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Pharmacokinetics and the drug–target residence time concept

https://doi.org/10.1016/j.drudis.2013.02.010Get rights and content

Highlights

  • Combined effect of pharmaco- and binding kinetics on duration is investigated.

  • Dissociation will only affect duration of binding when slower than the elimination.

  • For several marketed drugs the opposite is true; elimination is slower.

  • These findings greatly reduce the use of drug–target residence times.

  • Important to avoid kinetic generalizations and simplifications.

The concept of drug–target residence time has been in focus in recent drug discovery literature. However, few studies consider the combined effect of pharmacokinetics (PK) and binding kinetics (BK) on the duration of effect of a drug. Using a simple model that takes both PK and BK into account, we found that prolongation of binding owing to a long drug–target residence time can only occur when the binding dissociation is slower than the PK elimination. Data for several drugs and/or drug candidates in the literature indicate that the opposite is observed, that is, they have a slower elimination compared with dissociation. These observations greatly reduce the usability of drug–target residence times for estimating the duration of effect of a drug in vivo.

Section snippets

Combining PK and BK

The simplest PK model for describing a change in concentration over time is the single-compartment model (Fig. 2). The compound reaches the compartment (the target vicinity) in a process described by a single rate constant (kin), which is a composite of all the various steps involved in reaching the target vicinity; the effective influx rate constant. Once the compound reaches the compartment, it can be removed via a process described by another rate constant (kout), which corresponds to all

Simulations

The first thing that we wanted to explore with this PK–BK model was the binding profile over time for compounds with identical affinities but different binding rate constants. This is crucially different from other publications 1, 7, where a low off-rate was accompanied by a low Kd. In those cases, it is difficult to say whether a binding profile is the result of different BK or different affinities. A more potent compound will remain bound longer simply because of a concentration–affinity

The dissociation–elimination relation

Unless under rebinding conditions, the simulations show that the dissociation rate of a compound determines whether it will end up in the goldilocks zone. Thus, the question is then how is the dissociation connected to the PK? The first clue comes from examining the PK–BK model in Fig. 4. If one focuses on the decay of the compound–target complexes, it becomes clear that either the rate of dissociation of the compound (koff) or the effective rate of elimination from the compartment will

Target biology and kinetics

So far, we have focused primarily on the nature of the compound, looking at PK and target BK and how these affect the duration of binding for a compound. However, the biology of the target is also important. Even though the connection between the target biology and the desired PD effect is crucial, it is dependent on selecting the right target, which is outside the scope of this article. The target fraction bound and the duration of binding that is required to trigger and sustain the PD effect

The merits of BK profiling

What BK properties do drugs have? Figure 6 shows the drugs in Table 1 based on their BK, which enables several interesting observations. Most drugs cluster in a confined area, with Kd < 10 nm. In terms of BK, there are no clear trends other than that the association rate constant is > 103 M−1 s−1 and the dissociation is <10−2 s−1 for most of them. This indicates that, to make a successful drug, one needs potency, whereas the BK appears to be less, or not at all, important. For the duration of effect,

Outlook

That the drug discovery industry has fallen on hard times with fewer compounds reaching the market and at increasing costs is old news. The increased focus on BK and the introduction of the drug–target residence time concept was seen by many as a new way to look at the drug discovery process, with the potential to reduce attrition rates and predict in vivo outcomes. In this article, we have shown that it is not that simple. The concentration profile of a drug, as dictated by its PK properties,

Acknowledgments

We would like to thank Rutger Folmer, Stefan Geschwindner (Discovery Sciences, AstraZeneca R&D Mölndal), Ann-Charlotte Egnell (CVGI iMED, AstraZeneca R&D Mölndal), Mark Furber, Ulf Eriksson (R&I iMED, AstraZeneca R&D Mölndal) for insightful comments and remarks in the process of writing this review.

Göran Dahl is currently a senior research scientist in the Department of Structure and Biophysics at AstraZeneca R&D Mölndal, Sweden, where he predominantly performs affinity and binding kinetic characterization of small molecules using SPR. Previous to this, he held a position as a distinguished scientist at Boehringer Ingelheim RCV GmbH & Co KG, with responsibility for biophysical characterization of the binding of small molecules. He received his PhD in Biochemistry from Uppsala University

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    Göran Dahl is currently a senior research scientist in the Department of Structure and Biophysics at AstraZeneca R&D Mölndal, Sweden, where he predominantly performs affinity and binding kinetic characterization of small molecules using SPR. Previous to this, he held a position as a distinguished scientist at Boehringer Ingelheim RCV GmbH & Co KG, with responsibility for biophysical characterization of the binding of small molecules. He received his PhD in Biochemistry from Uppsala University in 2009, where he studied the kinetics of viral enzymes using biochemical- and SPR-based technologies. He has extensive practical and theoretical experience in obtaining and using binding data in drug discovery projects.

    Tomas Åkerud currently holds a staff position in the Department of Structure and Biophysics at AstraZeneca R&D Mölndal, Sweden, where he works as a protein NMR spectroscopist and project coordinator during early-stage drug discovery projects. He received his PhD in Biophysical Chemistry from Lund University in 2004, where he studied protein dynamics using NMR spectroscopy. Much of his PhD research was conducted at the Structural Chemistry Laboratory at Pharmacia/Biovitrum. He has developed methodology for determining affinities by ligand-detected NMR spectroscopy and has an extensive experience in fragment-based lead generation.

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