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A Population Dose-Response Model for Inhaled Technosphere Insulin Administered to Healthy Subjects.

ABSTRACT: Technosphere insulin (TI), an inhaled insulin with a fast onset of action, provides a novel option for the control of prandial glucose. A euglycemic glucose clamp study was performed to compare the effects of TI and regular human insulin (RHI) on the induced glucose infusion rate (GIR) in healthy volunteers. Generation of a dose-response relationship between insulin dose and effect (expressed as AUC of GIR) was not possible from the clinical data directly. The GIR recording time was too short to capture the full effect and higher doses were not tested. Thus, a pharmacokinetic-GIR model was developed to simulate GIR for a sufficient time window of 20 h and for higher doses. A dose-response model was then generated from the simulated GIR profiles. The resulting model provides an ED50 for TI that is 5-fold higher than for RHI, a ratio that can be used as conversion factor for equivalent doses of RHI and TI.

SUBMITTER: Ruppel D

PROVIDER: S-EPMC5488128 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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A Population Dose-Response Model for Inhaled Technosphere Insulin Administered to Healthy Subjects.

Rüppel D D Dahmen R R Boss A A Jäger R R Grant M M Baughman R R Klabunde T T

CPT: pharmacometrics & systems pharmacology 20170601 6

Technosphere insulin (TI), an inhaled insulin with a fast onset of action, provides a novel option for the control of prandial glucose. A euglycemic glucose clamp study was performed to compare the effects of TI and regular human insulin (RHI) on the induced glucose infusion rate (GIR) in healthy volunteers. Generation of a dose-response relationship between insulin dose and effect (expressed as AUC of GIR) was not possible from the clinical data directly. The GIR recording time was too short to ...[more]

PMID: 28568813

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Pharmacokinetics of indacaterol, glycopyrronium and mometasone furoate administered as an inhaled fixed-dose combination in Japanese and Caucasian healthy subjects.

Project description:BackgroundA once-daily (o.d.) fixed-dose combination of indacaterol acetate (IND), glycopyrronium bromide (GLY), and mometasone furoate (MF) delivered via the Breezhaler® device (IND/GLY/MF) is being developed for treatment of asthma. This study compared steady-state pharmacokinetics of IND, GLY and MF between Japanese and Caucasian male subjects after multiple inhalations of IND/GLY/MF o.d.MethodsThis was a single-center, open-label, 2-treatment crossover study with a 21-day washout period. Japanese and Caucasian subjects received IND/GLY/MF 150/50/80 μg (inhaled corticosteroid [ICS] medium-dose) or 150/50/160 μg o.d. (ICS high-dose) for 14 days in each period. Pharmacokinetics were characterized up to 24 h post-dose on Days 1 and 14.ResultsIn total, 16 Japanese (median age 31 years [range 20-40 years], mean weight 68.3 kg) and 17 Caucasian subjects (median age 27 years [range 21-43 years], mean weight 75.0 kg) were randomized. Geometric mean ratios (Japanese/Caucasian) [90% confidence interval (CI)] for Cmax for IND, GLY and MF at the high ICS dose on Day 14 were 1.31 [1.13, 1.51] 1.38 [1.13, 1.69] and 1.07 [0.969, 1.18], respectively. Geometric mean ratios (Japanese/Caucasian) [90% CI] for AUC0-24h on Day 14 for IND, GLY and MF at the high ICS dose were 1.17 [1.01, 1.35], 1.05 [0.920, 1.20] and 1.15 [1.05, 1.27] respectively. Similar trends were noted for all components for the medium ICS dose treatment. IND/GLY/MF was safe and well tolerated; no AEs suspected to be study drug-related were observed.ConclusionPharmacokinetics of IND, GLY and MF (high and medium dose) when delivered as a fixed-dose combination were comparable between Japanese and Caucasian subjects. The IND/GLY/MF combination at the administrated doses was safe and well tolerated in both ethnic groups.Trial registrationJapan Registry of Clinical Trial: jRCT2031200227, retrospectively registered on 04, December, 2020.

| S-EPMC7791651 | biostudies-literature

Efficacy and safety of Technosphere inhaled insulin compared with Technosphere powder placebo in insulin-naive type 2 diabetes suboptimally controlled with oral agents.

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Impact of symptomatic upper respiratory tract infections on insulin absorption and action of Technosphere inhaled insulin.

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| S-EPMC5013402 | biostudies-literature

Clinical results of an automated artificial pancreas using technosphere inhaled insulin to mimic first-phase insulin secretion.

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Hypoglycaemia is reduced with use of inhaled Technosphere® Insulin relative to insulin aspart in type 1 diabetes mellitus.

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| S-EPMC3952721 | biostudies-literature

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

Project description:BackgroundThis 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.ObjectivesThis 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.MethodsEach 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.ResultsInsulin 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.ConclusionsTechnosphere 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 registrationClinicalTrials.gov, NCT02470637; 12 June, 2015.

| S-EPMC8891188 | biostudies-literature

Safety and Pharmacokinetics of the Aminomethylcycline Antibiotic Omadacycline Administered to Healthy Subjects in Oral Multiple-Dose Regimens.

Project description:Omadacycline, a first-in-class aminomethylcycline antibiotic, is related to tetracyclines but is structurally modified to circumvent mechanisms of resistance to tetracyclines. Omadacycline demonstrates potent activity against a broad range of pathogens, including drug-resistant strains, and is in late-stage development for treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. Previous studies support an intravenous-to-oral transition regimen with 300-mg once-daily oral dosing. This phase 1 study investigated the pharmacokinetics and safety/tolerability of multiple oral omadacycline doses higher than 300 mg. Using a 3-period crossover design, healthy adults were randomized to receive oral omadacycline at 300, 450, and 600 mg in variable sequence (n = 26) or placebo (n = 7) once daily for 5 consecutive days per period. In plasma, omadacycline maximum concentration and total exposure increased with increasing dose but were less than dose proportional. The kinetics of omadacycline plasma accumulation were similar between dose levels; exposure on day 5 was ?50% higher than that on day 1. Omadacycline plasma concentrations on day 1 of 450-mg dosing were similar to those on day 5 of 300-mg dosing. All doses were generally well tolerated, but the 600-mg dose was associated with more gastrointestinal adverse events.

| S-EPMC5786815 | biostudies-literature

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| S-EPMC4564450 | biostudies-literature

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