Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Randomized Controlled Trial
. 2022 Mar;61(3):413-422.
doi: 10.1007/s40262-021-01084-0. Epub 2021 Nov 13.

Comparison of Pharmacokinetics and Pharmacodynamics of Inhaled Technosphere Insulin and Subcutaneous Insulin Lispro in the Treatment of Type 1 Diabetes Mellitus

Marshall Grant  1 , Tim Heise  2 , Robert Baughman  3
Affiliations
Randomized Controlled Trial

Comparison of Pharmacokinetics and Pharmacodynamics of Inhaled Technosphere Insulin and Subcutaneous Insulin Lispro in the Treatment of Type 1 Diabetes Mellitus

Marshall Grant et al. Clin Pharmacokinet. 2022 Mar.

Abstract

Background: This study was performed to satisfy a US Food and Drug Administration post-marketing requirement to compare the dose responses for Technosphere® Insulin (TI; MannKind Corporation, Westlake Village, CA, USA) and subcutaneous insulin lispro (LIS) across a wide range of doses.

Objectives: This single-center, open-label, randomized, cross-over study defined the pharmacokinetic/pharmacodynamic curves for inhaled TI vs subcutaneous LIS in persons with type 1 diabetes mellitus.

Methods: Each volunteer received six treatments while undergoing euglycemic clamps: three doses of TI (10, 30 and 120 U) and LIS (8, 30, and 90 U). Primary endpoint was area under the glucose infusion rate vs time curve from start of treatment administration to end of clamp. Key secondary endpoints included readouts of insulin exposure and timing of pharmacokinetic/pharmacodynamic profiles.

Results: Insulin exposure was more than dose proportional, increasing with dose1.08 for LIS and dose1.35 for TI. Time to reach 10% of the maximum glucose infusion rate was 7 to 15 min for TI vs 21 to 38 min for LIS. End of effect was dose dependent for both treatments, ranging from 2 to 6 h (TI) and 5 to 10 h (LIS). Glucose infusion rate exhibited saturation for both treatments. Technosphere Insulin produced a lesser total effect per unit insulin than LIS due to its faster absorption and correspondingly shorter duration of exposure. The difference was large enough to require significantly different doses to achieve the same total effect.

Conclusions: Technosphere Insulin has a considerably faster onset and shorter duration of action than LIS. Consequently, the overall effect of TI is smaller than that of LIS and unit-for-unit dose conversion is not appropriate.

Clinical trial registration: ClinicalTrials.gov, NCT02470637; 12 June, 2015.

PubMed Disclaimer

Conflict of interest statement

MG is a paid employee of MannKind Corporation and may hold stock and stock options with the company and is listed as an inventor on several MannKind Corporation patents. TH has received research funds from Adocia, Afon Technology, AstraZeneca, Biocon, Boehringer Ingelheim, Eli Lilly, Gan Lee Pharmaceuticals, Johnson&Johnson, Julphar, Mylan, Nestlé, Neuraly, Nordic Bioscience, Novo Nordisk, Sanofi, and Zealand Pharma and has received speaker honoraria and travel grants from Eli Lilly and Novo Nordisk; he is also a member of advisory panels for Novo Nordisk and Valbiotis. RB is on several MannKind Corporation patents.

Figures

Fig. 1
Fig. 1
Pharmacokinetic and pharmacodynamic comparison of Technosphere Insulin (TI) and insulin lispro (LIS). a TI mean concentration profiles, b LIS mean concentration profiles, c TI mean glucose infusion rate (GIR) profiles and d LIS mean GIR profiles
Fig. 2
Fig. 2
Dose dependence of key pharmacokinetic/pharmacodynamic summary parameters. a Insulin exposure (area under the concentration vs time curve from time 0 to the last measurable concentration [AUClast]), b insulin effect (glucose infusion rate area under the concentration vs time curve [GIR AUC]), c mean residence time (MRT), and d duration of effect (time to end of effect [taken to be the end of glucose infusion]) [tGIRend]. Solid curves are best fits calculated on log-transformed coordinates (lnY vs lnDose). LIS insulin lispro, TI Technosphere Insulin
Fig. 3
Fig. 3
Maximum effect (Emax) models for maximum glucose infusion rate (GIRmax). a GIRmax vs dose. Parameter estimates (standard error): Emax = 17.3 (0.9) mg/kg/min; median effective dose of insulin lispro (LIS) = 18.2 (3.0) U; median effective dose of Technosphere Insulin (TI) = 63.8 (8.8) U; γ = 1. b GIRmax vs maximum concentration (Cmax). Parameter estimates (standard error): Emax,LIS = 16.0 (0.9) mg/kg/min; Emax,TI = 11.5 (0.7) mg/kg/min; half-maximal effective concentration = 84.8 (10.1) µU/mL; γ = 1.37 (0.19). Solid curves represent best-fit curves. Dashed lines represent Emax
Fig. 4
Fig. 4
Pharmacodynamic effect as a function of insulin exposure. a Comparison of models based on treatment and area under the concentration vs time curve from time 0 to the last measurable concentration (AUClast) [solid curves] and AUClast and mean residence time (MRT) [dashed curves]—log-log plot, b comparison of models based on treatment and AUClast (solid curves) and AUClast and MRT (dashed curves)—linear coordinates, c scatter plot for model with treatment and AUClast, and d scatter plot for model with AUClast and MRT. AUC area under the concentration vs time curve, GIR glucose infusion rate, LIS insulin lispro, TI Technosphere Insulin
Fig. 5
Fig. 5
Comparison of pharmacokinetic (PK) and pharmacodynamic profiles at comparable insulin exposure. a Mean PK profiles (n = 5) with area under the concentration vs time curve from time 0 to the last measurable concentration (AUClast)  = 6537 (638) min∙µU/mL (Technosphere Insulin [TI]) and 6538 (65) min∙µU/mL (insulin lispro [LIS]), b mean PK profiles (n = 5) with AUClast = 61,489 (7327) min∙µU/mL (TI) and 61,371 (9082) min∙µU/mL (LIS), c mean glucose infusion rate (GIR) profiles corresponding to the mean PK profiles in (a), and d mean GIR profiles corresponding to the mean PK profiles in (b)
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Afrezza [package insert]. Westlake Village (CA): MannKind Corporation; 2018.
    1. MannKind Corporation. Afrezza® (insulin human) inhalation powder approved in Brazil. In: Investors: press releases. 3 Jun 2019. https://investors.mannkindcorp.com/news-releases/news-release-details/af.... Accessed 16 Jun 2021.
    1. Rüppel D, Dahmen R, Boss A, et al. A population dose-response model for inhaled Technosphere Insulin administered to healthy subjects. CPT Pharmacometrics Syst Pharmacol. 2017 doi: 10.1002/psp4.12189. - DOI - PMC - PubMed
    1. Becker RHA, Frick AD, Nosek L, Heinemann L, Rave K. Dose-response relationship of insulin glulisine in subjects with type 1 diabetes. Diabetes Care. 2007 doi: 10.2337/dc06-2114. - DOI - PubMed
    1. Howey D, Bowsher R, Brunelle R, Woodworth J. [Lys(B28), Pro(B29)]-human insulin: a rapidly absorbed analogue of human insulin. Diabetes. 1994;43:396–402. doi: 10.2337/diab.43.3.396. - DOI - PubMed

Publication types

Associated data

-