Pharmacokinetics and Pharmacodynamics of AC137 (25,28,29 Tripro‐Amylin, Human) After Intravenous Bolus and Infusion Doses in Patients with Insulin‐Dependent Diabetes

Colburn, Wayne A.; Gottlieb, Alan; Koda, Joy E.; Kolterman, Orville G.

doi:10.1002/j.1552-4604.1996.tb04147.x

Cited by 52 publications

(53 citation statements)

References 10 publications

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“…The temporal and causal relationships between drug exposure and the extent of glucose reduction have not been well characterized. In 1996, Colburn et al (13) first applied pharmacokinetic/pharmacodynamic (PK/PD) modeling to describe pramlintide effects on postprandial glucose using a linked biophase with an empirical sigmoid E max model. However, parameter estimates of the biophase rate constant, k eo , and EC 50 increased with dose, no fitted curves were provided, and the underlying basis of the drug action was not made clear.…”

Section: Introductionmentioning

confidence: 99%

“…A mechanism-based PK/PD model can provide meaningful and physiologically relevant insights into the control of pramlintide on complex postprandial glucose regulation. In this study, we used the data originally published (13). This study develops a PK/PD model based on the mechanisms of action of pramlintide that characterize the exposure of pramlintide and its effects on plasma glucose during the postprandial period using a nonlinear mixed effects modeling approach.…”

Section: Introductionmentioning

confidence: 99%

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Study Reanalysis Using a Mechanism-Based Pharmacokinetic/Pharmacodynamic Model of Pramlintide in Subjects with Type 1 Diabetes

Fang

Landersdorfer

Cirincione³

et al. 2012

AAPS J

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Abstract. This report describes a pharmacokinetic/pharmacodynamic model for pramlintide, an amylinomimetic, in type 1 diabetes mellitus (T1DM). Plasma glucose and drug concentrations were obtained following bolus and 2-h intravenous infusions of pramlintide at three dose levels or placebo in 25 T1DM subjects during the postprandial period in a crossover study. The original clinical data were reanalyzed by mechanism-based population modeling. Pramlintide pharmacokinetics followed a twocompartment model with zero-order infusion and first-order elimination. Pramlintide lowered overall postprandial plasma glucose AUC (AUC net ) and delayed the time to peak plasma glucose after a meal (T max ). The delay in glucose T max and reduction of AUC net indicate that overall plasma glucose concentrations might be affected by differing mechanisms of action of pramlintide. The observed increase in glucose T max following pramlintide treatment was independent of dose within the studied dose range and was adequately described by a dose-independent, maximum pramlintide effect on gastric emptying of glucose in the model. The inhibition of endogenous glucose production by pramlintide was described using a sigmoidal function with capacity and sensitivity parameter estimates of 0.995 for I max and 23.8 pmol/L for IC 50 . The parameter estimates are in good agreement with literature values and the IC 50 is well within the range of postprandial plasma amylin concentrations in healthy humans, indicating physiological relevance of the pramlintide effect on glucagon secretion in the postprandial state. This model may prove to be useful in future clinical studies of other amylinomimetics or antidiabetic drugs with similar mechanisms of action.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Study Reanalysis Using a Mechanism-Based Pharmacokinetic/Pharmacodynamic Model of Pramlintide in Subjects with Type 1 Diabetes

Fang

Landersdorfer

Cirincione³

et al. 2012

AAPS J

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“…However, the evidence base for such treatments is limited (5), and only pramlintide, an analog of human amylin (6), is currently approved by the U.S. Food and Drug Administration for use with mealtime insulin in people with type 1 diabetes (7).…”

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confidence: 99%

Efficacy and Safety of Liraglutide Added to Capped Insulin Treatment in Subjects With Type 1 Diabetes: The ADJUNCT TWO Randomized Trial

et al. 2016

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OBJECTIVETo investigate the efficacy and safety of liraglutide added to capped insulin doses in subjects with type 1 diabetes. RESEARCH DESIGN AND METHODSA 26-week, placebo-controlled, double-blind, parallel-group trial enrolling 835 subjects randomized 3:1 receiving once-daily subcutaneous liraglutide (1.8, 1.2, and 0.6 mg) or placebo added to an individually capped total daily dose of insulin. (-5.1, -4.0, and -2.5 kg for 1.8, 1.2, and 0.6 mg, respectively) versus placebo (-0.2 kg). Significant reductions in daily insulin dose and increases in quality of life were seen with liraglutide versus placebo. There were higher rates of symptomatic hypoglycemia (21.3 vs. 16.6 events/patient/year; P = 0.03) with liraglutide 1.2 mg vs. placebo and of hyperglycemia with ketosis >1.5 mmol/L with liraglutide 1.8 mg vs. placebo (0.5 vs. 0.1 events/patient/year; P = 0.01). RESULTS Mean CONCLUSIONSIn a broad population of subjects with long-standing type 1 diabetes, liraglutide added to capped insulin reduced HbA 1c , body weight, and insulin requirements but with higher rates of hypoglycemia for liraglutide 1.2 mg and hyperglycemia with ketosis for liraglutide 1.8 mg.Most people with type 1 diabetes do not currently reach glycemic targets (1), as both patients and providers are often reluctant to intensify glycemic therapy because of reasons such as concern about hypoglycemia and/or weight gain (2). Moreover, a recent study using electronic health records from the U.S. reported that 47.8% of people with type 1 diabetes are obese (3). Therefore, noninsulin adjunctive treatments with a low intrinsic risk of hypoglycemia and weight gain offer a potential means of complementing intensive insulin therapy in people

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“…7 In 13 of 18 patients receiving a 2-minute intravenous infusion of AC137, maximal concentrations were achieved at the point immediately following the end of the infusion (7 minutes post-infusion start), not at the end of the infusion (2 minutes post-infusion start) as would be expected. The authors proposed this could be because of a delayed distribution between the dosing site and sampling site in the contralateral arm or an infusion that was longer than the planned 2 minutes.…”

Section: Examplementioning

confidence: 83%

Infusions Are the Optimal Dosing Method in Intravenous ADME Studies Rather Than Bolus Dosing

Barbour¹,

Fossler²

2017

The Journal of Clinical Pharma

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A vast majority of new drugs are developed for oral administration. However, intravenous studies are often conducted to elucidate fundamental absorption, distribution, metabolism, and excretion (ADME) properties, such as bioavailability. A common study design involves a traditional 2-way crossover with oral and intravenous dosing using doses that achieve therapeutic concentrations. More novel designs employing microdosing in a phase 0 two-way crossover or in a single arm dosing the therapeutic oral dose with a microtracer, that is, a radiolabeled intravenous microdose typically administered at the T max of the oral dose, are increasing in application. These microdose studies, defined as studies in which the dose is ࣘ100 μg, ࣘ1/100th the no adverse event limit, and ࣘ1/100th the pharmacologically active dose, 1 are growing in popularity as the value is realized because of the potential cost savings of an exploratory investigational new drug (IND) application and selection of a candidate with acceptable pharmacokinetics for further development, compared with a full IND (0.5-0.75 vs 1.5-2.5 M). 2 In addition, utilization of microdose studies may continue to grow as the potential applications expand and experience is gained with these applications, such as phase 0 exploration of a compound as a potential victim of drug-drug interactions or pharmacodynamic exploration. Finally, these study designs are used to fulfill the regulatory requirement from the Australian Healthy authorities to understand the absolute bioavailability. 3 To highlight one recent example, 4 Nav1.7 inhibitors were explored in a phase 0 microdose study whereby 100 μg of each compound was dosed both intravenously and orally. 4 Using the intravenous and in vitro ADME data, a physiologically based pharmacokinetic (PBPK) model was developed and validated using the oral data. This model was then used to predict pharmacokinetic (PK) profiles for each compound at various potential clinical doses and compare the Cmin relative to the Nav1.7 IC50, leading to the selection of the development candidate. Thorough reviews of various applications and methods of microdose and microtracer studies are provided elsewhere. 2,5 Study Design With Regard to Intravenous Dose Administration

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Pharmacokinetics and Pharmacodynamics of AC137 (25,28,29 Tripro‐Amylin, Human) After Intravenous Bolus and Infusion Doses in Patients with Insulin‐Dependent Diabetes

Cited by 52 publications

References 10 publications

Study Reanalysis Using a Mechanism-Based Pharmacokinetic/Pharmacodynamic Model of Pramlintide in Subjects with Type 1 Diabetes

Study Reanalysis Using a Mechanism-Based Pharmacokinetic/Pharmacodynamic Model of Pramlintide in Subjects with Type 1 Diabetes

Efficacy and Safety of Liraglutide Added to Capped Insulin Treatment in Subjects With Type 1 Diabetes: The ADJUNCT TWO Randomized Trial

Infusions Are the Optimal Dosing Method in Intravenous ADME Studies Rather Than Bolus Dosing

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