Effect of renal impairment on the pharmacokinetics of exenatide Linnebjerg, Helle; Kothare, Prajakti A.; Park, Soomin ...
BJCP. British journal of clinical pharmacology/British journal of clinical pharmacology,
September 2007, Letnik:
64, Številka:
3
Journal Article
Recenzirano
Odprti dostop
What is already known about this subject
• Nonclinical studies have shown that exenatide is primarily cleared by the renal system.
• It was not known to what degree the clinical pharmacokinetics and ...tolerability would be affected by increasing renal impairment (RI).
What this study adds
• Patients with mild to moderate RI adequately tolerate current therapeutic doses of exenatide.
• However, exenatide is not recommended in patients with severe RI or end‐stage renal disease.
Aims
To evaluate the pharmacokinetics (PK), safety and tolerability of a single exenatide dose in patients with renal impairment (RI).
Methods
Exenatide (5 or 10 µg) was injected subcutaneously in 31 subjects (one with Type 2 diabetes) stratified by renal function Cockcroft–Gault creatinine clearance (CrCL), number of subjects: normal (>80 ml min−1, n = 8), mild RI (51–80 ml min−1, n = 8), moderate RI (31–50 ml min−1, n = 7) or end‐stage renal disease (ESRD) requiring haemodialysis (n = 8). PK data were combined with four previous single‐dose studies in patients with Type 2 diabetes to explore the relationship of exenatide clearance (CLp/F) and CrCL.
Results
Mean half‐life for healthy, mild RI, moderate RI and ESRD groups were 1.5, 2.1, 3.2 and 6.0 h, respectively. After combining data from multiple studies, least squares geometric means for CLp/F in subjects with normal renal function, mild RI, moderate RI and ESRD were 8.14, 5.19, 7.11 and 1.3 l h−1, respectively. Exenatide was generally well tolerated in the mild and moderate RI groups, but not in subjects with ESRD due to nausea and vomiting. Simulations of exenatide plasma concentrations also suggest patients with ESRD should have a propensity for poor tolerability at the lowest available therapeutic dosage (5 µg q.d.).
Conclusions
Since tolerability and PK changes were considered clinically acceptable in patients with mild to moderate RI, it would be appropriate to administer exenatide to these patients without dosage adjustment. However, poor tolerability and significant changes in PK make the currently available therapeutic doses (5 and 10 µg) unsuitable in severe RI or ESRD.
A body of work is starting to emerge that seeks to build on the challenges and lessons of the current global coronavirus crisis for long term sustainability planning and development. This perspective ...article argues that central to such reflections should be an acknowledgment of the intense territorial impact of the crisis, especially in the places where most of the world's population is increasingly living: cities. We review existing frameworks for SDG implementation in the cities of Bengaluru (India), Medellin (Colombia), and Cape Town (South Africa) and use this as the backdrop for an analysis of local responses to the pandemic. We build on this analysis to reflect on three main avenues for SDG implementation going forward: multi-level governance, the science-policy interface and citizen and society engagement. We argue that strengthening these structures and collaborations will be central to more sustainable, long-term inclusive, and evidence-based decision-making processes and global policy implementation in cities in a post COVID-19 world.
Insulin lispro 200 U/mL (IL200) is a new strength formulation of insulin lispro (Humalog®, IL100), developed as an option for diabetic patients on higher daily mealtime insulin doses. This phase 1, ...open‐label, 2‐sequence, 4‐period crossover, randomized, 8‐hour euglycemic clamp study aimed to demonstrate the bioequivalence of IL200 and IL100 after subcutaneous administration of 20 U (U) to healthy subjects (n = 38). Pharmacokinetic (PK) and pharmacodynamic (PD) responses were similar in both formulations. All 90%CIs for the ratios of area under the concentration‐versus‐time curve from time zero to the time of the last measurable concentration (AUC0–tlast) and maximum observed drug concentration (Cmax), as well as the total glucose infused throughout the clamp (Gtot) and the maximum glucose infusion rate (Rmax), were contained within 0.80 and 1.25. Time of maximum observed drug concentration (tmax) was similar between formulations, with a median difference of 15 minutes and a 95%CI of the difference that included zero. Inter‐ and intrasubject variability estimates were similar for both formulations. Both formulations were well tolerated. IL200 was bioequivalent to IL100 after subcutaneous administration of 20‐U single doses, and PD responses were comparable between formulation strengths.
Effect of age on the pharmacokinetics of duloxetine in women Skinner, Michael H.; Kuan, Han‐Yi; Skerjanec, Andrej ...
BJCP. British journal of clinical pharmacology/British journal of clinical pharmacology,
January 2004, Letnik:
57, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Aims The effect of age on duloxetine pharmacokinetics was evaluated in healthy volunteers and in patients with urinary incontinence.
Methods Twenty‐four healthy subjects (12 women 65–77 years, and ...12 women 32–50 years) were given a single 40‐mg oral dose of duloxetine in Study 1. Plasma concentration‐time data were analysed by noncompartmental pharmacokinetic methods. Sparse plasma samples were obtained from patients with urinary incontinence treated in two phase II studies: 70 women (24–77 years) who received duloxetine 20 mg day−1, 30 mg day−1, or 40 mg day−1 in Study 2A and 128 women (28–64 years) who received duloxetine 20 mg day−1, 40 mg day−1, or 80 mg day−1 in Study 2B. Based upon the combined data, a model was developed to characterize population pharmacokinetics of duloxetine using the nonlinear mixed‐effects modelling program (NONMEM).
Results In Study 1, the elderly (≥ 65 years) exhibited a statistically significant slower elimination rate constant λz compared with younger subjects {elderly‐younger difference = −0.022 h−195% confidence interval (CI) − 0.036, − 0.008}. However, no statistically significant differences in either CL/F elderly‐younger difference = −17.4 l h−1 (95% CI − 41.1, 6.23) or V/F elderly‐younger difference = 115.9 l (95% CI − 168.6, 400.4) were observed. The population pharmacokinetic analysis of Studies 2A and 2B revealed that the CL/F of duloxetine decreased with increasing age. Despite statistical significance, the age effect only accounted for 3% of the interindividual variability in CL/F and unexplained sources of the variation in clearance were still substantial (> 50%). Adverse events were generally mild to moderate, and the incidence of adverse events was generally similar in elderly and non‐elderly participants in these studies.
Conclusions Whereas the results suggest that age has an effect on duloxetine pharmacokinetics, primarily reflected as a slower λz in the elderly, the magnitude of mean changes in CL/F, or V/F was small relative to the large interindividual variation in pharmacokinetics. Elderly participants had a safety profile of duloxetine comparable to their younger counterparts. Specific dose recommendations for duloxetine in the elderly are not warranted.
Aims
To compare the pharmacokinetics (PK), glucodynamics (GD) and tolerability following single and multiple daily subcutaneous doses of ultra rapid lispro (URLi) and Humalog® in patients with type 2 ...diabetes mellitus (T2D).
Materials and Methods
This was a two‐part, randomized, double‐blind Phase 1b study. Part A used a six‐period crossover design to assess PK and GD response to a solid mixed meal tolerance test (MMTT) following a single dose of URLi or Humalog administered 15 minutes before, immediately before, or 15 minutes after the start of the meal. Part B evaluated URLi or Humalog during 2 weeks of multiple daily dosing with a parallel design. The PK and GD were assessed following MMTTs at the beginning and end of the 2 weeks when insulins were administered immediately before the start of the meal.
Results
URLi increased the insulin exposure within the first 30 minutes postdose by 2.2‐fold and reduced the time to the early half‐maximal drug concentration by 22.6% compared with Humalog. Overall, URLi resulted in better postprandial glucose lowering when dosed before, immediately before, or after a meal. In comparing the same meal‐to‐dose timing between the insulins, the postprandial glucose excursion over 5 hours was significantly reduced by 29%‐105% for all three dose timings (−15, 0 and +15 minutes) with URLi. The PK and GD were sustained after daily subcutaneous dosing for 2 weeks in patients with T2D. URLi had more hypoglycaemic events during the MMTTs; few events occurred for both treatments during the 2 weeks of outpatient dosing.
Conclusions
URLi demonstrated accelerated insulin lispro absorption and greater postprandial glucose reduction at different meal‐to‐dose timings compared with Humalog and was well tolerated in patients with T2D.
Abstract
Aims
To compare the pharmacokinetics (PK), glucodynamics (GD) and tolerability following single and multiple daily subcutaneous doses of ultra rapid lispro (URLi) and Humalog® in patients ...with type 2 diabetes mellitus (T2D).
Materials and Methods
This was a two‐part, randomized, double‐blind Phase 1b study. Part A used a six‐period crossover design to assess PK and GD response to a solid mixed meal tolerance test (MMTT) following a single dose of URLi or Humalog administered 15 minutes before, immediately before, or 15 minutes after the start of the meal. Part B evaluated URLi or Humalog during 2 weeks of multiple daily dosing with a parallel design. The PK and GD were assessed following MMTTs at the beginning and end of the 2 weeks when insulins were administered immediately before the start of the meal.
Results
URLi increased the insulin exposure within the first 30 minutes postdose by 2.2‐fold and reduced the time to the early half‐maximal drug concentration by 22.6% compared with Humalog. Overall, URLi resulted in better postprandial glucose lowering when dosed before, immediately before, or after a meal. In comparing the same meal‐to‐dose timing between the insulins, the postprandial glucose excursion over 5 hours was significantly reduced by 29%‐105% for all three dose timings (−15, 0 and +15 minutes) with URLi. The PK and GD were sustained after daily subcutaneous dosing for 2 weeks in patients with T2D. URLi had more hypoglycaemic events during the MMTTs; few events occurred for both treatments during the 2 weeks of outpatient dosing.
Conclusions
URLi demonstrated accelerated insulin lispro absorption and greater postprandial glucose reduction at different meal‐to‐dose timings compared with Humalog and was well tolerated in patients with T2D.
Aim
To compare the pharmacokinetics (PK), glucodynamics (GD), and tolerability following single and multiple daily subcutaneous (SC) doses of ultra rapid lispro (URLi) and Humalog® in patients with ...type 1 diabetes mellitus (T1D).
Materials and Methods
This was a two‐part, randomized, double‐blind, Phase 1b study. Part A used a six‐period crossover design to assess PK and GD response to a solid mixed meal tolerance test (MMTT) following a single dose of URLi or Humalog administered 15 min before, immediately before, and 15 min after the start of the meal. Part B evaluated URLi or Humalog during 2 weeks of multiple daily dosing with a parallel design. The PK and GD were assessed following MMTTs at the beginning and end of the 2‐week period when insulins were administered immediately before the start of the meal.
Results
URLi increased the insulin exposure within the first 30 min postdose by 2.2‐fold and reduced the time to early half‐maximal drug concentration by 37% compared with Humalog. Overall, URLi resulted in better postprandial glucose lowering when dosed before, immediately before, or after a meal compared with Humalog. Comparing the same meal‐to‐dose timing between the insulins, postprandial glucose excursion over 5 hours was reduced by 40%‐44% for all three dose timings (−15, 0, and +15 min) with URLi, achieving statistical significance for the 0‐ and +15‐min timings. The PK and GD profiles were sustained after daily SC dosing for 2 weeks in patients with T1D. The number of documented hypoglycaemic events was similar between URLi and Humalog during the postprandial period of the MMTTs and the outpatient period.
Conclusions
URLi showed accelerated insulin lispro absorption and greater postprandial glucose reduction at different meal‐to‐dose timings compared with Humalog and was well tolerated in patients with T1D.
URLi (LY900014), a novel ultra-rapid mealtime insulin in Phase 3 development, is shown to reduce postprandial glucose after subcutaneous injection. This study evaluated the pharmacokinetics and ...pharmacodynamics (PD) of URLi via CSII. In a double-blind, randomized cross-over study, 24 adult patients with T1D received URLi or insulin lispro (Humalog®; HL) for 3 days. Mixed meal tolerance tests (MMTT) were conducted on Days 1 and 3 after catheter insertion using a standard (1.5 U/min) single-wave bolus. URLi showed faster insulin lispro absorption on both days compared to HL. URLi reduced time to early half-maximal drug concentration by 37% (-8.5 min) and 32% (-5.3 min) compared to HL on Days 1 and 3 (both p<0.0001). Area under the insulin lispro concentration time curve (AUC) for the first 15 min was >50% higher than HL after dosing with URLi on Days 1 and 3 (p<0.005). URLi reduced 1-hour postprandial glucose excursion of the MMTT by 45% on Day 1 (p=NS) and 47% on Day 3 (p=0.059) compared with HL (Figure). Accelerated URLi absorption was associated with trends toward lower postprandial glucose excursion for the entire MMTT (57% and 20% reductions in ∆AUC0-5h on Days 1 and 3; both NS). The study was not powered for PD assessment which may contribute to the lack of statistical significance. No differences were seen in the number or severity of hypoglycemic events or local tolerability between URLi and HL.
Disclosure
C.M. Kazda: Employee; Self; Eli Lilly and Company. J. Leohr: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. Employee; Spouse/Partner; Accenture. Stock/Shareholder; Spouse/Partner; Accenture. R. Liu: Employee; Self; Eli Lilly and Company. Employee; Spouse/Partner; Eli Lilly and Company. T. Hardy: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. S. Reddy: None. S.P.C. Chua: Employee; Self; Eli Lilly and Company. X. Guo: None. U. Hovelmann: None. C. Kapitza: Research Support; Self; ADOCIA, Boehringer Ingelheim GmbH, Dance Biopharm, Eli Lilly and Company, Johnson & Johnson Services, Inc., MedImmune, MSD K.K., Mylan, Nordic Bioscience, Novo Nordisk Inc., Poxel SA, Roche Diagnostics Corporation, Saniona, Sanofi-Aventis, Senseonics, Zealand Pharma A/S.
URLi is a novel prandial insulin lispro formulation developed to more closely match physiological insulin secretion. This randomized, double-blind, 2 period, crossover, 10 hour euglycemic clamp study ...assessed the pharmacokinetics, glucodynamics and tolerability of insulin lispro after a single 15U SC dose of URLi and lispro (Humalog®) in 38 patients with T2D (mean ±SD age, 60.0 ± 7.9 years; duration of diabetes, 17.4 ± 7.65 years; HbA1c, 7.4 ± 0.80%; BMI, 30.0 ± 2.97 kg/m2).
After dosing URLi, onset of insulin lispro appearance in serum was faster (1.97 vs. 7.28 min; p<0.0001). The time to early half maximal drug concentration was reduced by 10.9 min (p<0.0001) with URLi (18.6 min) vs. lispro (29.6 min). This resulted in greater early insulin lispro exposure: 6.4 fold in the first 15 min and 2.9-fold in the first 30 min after injection vs. lispro (both p<0.0001). Total exposure or time to maximum observed drug concentration did not differ between URLi and lispro.
The onset of insulin action was also faster (31.99 vs. 44.69 min; p<0.0001) and early insulin action (as measured by glucose infusion rate) was increased by 4.3 fold (p<0.0001) in the first 30 min of the clamp for URLi vs. lispro. Late insulin action (glucose infused from 4 hours to the end of the clamp) was reduced by 19% (p=0.0108) with URLi vs. lispro. The overall total glucose infused was 12% higher (p=0.0488) for URLi vs. lispro.
No differences were seen in tolerability between URLi and lispro.
In patients with T2D, URLi showed an accelerated insulin lispro absorption with a reduced late exposure and overall shorter duration vs. lispro resulting in faster onset of action and reduced late insulin action. This was the first study to investigate URLi in patients with T2D using a euglycemic clamp and results confirmed the faster PK and GD profile of URLi in this population.
Disclosure
J. Leohr: Employee; Spouse/Partner; Accenture. Employee; Self; Eli Lilly and Company. Stock/Shareholder; Spouse/Partner; Accenture. Stock/Shareholder; Self; Eli Lilly and Company. M.A. Dellva: Employee; Self; Eli Lilly and Company. D.E. Coutant: Employee; Self; Eli Lilly and Company. Employee; Spouse/Partner; Eli Lilly and Company. E.S. LaBell: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company, Johnson & Johnson, Novartis AG. S. Reddy: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. T. Heise: Advisory Panel; Self; Mylan. Research Support; Self; ADOCIA, Boehringer Ingelheim International GmbH, Dance Biopharm Holdings Inc., Eli Lilly and Company, Gan & Lee Pharmaceuticals, Johnson & Johnson, MedImmune, Mylan, Nordic Bioscience, Novo Nordisk A/S, Pfizer Inc., Poxel, Saniona, Sanofi, Wockhardt, Zealand Pharma A/S. Speaker's Bureau; Self; Eli Lilly and Company, Novo Nordisk A/S. G. Andersen: None. E. Zijlstra: Speaker's Bureau; Self; Novo Nordisk A/S. L. Hermanski: None. L. Nosek: None. H. Linnebjerg: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company.
Funding
Eli Lilly and Company
URLi is a novel prandial insulin lispro formulation developed to more closely match physiological insulin secretion. This randomized, double-blind, 4-period, crossover study, compared the PK and ...glucodynamics (GD) of URLi, Humalog® (HL), NovoRapid® (NR) and Fiasp® (FA) after a test meal in 68 adults with T1D, after single individualized SC dose. Twelve healthy subjects provided the “normal” insulin secretory and glucose response to the test meal.
URLi had the fastest insulin absorption: early half maximal drug concentration was reached at 13 min (URLi), 19 min (FA), 25 min (HL), and 27 min (NR) (p<0.05, URLi vs. other insulins). Early insulin exposure increased more with URLi: 1.5-fold vs. FA, 5-fold vs. HL, and 5-fold vs. NR in the first 15 min after dose (all p<0.002). Late insulin exposure (2h to 7h) was reduced more with URLi: 37% vs. FA, 30% vs. HL, and 45% vs. NR (all p<0.001).
URLi significantly reduced PPG excursions up to 4h vs. HL and NR (Figure) and URLi’s PPG profile more closely matched that of healthy subjects in the first 2 hours post-meal (Figure). Hypoglycemic events were similar between insulins during the test meal.
URLi demonstrated the fastest insulin absorption and the lowest PPG compared to all insulins tested and more closely matched the normal physiological profile of nondiabetic subjects.
Disclosure
T. Heise: Advisory Panel; Self; Mylan. Research Support; Self; ADOCIA, Boehringer Ingelheim International GmbH, Dance Biopharm Holdings Inc., Eli Lilly and Company, Gan & Lee Pharmaceuticals, Johnson & Johnson, MedImmune, Mylan, Nordic Bioscience, Novo Nordisk A/S, Pfizer Inc., Poxel, Saniona, Sanofi, Wockhardt, Zealand Pharma A/S. Speaker's Bureau; Self; Eli Lilly and Company, Novo Nordisk A/S. H. Linnebjerg: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. D. Cao: Employee; Self; Eli Lilly and Company. D.E. Coutant: Employee; Self; Eli Lilly and Company. Employee; Spouse/Partner; Eli Lilly and Company. E.S. LaBell: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company, Johnson & Johnson, Novartis AG. S. Reddy: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. E. Zijlstra: Speaker's Bureau; Self; Novo Nordisk A/S. C. Kapitza: Research Support; Self; ADOCIA, Biocon, Boehringer Ingelheim Pharmaceuticals, Inc., Dance Biopharm Holdings Inc., Eli Lilly and Company, Gan & Lee Pharmaceuticals, MedImmune, Mylan, Nestlé, Nordic Bioscience, Novo Nordisk A/S, Poxel SA, Sanofi-Aventis, Wockhardt, Xeris Pharmaceuticals, Inc., Zealand Pharma A/S. J.M. Bue-Valleskey: Employee; Self; Eli Lilly and Company. Q. Zhang: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. J. Leohr: Employee; Spouse/Partner; Accenture. Employee; Self; Eli Lilly and Company. Stock/Shareholder; Spouse/Partner; Accenture. Stock/Shareholder; Self; Eli Lilly and Company.
Funding
Eli Lilly and Company
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