Publications by authors named "Xiaosu Ma"

13 Publications

  • Page 1 of 1

Simulation-Based Evaluation of Dose Titration Algorithms for U-500R Insulin by Pump in Subjects with Type 2 Diabetes.

J Diabetes Sci Technol 2021 Jul 1:19322968211026626. Epub 2021 Jul 1.

Endocrine Clinic of Southeast TX PA, Beaumont, TX, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/19322968211026626DOI Listing
July 2021

Pharmacokinetics and Pharmacodynamics of Human Regular U-500 Insulin Administered via Continuous Subcutaneous Insulin Infusion Versus Subcutaneous Injection in Adults With Type 2 Diabetes and High-Dose Insulin Requirements.

J Diabetes Sci Technol 2020 Nov 26:1932296820972719. Epub 2020 Nov 26.

Eli Lilly and Company, Indianapolis, IN, USA.

Introduction: Human regular U-500 insulin (U-500R) is approved for subcutaneous (SC) injection in patients with diabetes requiring >200 units/day of insulin. Here, pharmacokinetic and pharmacodynamic (PK/PD) profiles following U-500R administered by continuous subcutaneous insulin infusion (CSII) and SC injection in adults with type 2 diabetes (T2D) on high-dose insulin were studied.

Methods: In this randomized, crossover, euglycemic clamp study, patients received a 100-unit bolus of U-500R via SC injection or CSII with basal infusion using a U-500R specific pump. PK parameters were estimated using non-compartmental methods. PD estimates were derived from the glucose infusion rate during the euglycemic clamp procedure.

Results: When corrected for the basal infusion, the PK profiles for the 100-unit bolus of U-500R were similar for CSII and SC injection. Without correction for basal infusion, PK and PD profiles showed a greater insulin concentration and effect when U-500R was administered via CSII compared to SC injection, primarily due to basal insulin infusion for CSII. The ratio of geometric least squares AUC means SC:CSII (90% CI) is 0.857 (0.729, 1.01) with correction (mean AUC: 5230 pmol*L/h [SC injection] and 6070 pmol*L/h [CSII, with correction]) and 0.424 (0.361, 0.499) without correction (mean AUC: 12300 pmol*L/h [CSII, without correction]). Median time-to-peak insulin concentration was six hours (range 0.5-8 hours) via SC injection and five hours (0.5-12 hours) via CSII.

Conclusions: In adults with T2D on high-dose insulin, U-500R PK/PD parameters were similar for a 100-unit bolus when given by SC injection or CSII via a U-500R pump.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1932296820972719DOI Listing
November 2020

Development and Verification of a Body Weight-Directed Disease Trial Model for Glucose Homeostasis.

J Clin Pharmacol 2021 02 7;61(2):234-243. Epub 2020 Sep 7.

Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, Florida, USA.

Weight loss has been associated with improvement in insulin sensitivity. It is consequently a cornerstone in the management of type 2 diabetes mellitus (T2DM). However, the strictly quantitative relationship between weight loss, insulin sensitivity, and clinically relevant glucose homeostasis biomarkers as well as changes therein as T2DM progresses is not yet fully understood. Therefore, the objective of our research was to establish a body weight-directed disease trial model for glucose homeostasis. To that end, we conducted a model-based meta-analysis using time course data of body weight loss (following lifestyle change or surgical procedure) and corresponding improvement of insulin sensitivity expressed as the Matsuda index. Changes in body weight were best described by a sigmoidal E model, whereas changes in the Matsuda index were best described by a linear model with a slope of 3.49. Once developed and verified, the model-based meta-analysis was linked to a disease-drug trial model for T2DM previously developed by our group to characterize and predict the impact of weight loss on clinically relevant glucose homeostasis biomarkers. The joint model was then used to conduct clinical trial simulations, which showed that weight loss can greatly improve clinically relevant glucose homeostasis biomarkers in T2DM patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jcph.1728DOI Listing
February 2021

Pharmacodynamics of Glyburide, Metformin, and Glyburide/Metformin Combination Therapy in the Treatment of Gestational Diabetes Mellitus.

Clin Pharmacol Ther 2020 06 25;107(6):1362-1372. Epub 2020 Jan 25.

Department of Obstetrics & Gynecology, University of Washington, Seattle, Washington, USA.

In gestational diabetes mellitus (GDM), women are unable to compensate for the increased insulin resistance during pregnancy. Data are limited regarding the pharmacodynamic effects of metformin and glyburide during pregnancy. This study characterized insulin sensitivity (SI), β-cell responsivity, and disposition index (DI) in women with GDM utilizing a mixed-meal tolerance test (MMTT) before and during treatment with glyburide monotherapy (GLY, n = 38), metformin monotherapy (MET, n = 34), or GLY and MET combination therapy (COMBO; n = 36). GLY significantly decreased dynamic β-cell responsivity (31%). MET and COMBO significantly increased SI (121% and 83%, respectively). Whereas GLY, MET, and COMBO improved DI, metformin (MET and COMBO) demonstrated a larger increase in DI (P = 0.05) and a larger decrease in MMTT peak glucose concentrations (P = 0.03) than subjects taking only GLY. Maximizing SI with MET followed by increasing β-cell responsivity with GLY or supplementing with insulin might be a more optimal strategy for GDM management than monotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpt.1749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7561209PMC
June 2020

Pharmacodynamics of Metformin in Pregnant Women With Gestational Diabetes Mellitus and Nonpregnant Women With Type 2 Diabetes Mellitus.

J Clin Pharmacol 2020 04 19;60(4):540-549. Epub 2019 Nov 19.

University of Washington, Departments of Pharmaceutics, Obstetrics & Gynecology, and Pharmacy, Seattle, Washington, USA.

Gestational diabetes mellitus is a condition similar to type 2 diabetes mellitus (T2DM) in that patients are unable to compensate for the degree of insulin resistance, and both conditions are often treated with metformin. The comparative pharmacodynamic response to metformin in these 2 populations has not been studied. This study characterized insulin sensitivity, β-cell responsivity, and disposition index following a mixed-meal tolerance test utilizing a minimal model of glucose, insulin, and C-peptide kinetics before and during treatment with metformin. The study included women with gestational diabetes mellitus (n = 34), T2DM (n = 14), and healthy pregnant women (n = 30). Before treatment, the gestational diabetes mellitus group had significantly higher baseline (45%), dynamic (68%), static (71%), and total β-cell responsivity (71%) than the T2DM group. Metformin significantly increased insulin sensitivity (51%) as well as disposition index (97%) and decreased mixed-meal tolerance test peak glucose concentrations (8%) in women with gestational diabetes mellitus after adjustment for gestational age-dependent effects; however, in women with T2DM metformin only significantly affected peak glucose concentrations (22%) and had no significant effect on any other parameters. Metformin had a greater effect on the change in disposition index (Δ disposition index) in women with gestational diabetes mellitus than in those with T2DM (P = .01). In conclusion, response to metformin in women with gestational diabetes mellitus is significantly different from that in women with T2DM, which is likely related to the differences in disease severity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jcph.1549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064374PMC
April 2020

Discovery of LY3104607: A Potent and Selective G Protein-Coupled Receptor 40 (GPR40) Agonist with Optimized Pharmacokinetic Properties to Support Once Daily Oral Treatment in Patients with Type 2 Diabetes Mellitus.

J Med Chem 2018 02 5;61(3):934-945. Epub 2018 Jan 5.

Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center , DC: 0540, Indianapolis, Indiana 46285, United States.

As a part of our program to identify potent GPR40 agonists capable of being dosed orally once daily in humans, we incorporated fused heterocycles into our recently disclosed spiropiperidine and tetrahydroquinoline acid derivatives 1, 2, and 3 with the intention of lowering clearance and improving the maximum absorbable dose (Dabs). Hypothesis-driven structural modifications focused on moving away from the zwitterion-like structure. and mitigating the N-dealkylation and O-dealkylation issues led to triazolopyridine acid derivatives with unique pharmacology and superior pharmacokinetic properties. Compound 4 (LY3104607) demonstrated functional potency and glucose-dependent insulin secretion (GDIS) in primary islets from rats. Potent, efficacious, and durable dose-dependent reductions in glucose levels were seen during glucose tolerance test (GTT) studies. Low clearance, volume of distribution, and high oral bioavailability were observed in all species. The combination of enhanced pharmacology and pharmacokinetic properties supported further development of this compound as a potential glucose-lowering drug candidate.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.7b01411DOI Listing
February 2018

Simulation-Based Evaluation of Dose-Titration Algorithms for Rapid-Acting Insulin in Subjects with Type 2 Diabetes Mellitus Inadequately Controlled on Basal Insulin and Oral Antihyperglycemic Medications.

Diabetes Technol Ther 2017 08 12;19(8):483-490. Epub 2017 Jul 12.

2 Merck & Co, Inc. , Kenilworth, Pennsylvania.

Background: The purpose of this prospective, model-based simulation approach was to evaluate the impact of various rapid-acting mealtime insulin dose-titration algorithms on glycemic control (hemoglobin A1c [HbA1c]).

Methods: Seven stepwise, glucose-driven insulin dose-titration algorithms were evaluated with a model-based simulation approach by using insulin lispro. Pre-meal blood glucose readings were used to adjust insulin lispro doses. Two control dosing algorithms were included for comparison: no insulin lispro (basal insulin+metformin only) or insulin lispro with fixed doses without titration.

Results: Of the seven dosing algorithms assessed, daily adjustment of insulin lispro dose, when glucose targets were met at pre-breakfast, pre-lunch, and pre-dinner, sequentially, demonstrated greater HbA1c reduction at 24 weeks, compared with the other dosing algorithms. Hypoglycemic rates were comparable among the dosing algorithms except for higher rates with the insulin lispro fixed-dose scenario (no titration), as expected. The inferior HbA1c response for the "basal plus metformin only" arm supports the additional glycemic benefit with prandial insulin lispro.

Conclusions: Our model-based simulations support a simplified dosing algorithm that does not include carbohydrate counting, but that includes glucose targets for daily dose adjustment to maintain glycemic control with a low risk of hypoglycemia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/dia.2016.0361DOI Listing
August 2017

The Discovery, Preclinical, and Early Clinical Development of Potent and Selective GPR40 Agonists for the Treatment of Type 2 Diabetes Mellitus (LY2881835, LY2922083, and LY2922470).

J Med Chem 2016 12 11;59(24):10891-10916. Epub 2016 Nov 11.

Lilly Research Laboratories, A division of Eli Lilly and Company , Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States.

The G protein-coupled receptor 40 (GPR40) also known as free fatty acid receptor 1 (FFAR1) is highly expressed in pancreatic, islet β-cells and responds to endogenous fatty acids, resulting in amplification of insulin secretion only in the presence of elevated glucose levels. Hypothesis driven structural modifications to endogenous FFAs, focused on breaking planarity and reducing lipophilicity, led to the identification of spiropiperidine and tetrahydroquinoline acid derivatives as GPR40 agonists with unique pharmacology, selectivity, and pharmacokinetic properties. Compounds 1 (LY2881835), 2 (LY2922083), and 3 (LY2922470) demonstrated potent, efficacious, and durable dose-dependent reductions in glucose levels along with significant increases in insulin and GLP-1 secretion during preclinical testing. A clinical study with 3 administered to subjects with T2DM provided proof of concept of 3 as a potential glucose-lowering therapy. This manuscript summarizes the scientific rationale, medicinal chemistry, preclinical, and early development data of this new class of GPR40 agonists.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.6b00892DOI Listing
December 2016

OPTIMIZED HUMAN REGULAR U-500 INSULIN TREATMENT IMPROVES β-CELL FUNCTION IN SEVERELY INSULIN-RESISTANT PATIENTS WITH LONG-STANDING TYPE 2 DIABETES AND HIGH INSULIN REQUIREMENTS.

Endocr Pract 2015 Dec 26;21(12):1344-52. Epub 2015 Aug 26.

Objective: To assess β-cell function and insulin sensitivity following improvement in glycemic control in severely insulin-resistant patients with poorly controlled type 2 diabetes (T2D).

Methods: A subset of patients in a 24-week, open-label, randomized trial comparing thrice-daily (n = 14/162) versus twice-daily (n = 11/163) human regular U-500 insulin (U-500R) underwent mixed meal tolerance testing at baseline and endpoint. Baseline characteristics were similar between treatment groups (combined means: age, 54.0 years; diabetes duration, 13.6 years; body mass index, 38.8 kg/m(2); glycated hemoglobin [HbA1c], 8.3%; U-100 insulin dose, 287.6 units/day, 2.6 units/kg/day). Primary outcome measure was ratio of area under the curve (AUC) for C-peptide to glucose (AUCC-peptide/AUCglucose) at 24-week endpoint.

Results: Change from baseline HbA1c, daily U-500R dose, and weight were -1.17% (P = .0002), +80.8 units (P = .0003), and +5.9 kg (P = .33), respectively. β-Cell function significantly improved after 24 weeks of U-500R therapy in combined treatment groups. The AUCC-peptide/AUCglucose increased 34.0% (ratio of least-squares geometric mean, 1.34; 95% confidence interval, 1.18 to 1.52; P = .0001). Integral of total insulin secretion rate increased from 27.0 to 33.7 nmol/m(2), and glucose sensitivity improved from 18.3 to 24.0 pmol/min/m(2)/mM (both, P = .02). Matsuda index improved from 0.8 to 1.3 (P = .008).

Conclusion: Despite long-standing diabetes and poor glycemic control at baseline, functional recovery of β-cells was observed with improved glycemic control in these severely insulin-resistant patients with T2D, possibly due to alleviation of glucotoxicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4158/EP15898.ORDOI Listing
December 2015

Application of PK/PD modeling and simulation to dosing regimen optimization of high-dose human regular U-500 insulin.

J Diabetes Sci Technol 2014 Jul 12;8(4):821-9. Epub 2014 May 12.

Lilly USA, Indianapolis, IN, USA.

Pharmacokinetic/pharmacodynamic (PK/PD) studies of human regular U-500 insulin (U-500R) at high doses commonly used in clinical practice (>100 units) have not been performed. The current analysis applied PK/PD modeling/simulation to fit the data and simulate single-dose and steady-state PK/PD of U-500R high-dose regimens. Data from 3 single-dose euglycemic clamp studies in healthy obese and normal-weight patients, and normal-weight patients with type 1 diabetes were used to build the model. The model was sequential (PK inputs fed into PD component). PK was described using a 1-compartment model with first-order absorption and elimination. The model estimated separate absorption rate constants for U-500R and human regular U-100 insulin. The PD component used an effect compartment model, parameterized in terms of maximum pharmacologic effect (E(max)) and concentration to achieve 50% of E(max). The model described the data well. Steady-state PK for once-daily (QD), twice-daily (BID), or thrice-daily (TID) administration appeared to be reached 24 hours after the first dose. At steady-state, QD dosing showed the greatest fluctuations in PK/PD. BID dosing showed a gradual increase in insulin action with each dose and a fairly stable basal insulin effect. For TID dosing, activity was maintained throughout the dosing interval. PK/PD modeling/simulation of high U-500R doses supports BID or TID administration with an extended duration of activity relative to QD. TID dosing may provide slightly better full-day insulin effect. Additional PK/PD studies and randomized controlled trials of U-500R are needed to validate model predictions in patients with insulin-resistant diabetes requiring high-dose insulin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1932296814532326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4764242PMC
July 2014

The effect of age on insulin sensitivity and insulin secretion in first-degree relatives of type 1 diabetic patients: a population analysis.

J Clin Endocrinol Metab 2009 Jul 28;94(7):2446-51. Epub 2009 Apr 28.

Department of Bioengineering, University of Washington, Seattle, Washington 98195, USA.

Context: Understanding the role of insulin resistance in type 1 diabetes may lead to new prevention strategies. Estimates of insulin resistance in first-degree relatives of those with type 1 diabetes may be obtained using the minimal model of glucose kinetics incorporating a population approach.

Objective: The objective of the study was to explore parameters contributing to glucose homeostasis in a cross-sectional study of first-degree relatives across a wide age range.

Design: Insulin sensitivity (SI) was assessed using the minimal model of glucose kinetics after an oral glucose tolerance test combined with nonlinear mixed-effects modeling. Beta-cell function was measured from the insulinogenic index at 30 min (IGI(30)). Disposition index (DI) was estimated as the product of SI and IGI(30).

Setting: The study was conducted at an academic center.

Subjects: Subjects included 1241 first-degree relatives (aged 2-75 yr).

Results: SI was found to be negatively correlated with age, whereas IGI(30) increased until young adulthood. The increase IGI(30) was apparently insufficient to compensate for the insulin resistance because DI decreased linearly at the rate of 0.035 (10(-2) min(-1) mmol(-1) liter per year) after young adulthood. Both IGI(30) and DI were significantly lower in those with vs. without autoantibodies, whereas there was no difference between these groups with respect to SI.

Conclusions: Beta-cell function, adjusted for age-related insulin resistance, decreases throughout life in first-degree relatives. This deterioration may be exacerbated in the presence of autoantibodies. Oral glucose tolerance test data combined with a nonlinear mixed-effect modeling population approach may be a useful technique to evaluate SI and secretion in a population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/jc.2008-2687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2708949PMC
July 2009

Experiment on parallel correlated recognition of 2030 human faces based on speckle modulation.

Opt Express 2004 Aug;12(17):4047-52

In this paper, the experiment on parallel correlated recognition of 2030 human faces in Fe:LiNbO(3) crystal is detailedly presented, a very clear correlation spots array was achieved and the recognition accuracy is better than 95%. According to the experiment, it is proved that speckle modulation on the object beam of volume holographic correlators can well suppress the crosstalk, so that the multiplexing spacing is markedly reduced and the channel density is increased 10 times compared with the traditional holographic correlators without speckle modulation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1364/opex.12.004047DOI Listing
August 2004

Exposure-schedule study of uniform diffraction efficiency for DSSM holographic storage.

Opt Express 2004 Mar;12(6):984-9

An exposure-schedule theory of uniform diffraction efficiency for a Dynamic-Static speckle multiplexing (DSSM) volume holographic storage system is proposed. The overlap-factor (? overlap) is introduced into the system to compensate for the erasure effect of the static speckle multiplexing scheme. The exposure-schedule which is an inverse recursion formula is determined. Experimental results are obtained in a LiNbO(3):Fe crystal and 400 holograms with uniform diffraction efficiency are achieved by the use of the new exposure-schedule.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1364/opex.12.000984DOI Listing
March 2004