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This study was a prospective, interventional, two-part pilot clinical study conducted over 3 months on cirrhotic patients with diabetes mellitus and diabetic neuropathy, evaluating the real-world applicability of selected PBPK-guided dosing regimens. Patients were stratified according to Child-Pugh class (CP-A , CP-B, and CP-C) in case of sitagliptin and CP-A in duloxetine at doses corresponding to the closest commercially available strengths to Simcyp®-optimized doses.
Clinical evaluation included glycemic parameters(HbA1C,fasting blood glucose,2-hr post prandial glucose level) and pain reduction. Routine laboratory investigations were conducted to assess efficacy and safety and included liver function tests (serum albumin, total bilirubin, alanine aminotransferase [ALT],and aspartate aminotransferase [AST]), kidney function tests (serum creatinine and blood urea nitrogen [BUN]),and CBC.
This study was a prospective, interventional, two-part pilot clinical study conducted over 3 months on Egyptian cirrhotic patients with diabetes mellitus and diabetic neuropathy. Adult patients aged >18 years with confirmed liver cirrhosis, concomitant diabetes mellitus and diabetic neuropathy were eligible for inclusion. Patients were experienced acute episodes of disease associated with deterioration of hepatic function within 2 months prior to screening, and received concomitant medications known to strongly interact with the study drugs were excluded. In part 1: Sitagliptin dosing was determined based on Simcyp -generated predictions and clinical assessment. 100mg,100 mg, 50 mg, and 50 mg received by control, CP-A, CP-B, and CP-C cirrhosis patients, respectively, orally once daily. In part 2: Duloxetine dosing was determined based on Simcyp-generated predictions and clinical assessment. 60 mg ,30 mg received by control, and CP-A cirrhotic patients orally once daily, respectively. Clinical evaluation included glycemic parameters(HbA1C,fasting blood glucose,2-hr post prandial glucose level) and pain reduction. Routine laboratory investigations were conducted to assess efficacy and safety and included liver function tests (serum albumin, total bilirubin, alanine aminotransferase [ALT],and aspartate aminotransferase [AST]), kidney function tests (serum creatinine and blood urea nitrogen [BUN]),and CBC.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Control -Standard Dose Sitagliptin | Active Comparator | Sitagliptin (100 mg) |
|
| Child-Pugh A Sitagliptin | Experimental | CP-A: Sitagliptin 100 mg |
|
| Child-Pugh B Sitagliptin | Experimental | CP-B: Sitagliptin 50 mg |
|
| Child-Pugh C Sitagliptin | Experimental | CP-C :Sitagliptin 50 mg |
|
| Control -Standard Dose Duloxetine | Active Comparator | Duloxetine (60 mg) |
|
| Child-Pugh A | Experimental | CP-A: 30 mg Duloxetine |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Sitagliptin (Januvia) | Drug | Diabetic patients with Child-Pugh class A hepatic cirrhosis receiving 100 mg model -informed adjusted dose of sitagliptin. Sitagliptin is an oral dipeptidyl peptidase-4 (DPP-4) inhibitor used in conjunction with diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. The effect of this medication leads to glucose dependent increases in insulin and decreases in glucagon to improve control of blood sugar. |
| Measure | Description | Time Frame |
|---|---|---|
| Management of diabetes mellitus and diabetic neuropathy | by measuring glycemic parameters ( fasting blood glucose level,2-hr postprandial glucose level) (mg/dL). | 3 months |
| Measure | Description | Time Frame |
|---|---|---|
| Adverse Effects Monitoring | Adverse effects including headache, dry mouth, nasopharyngitis, dizziness, nausea, and diarrhea will be recorded | 3 months |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Noha Mahmoud ELkhodary, PhD | Clinical Pharmacy Department, Faculty of Pharmacy, Kafrelsheikh University | Study Director |
| Aya Emad Fouda, MSc in Clinical Pharmacy | Clinical Pharmacy Department, Faculty of Pharmacy, Kafrelsheikh University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Kafr El-Sheikh University | Cairo | Kafrelsheikh | 33511 | Egypt |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 26191473 | Result | Asakawa M, Mitsui H, Akihisa M, Sekine T, Niitsu Y, Kobayashi A, Miyake A, Hashimoto N, Kawamura M, Ogawa Y. Efficacy and safety of sitagliptin for the treatment of diabetes mellitus complicated by chronic liver injury. Springerplus. 2015 Jul 15;4:346. doi: 10.1186/s40064-015-1135-z. eCollection 2015. |
| Label | URL |
|---|---|
| Related Info | View source |
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| ID | Term |
|---|---|
| D008103 | Liver Cirrhosis |
| D003920 | Diabetes Mellitus |
| ID | Term |
|---|---|
| D008107 | Liver Diseases |
| D004066 | Digestive System Diseases |
| D005355 | Fibrosis |
| D010335 | Pathologic Processes |
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| ID | Term |
|---|---|
| D000068900 | Sitagliptin Phosphate |
| D000068736 | Duloxetine Hydrochloride |
| ID | Term |
|---|---|
| D014230 | Triazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
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Parallel-assignment interventional study to compare dose-adjusted sitagliptin and duloxetine across Child-Pugh classes with standard-dose diabetic controls."
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Parallel-assignment interventional study to compare dose-adjusted [Drug name] across Child-Pugh classes with standard-dose diabetic controls."
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|
| Sitagliptin (JANUVIA®) | Drug | Diabetic patients with Child-Pugh class C hepatic cirrhosis receiving 50 mg model -informed adjusted dose of sitagliptin. Sitagliptin is an oral dipeptidyl peptidase-4 (DPP-4) inhibitor used in conjunction with diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. The effect of this medication leads to glucose dependent increases in insulin and decreases in glucagon to improve control of blood sugar. |
|
| Sitagliptin (JANUVIA®) | Drug | Diabetic patients with Child-Pugh class B hepatic cirrhosis receiving 50 mg model -informed adjusted dose of sitagliptin. Sitagliptin is an oral dipeptidyl peptidase-4 (DPP-4) inhibitor used in conjunction with diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. The effect of this medication leads to glucose dependent increases in insulin and decreases in glucagon to improve control of blood sugar. |
|
| Sitagliptin (JANUVIA®) | Drug | Diabetic patients without hepatic cirrhosis receiving the standard recommended dose of 100 mg sitagliptin. Sitagliptin is an oral dipeptidyl peptidase-4 (DPP-4) inhibitor used in conjunction with diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. The effect of this medication leads to glucose dependent increases in insulin and decreases in glucagon to improve control of blood sugar. |
|
| Duloxetine (60 mg) once daily | Drug | Diabetic patients without hepatic cirrhosis receiving the standard recommended dose of 60 mg Duloxetine. Duloxetine is a dual serotonin and norepinephrine reuptake inhibitor, It has since received approval for a variety of indications including the treatment of neuropathic pain. |
|
| Duloxetine 30mg once daily | Drug | Diabetic patients with peripheral diabetic neuropathy and Child-Pugh class A hepatic cirrhosis receiving 30 mg model -informed adjusted dose of duloxetine. Duloxetine is a dual serotonin and norepinephrine reuptake inhibitor, It has since received approval for a variety of indications including the treatment of neuropathic pain. |
|
| D013568 |
| Pathological Conditions, Signs and Symptoms |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D004700 | Endocrine System Diseases |
| D011719 |
| Pyrazines |
| D013876 | Thiophenes |
| D013457 | Sulfur Compounds |
| D009930 | Organic Chemicals |