes</subject><ispartof>Clinical therapeutics, 2006, Vol.28 (1), p.55-72</ispartof><rights>2006 Excerpta Medica, Inc.</rights><rights>2006 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c493t-1940de937caf29607d734a7aed81893d72b01bad307021a583a102cbfeec51463</citedby><cites>FETCH-LOGICAL-c493t-1940de937caf29607d734a7aed81893d72b01bad307021a583a102cbfeec51463</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0149291806000294$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,4010,27900,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17548034$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16490580$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bergman, Arthur J.</creatorcontrib><creatorcontrib>Stevens, Catherine</creatorcontrib><creatorcontrib>Zhou, YanYan</creatorcontrib><creatorcontrib>Yi, Bingming</creatorcontrib><creatorcontrib>Laethem, Martine</creatorcontrib><creatorcontrib>De Smet, Marina</creatorcontrib><creatorcontrib>Snyder, Karen</creatorcontrib><creatorcontrib>Hilliard, Deborah</creatorcontrib><creatorcontrib>Tanaka, Wesley</creatorcontrib><creatorcontrib>Zeng, Wei</creatorcontrib><creatorcontrib>Tanen, Michael</creatorcontrib><creatorcontrib>Wang, Amy Q.</creatorcontrib><creatorcontrib>Chen, Li</creatorcontrib><creatorcontrib>Winchell, Gregory</creatorcontrib><creatorcontrib>Davies, Michael J.</creatorcontrib><creatorcontrib>Ramael, Steven</creatorcontrib><creatorcontrib>Wagner, John A.</creatorcontrib><creatorcontrib>Herman, Gary A.</creatorcontrib><title>Pharmacokinetic and pharmacodynamic properties of multiple oral doses of sitagliptin, a dipeptidyl peptidase-IV inhibitor: A double-blind, randomized, placebo-controlled study in healthy male volunteers</title><title>Clinical therapeutics</title><addtitle>Clin Ther</addtitle><description>Dipeptidyl peptidase-IV (DPP-IV) inhibitorsrepresent a new class of oral antihyperglycemic agents. Sitagliptin is an orally active and selective DPP-IV inhibitor currently in Phase III development for the treatment of type 2 diabetes mellitus.
The aim of this study was to assess the pharmacokinetic and pharmacodynamic (PK/PD) properties and tolerability of multiple oral once-daily or twice-daily doses of sitagliptin.
This double-blind, randomized, placebo-controlled,incremental oral-dose study was conducted at SGS Biopharma, Antwerp, Belgium. Healthy, nonsmoking male volunteers aged 18 to 45 years with a creatinine clearance rate of >80 mL/min and normoglycemia and weighing within 15% of their ideal height/weight range were randomly assigned to 1 of 8 treatment groups: sitagliptin 25, 50, 100, 200, or 400 mg or placebo, QD for 10 days; a single dose of sitagliptin 800 mg administered on day 1 followed by 600 mg QD on days 3 to 10; or sitagliptin 300 mg BID for 10 days. For analysis of PK properties, plasma and urine samples were obtained before study drug administration on day 1 and at 0.5, 1, 2, 4, 6, 8, 10, 12, and 16 hours after study drug administration on day 1; before study drug administration on days 2 to 9; and every 24 hours for 96 hours after the last dose on day 10, and analyzed for sitagliptin concentrations. Assays were used to measure inhibition of plasma DPP-IV activity and plasma concentrations of active and total glucagon-like peptide-1 (GLP-1), glucose, and glucagon, and serum concentrations of insulin, C-peptide, insulin-like growth factor-1, and insulin like growth factor binding protein-3. Tolerability was assessed throughout the study using physical examination, including vital sign measurements; 12-lead electrocardiography; and laboratory analysis, including hematology, biochemistry (hepatic aminotransferase and creatine phosphokinase), and urinalysis.
Seventy subjects were enrolled (mean age, 32.9 years [range, 18–45 years]; mean weight, 79.7 kg [range, 63.4–97.7 kg]; 8 patients per sitagliptin study group and 14 patients in the control group). In the sitagliptin groups, the plasma concentration-time profiles and principal PK parameters (T
max, C
max, and t
½) were statistically similar at days 1 (single dose) and 10 (steady state). In the groups receiving sitagliptin QD doses, accumulation of sitagliptin was modest (AUC accumulation ratio [day 10/day 1] range, 1.05–1.29), and the apparent terminal elimination t
½ was 11.8 to 14.4 hours. At steady state in the sitagliptin QD groups, the mean proportion of drug excreted unchanged in the urine was ∼70.6%. Dose-dependent inhibition of plasma DPP-IV activity was apparent, and the pattern of inhibition at steady state (day 10) was statistically similar to that observed on day 1. Day-10 weighted mean inhibition of plasma DPP-IV activity over 24 hours was ≥ 80% for doses of ≥ 50 mg QD. After a standard meal, active GLP-1 concentrations were significantly increased in the sitagliptin groups by ∼2-fold compared with that in the control group, a finding consistent with near-maximal acute glucose lowering in preclinical studies. Across doses, no apparent adverse effects, including hypoglycemia, were found or reported.
The results from this study in a select population of healthy male volunteers suggest that multiple oral doses of sitagliptin inhibited plasma DPP-IV activity and affected active GLP-1 concentrations in a dose-dependent manner, without producing hypoglycemia. Multiple dosing of sitagliptin exhibited a PK/PD profile consistent with that of a QD regimen and was well tolerated.</description><subject>Administration, Oral</subject><subject>Adolescent</subject><subject>Adult</subject><subject>antihyperglycemic agents</subject><subject>Biological and medical sciences</subject><subject>Blood Glucose - drug effects</subject><subject>Blood Glucose - metabolism</subject><subject>Diabetes</subject><subject>Diabetes Mellitus, Type 2 - blood</subject><subject>Diabetes Mellitus, Type 2 - drug therapy</subject><subject>Diabetes. Impaired glucose tolerance</subject><subject>Dipeptidyl Peptidase 4 - blood</subject><subject>Dipeptidyl Peptidase 4 - drug effects</subject><subject>dipeptidyl peptidase-IVinhibitor</subject><subject>Dose-Response Relationship, Drug</subject><subject>Double-Blind Method</subject><subject>DPP-IV</subject><subject>Drug dosages</subject><subject>Endocrine pancreas. Apud cells (diseases)</subject><subject>Endocrinopathies</subject><subject>Enzyme-Linked Immunosorbent Assay</subject><subject>Etiopathogenesis. Screening. Investigations. Target tissue resistance</subject><subject>Follow-Up Studies</subject><subject>Glucagon</subject><subject>Glucagon-Like Peptide 1 - blood</subject><subject>Glucose</subject><subject>Humans</subject><subject>incretins</subject><subject>Insulin-Like Growth Factor Binding Protein 3 - blood</subject><subject>Insulin-Like Growth Factor I - metabolism</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Metabolism</subject><subject>Metabolites</subject><subject>Middle Aged</subject><subject>MK-0431</subject><subject>Pharmacokinetics</subject><subject>Pharmacology. Drug treatments</subject><subject>Polypeptides</subject><subject>Pyrazines - administration & dosage</subject><subject>Pyrazines - pharmacokinetics</subject><subject>Reference Values</subject><subject>sitagliptin</subject><subject>Sitagliptin Phosphate</subject><subject>Triazoles - administration & dosage</subject><subject>Triazoles - pharmacokinetics</subject><subject>type 2 diabetes</subject><issn>0149-2918</issn><issn>1879-114X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqFkduKFDEQhhtR3HH1FTQgerU9Jn2Od8PiYWFBL1S8a6qTaidjOmmT9EL7iD6Vtc7ggjeSghTF91cq9WfZM8G3govm1WGrrHFpjwG2BefNlguK-l62EV0rcyGqr_ezDReVzAspurPsUYwHznkp6-JhdiaaSvK645vs18c9hAmU_24cJqMYOM3mU02vDiaqzcHPGJLByPzIpsUmM1tkPoBl2sdjOZoE36yZk3EXDJg2M1KuV8uOCUTMr74w4_ZmMMmH12xH4mWwmA_0F33BAr3tJ_MTKZ8tKBx8rrxLwVuLmsW06JX0bI9g035lE9AQN94uLiGG-Dh7MIKN-OR0n2ef3775dPk-v_7w7upyd52rSpYpF7LiGmXZKhgL2fBWt2UFLaDuRCdL3RYDFwPokre8EFB3JQheqGFEVLWomvI8e3nsS2v5sWBM_WSiQmvBoV9i37R0qloQ-Pwf8OCX4Gi2XvCykGTcn3btkVLBxxhw7OdgJggrQf2t2f2h_2t2f2t2zwVFTcqnp_7LMKG-053cJeDFCYCowI60YGXiHdfWFVEVcbsjh7S2G4Ohj8qgU6hNQJV67c1_h_kNuQfRPQ</recordid><startdate>2006</startdate><enddate>2006</enddate><creator>Bergman, Arthur J.</creator><creator>Stevens, Catherine</creator><creator>Zhou, YanYan</creator><creator>Yi, Bingming</creator><creator>Laethem, Martine</creator><creator>De Smet, Marina</creator><creator>Snyder, Karen</creator><creator>Hilliard, Deborah</creator><creator>Tanaka, Wesley</creator><creator>Zeng, Wei</creator><creator>Tanen, Michael</creator><creator>Wang, Amy Q.</creator><creator>Chen, Li</creator><creator>Winchell, Gregory</creator><creator>Davies, Michael J.</creator><creator>Ramael, Steven</creator><creator>Wagner, John A.</creator><creator>Herman, Gary A.</creator><general>EM Inc USA</general><general>Excerpta Medica</general><general>Elsevier Limited</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88C</scope><scope>88E</scope><scope>8AO</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>K9.</scope><scope>KB0</scope><scope>M0S</scope><scope>M0T</scope><scope>M1P</scope><scope>M2O</scope><scope>M7N</scope><scope>MBDVC</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>7X8</scope></search><sort><creationdate>2006</creationdate><title>Pharmacokinetic and pharmacodynamic properties of multiple oral doses of sitagliptin, a dipeptidyl peptidase-IV inhibitor: A double-blind, randomized, placebo-controlled study in healthy male volunteers</title><author>Bergman, Arthur J. ; Stevens, Catherine ; Zhou, YanYan ; Yi, Bingming ; Laethem, Martine ; De Smet, Marina ; Snyder, Karen ; Hilliard, Deborah ; Tanaka, Wesley ; Zeng, Wei ; Tanen, Michael ; Wang, Amy Q. ; Chen, Li ; Winchell, Gregory ; Davies, Michael J. ; Ramael, Steven ; Wagner, John A. ; Herman, Gary A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c493t-1940de937caf29607d734a7aed81893d72b01bad307021a583a102cbfeec51463</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Administration, Oral</topic><topic>Adolescent</topic><topic>Adult</topic><topic>antihyperglycemic agents</topic><topic>Biological and medical sciences</topic><topic>Blood Glucose - drug effects</topic><topic>Blood Glucose - metabolism</topic><topic>Diabetes</topic><topic>Diabetes Mellitus, Type 2 - blood</topic><topic>Diabetes Mellitus, Type 2 - drug therapy</topic><topic>Diabetes. Impaired glucose tolerance</topic><topic>Dipeptidyl Peptidase 4 - blood</topic><topic>Dipeptidyl Peptidase 4 - drug effects</topic><topic>dipeptidyl peptidase-IVinhibitor</topic><topic>Dose-Response Relationship, Drug</topic><topic>Double-Blind Method</topic><topic>DPP-IV</topic><topic>Drug dosages</topic><topic>Endocrine pancreas. Apud cells (diseases)</topic><topic>Endocrinopathies</topic><topic>Enzyme-Linked Immunosorbent Assay</topic><topic>Etiopathogenesis. Screening. Investigations. Target tissue resistance</topic><topic>Follow-Up Studies</topic><topic>Glucagon</topic><topic>Glucagon-Like Peptide 1 - blood</topic><topic>Glucose</topic><topic>Humans</topic><topic>incretins</topic><topic>Insulin-Like Growth Factor Binding Protein 3 - blood</topic><topic>Insulin-Like Growth Factor I - metabolism</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Metabolism</topic><topic>Metabolites</topic><topic>Middle Aged</topic><topic>MK-0431</topic><topic>Pharmacokinetics</topic><topic>Pharmacology. Drug treatments</topic><topic>Polypeptides</topic><topic>Pyrazines - administration & dosage</topic><topic>Pyrazines - pharmacokinetics</topic><topic>Reference Values</topic><topic>sitagliptin</topic><topic>Sitagliptin Phosphate</topic><topic>Triazoles - administration & dosage</topic><topic>Triazoles - pharmacokinetics</topic><topic>type 2 diabetes</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bergman, Arthur J.</creatorcontrib><creatorcontrib>Stevens, Catherine</creatorcontrib><creatorcontrib>Zhou, YanYan</creatorcontrib><creatorcontrib>Yi, Bingming</creatorcontrib><creatorcontrib>Laethem, Martine</creatorcontrib><creatorcontrib>De Smet, Marina</creatorcontrib><creatorcontrib>Snyder, Karen</creatorcontrib><creatorcontrib>Hilliard, Deborah</creatorcontrib><creatorcontrib>Tanaka, Wesley</creatorcontrib><creatorcontrib>Zeng, Wei</creatorcontrib><creatorcontrib>Tanen, Michael</creatorcontrib><creatorcontrib>Wang, Amy Q.</creatorcontrib><creatorcontrib>Chen, Li</creatorcontrib><creatorcontrib>Winchell, Gregory</creatorcontrib><creatorcontrib>Davies, Michael J.</creatorcontrib><creatorcontrib>Ramael, Steven</creatorcontrib><creatorcontrib>Wagner, John A.</creatorcontrib><creatorcontrib>Herman, Gary A.</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Healthcare Administration Database (Alumni)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Healthcare Administration Database</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Research Library (Corporate)</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><jtitle>Clinical therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bergman, Arthur J.</au><au>Stevens, Catherine</au><au>Zhou, YanYan</au><au>Yi, Bingming</au><au>Laethem, Martine</au><au>De Smet, Marina</au><au>Snyder, Karen</au><au>Hilliard, Deborah</au><au>Tanaka, Wesley</au><au>Zeng, Wei</au><au>Tanen, Michael</au><au>Wang, Amy Q.</au><au>Chen, Li</au><au>Winchell, Gregory</au><au>Davies, Michael J.</au><au>Ramael, Steven</au><au>Wagner, John A.</au><au>Herman, Gary A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pharmacokinetic and pharmacodynamic properties of multiple oral doses of sitagliptin, a dipeptidyl peptidase-IV inhibitor: A double-blind, randomized, placebo-controlled study in healthy male volunteers</atitle><jtitle>Clinical therapeutics</jtitle><addtitle>Clin Ther</addtitle><date>2006</date><risdate>2006</risdate><volume>28</volume><issue>1</issue><spage>55</spage><epage>72</epage><pages>55-72</pages><issn>0149-2918</issn><eissn>1879-114X</eissn><abstract>Dipeptidyl peptidase-IV (DPP-IV) inhibitorsrepresent a new class of oral antihyperglycemic agents. Sitagliptin is an orally active and selective DPP-IV inhibitor currently in Phase III development for the treatment of type 2 diabetes mellitus.
The aim of this study was to assess the pharmacokinetic and pharmacodynamic (PK/PD) properties and tolerability of multiple oral once-daily or twice-daily doses of sitagliptin.
This double-blind, randomized, placebo-controlled,incremental oral-dose study was conducted at SGS Biopharma, Antwerp, Belgium. Healthy, nonsmoking male volunteers aged 18 to 45 years with a creatinine clearance rate of >80 mL/min and normoglycemia and weighing within 15% of their ideal height/weight range were randomly assigned to 1 of 8 treatment groups: sitagliptin 25, 50, 100, 200, or 400 mg or placebo, QD for 10 days; a single dose of sitagliptin 800 mg administered on day 1 followed by 600 mg QD on days 3 to 10; or sitagliptin 300 mg BID for 10 days. For analysis of PK properties, plasma and urine samples were obtained before study drug administration on day 1 and at 0.5, 1, 2, 4, 6, 8, 10, 12, and 16 hours after study drug administration on day 1; before study drug administration on days 2 to 9; and every 24 hours for 96 hours after the last dose on day 10, and analyzed for sitagliptin concentrations. Assays were used to measure inhibition of plasma DPP-IV activity and plasma concentrations of active and total glucagon-like peptide-1 (GLP-1), glucose, and glucagon, and serum concentrations of insulin, C-peptide, insulin-like growth factor-1, and insulin like growth factor binding protein-3. Tolerability was assessed throughout the study using physical examination, including vital sign measurements; 12-lead electrocardiography; and laboratory analysis, including hematology, biochemistry (hepatic aminotransferase and creatine phosphokinase), and urinalysis.
Seventy subjects were enrolled (mean age, 32.9 years [range, 18–45 years]; mean weight, 79.7 kg [range, 63.4–97.7 kg]; 8 patients per sitagliptin study group and 14 patients in the control group). In the sitagliptin groups, the plasma concentration-time profiles and principal PK parameters (T
max, C
max, and t
½) were statistically similar at days 1 (single dose) and 10 (steady state). In the groups receiving sitagliptin QD doses, accumulation of sitagliptin was modest (AUC accumulation ratio [day 10/day 1] range, 1.05–1.29), and the apparent terminal elimination t
½ was 11.8 to 14.4 hours. At steady state in the sitagliptin QD groups, the mean proportion of drug excreted unchanged in the urine was ∼70.6%. Dose-dependent inhibition of plasma DPP-IV activity was apparent, and the pattern of inhibition at steady state (day 10) was statistically similar to that observed on day 1. Day-10 weighted mean inhibition of plasma DPP-IV activity over 24 hours was ≥ 80% for doses of ≥ 50 mg QD. After a standard meal, active GLP-1 concentrations were significantly increased in the sitagliptin groups by ∼2-fold compared with that in the control group, a finding consistent with near-maximal acute glucose lowering in preclinical studies. Across doses, no apparent adverse effects, including hypoglycemia, were found or reported.
The results from this study in a select population of healthy male volunteers suggest that multiple oral doses of sitagliptin inhibited plasma DPP-IV activity and affected active GLP-1 concentrations in a dose-dependent manner, without producing hypoglycemia. Multiple dosing of sitagliptin exhibited a PK/PD profile consistent with that of a QD regimen and was well tolerated.</abstract><cop>Belle Mead, NJ</cop><pub>EM Inc USA</pub><pmid>16490580</pmid><doi>10.1016/j.clinthera.2006.01.015</doi><tpages>18</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0149-2918 |
| ispartof | Clinical therapeutics, 2006, Vol.28 (1), p.55-72 |
| issn | 0149-2918 1879-114X |
| language | eng |
| recordid | cdi_proquest_miscellaneous_67676451 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Administration, Oral Adolescent Adult antihyperglycemic agents Biological and medical sciences Blood Glucose - drug effects Blood Glucose - metabolism Diabetes Diabetes Mellitus, Type 2 - blood Diabetes Mellitus, Type 2 - drug therapy Diabetes. Impaired glucose tolerance Dipeptidyl Peptidase 4 - blood Dipeptidyl Peptidase 4 - drug effects dipeptidyl peptidase-IVinhibitor Dose-Response Relationship, Drug Double-Blind Method DPP-IV Drug dosages Endocrine pancreas. Apud cells (diseases) Endocrinopathies Enzyme-Linked Immunosorbent Assay Etiopathogenesis. Screening. Investigations. Target tissue resistance Follow-Up Studies Glucagon Glucagon-Like Peptide 1 - blood Glucose Humans incretins Insulin-Like Growth Factor Binding Protein 3 - blood Insulin-Like Growth Factor I - metabolism Male Medical sciences Metabolism Metabolites Middle Aged MK-0431 Pharmacokinetics Pharmacology. Drug treatments Polypeptides Pyrazines - administration & dosage Pyrazines - pharmacokinetics Reference Values sitagliptin Sitagliptin Phosphate Triazoles - administration & dosage Triazoles - pharmacokinetics type 2 diabetes |
| title | Pharmacokinetic and pharmacodynamic properties of multiple oral doses of sitagliptin, a dipeptidyl peptidase-IV inhibitor: A double-blind, randomized, placebo-controlled study in healthy male volunteers |
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