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Review
. 2017 Jan;19(1):3-12.
doi: 10.1111/dom.12782. Epub 2016 Sep 26.

Impact of the mode of protraction of basal insulin therapies on their pharmacokinetic and pharmacodynamic properties and resulting clinical outcomes

Tim Heise  1 , Chantal Mathieu  2
Affiliations
Review

Impact of the mode of protraction of basal insulin therapies on their pharmacokinetic and pharmacodynamic properties and resulting clinical outcomes

Tim Heise et al. Diabetes Obes Metab. 2017 Jan.

Abstract

Manufacturers of insulin products for diabetes therapy have long sought ways to modify the absorption rate of exogenously administered insulins in an effort to better reproduce the naturally occurring pharmacokinetics of endogenous insulin secretion. Several mechanisms of protraction have been used in pursuit of a basal insulin, for which a low injection frequency would provide tolerable and reproducible glucose control; these mechanisms have met with varying degrees of success. Before the advent of recombinant DNA technology, development focused on modifications to the formulation that increased insulin self-association, such as supplementation with zinc or the development of preformed precipitates using protamine. Indeed, NPH insulin remains widely used today despite a frequent need for a twice-daily dosing and a relatively high incidence of hypoglycaemia. The early insulin analogues used post-injection precipitation (insulin glargine U100) or dimerization and albumin binding (insulin detemir) as methods of increasing therapeutic duration. These products approached a 24-hour glucose-lowering effect with decreased variability in insulin action. Newer basal insulin analogues have used up-concentration in addition to precipitation (insulin glargine U300), and multihexamer formation in addition to albumin binding (insulin degludec), to further increase duration of action and/or decrease the day-to-day variability of the glucose-lowering profile. Clinically, the major advantage of these recent analogues has been a reduction in hypoglycaemia with similar glycated haemoglobin control when compared with earlier products. Future therapies may bring clinical benefits through hepato-preferential insulin receptor binding or very long durations of action, perhaps enabling once-weekly administration and the potential for further clinical benefits.

Keywords: basal insulin; hypoglycaemia; pharmacodynamics; pharmacokinetics.

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Figures

Figure 1
Figure 1
Summary of the different mechanisms of protraction. NPH insulin is injected as a pre‐formed protein–insulin conglomerate. On injection, the solvent from NPH insulin suspensions diffuses freely into the subcutaneous tissue but the crystals are retained in “heaps” at the injection depot. IGlar U100 is soluble in acidic formulation but, on subcutaneous injection and reaching physiological pH, it forms crystals. IGlar U300 also precipitates at physiological pH but these precipitates are much more compact compared with those of IGlar U100, so the surface area from which absorption can occur is reduced, thereby further slowing absorption. Acylation of IDet with a fatty acid side chain facilitates self‐association of IDet at the injection depot as dihexamers and reversible binding to albumin, both in the depot and in circulation, thereby slowing its absorption. IDeg also has a fatty acid side chain, which facilitates dihexamer formation in the vial and albumin binding in the circulation. However, protraction of absorption is primarily achieved via multihexamer chain formation in the depot. Subsequent dissociation of zinc causes the terminal hexamers to break down. The large hydrodynamic size of PEGlispro prolongs its action by slowing absorption and reducing clearance, effectively producing a circulating depot. The PEGlispro clinical trial programme was terminated in 2015.
Figure 2
Figure 2
Molecular structure of insulin analogues. Molecular modifications made to the human insulin molecule in order to protract action are shown. The isoelectric point of IGlar U100 was raised by substituting glycine 21 on the A chain (A21) of human insulin for asparagine, and adding 2 asparagine molecules to the amino terminal of the B chain. IDet is an analogue in which threonine B30 has been removed and lysine B29 is acylated with a 14‐carbon myristoyl fatty acid. Threonine B30 is also removed in IDeg but lysine B29 is attached to a 16‐carbon fatty diacid via a glutamic acid spacer. In PEGlispro, the order of proline and lysine is reversed such that proline 29 follows lysine 28, which is attached to a polyethylene glycol chain via a urethane bond.
Figure 3
Figure 3
IDeg dihexamer formation.51, 52, 53 Insulin hexamers are arranged such that they have 2 poles, each formed by 3 of the constituent monomers, and these poles can be “open” (to expose the zinc‐containing core of the hexamer) or “closed” (shielding the core). In the presence of phenol or phenolic derivatives, which bind to hydrophobic pockets of the hexamers, the poles are closed.51, 52, 53 Two IDeg hexamers link together to form stable dihexamers, by the interaction of a single fatty diacid chain from one hexamer with a zinc atom of a neighbouring hexamer. On subcutaneous injection, these dihexamers link up to form multihexamer chains in the same manner because depletion of phenol after injection causes the closed poles to open, thereby exposing the second zinc ion. Ultimately, diffusion of zinc causes the terminal hexamers of these chains to break down into dimers, which then dissociate into monomers. Figure adapted from Jonassen et al.2 Republished with permission from Springer New York LLC; permission conveyed through Copyright Clearance Center, Inc.
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