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. 2022 Jul 27;23(15):8295.
doi: 10.3390/ijms23158295.

Pharmacological Probes to Validate Biomarkers for Analgesic Drug Development

Johannes van Niel  1 , Petra Bloms-Funke  2 , Ombretta Caspani  3 , Jose Maria Cendros  4 , Luis Garcia-Larrea  5 , Andrea Truini  6 , Irene Tracey  7 , Sonya C Chapman  8 , Nicolás Marco-Ariño  9 , Iñaki F Troconiz  9 , Keith Phillips  10 , Nanna Brix Finnerup  11 , André Mouraux  12 , Rolf-Detlef Treede  3
Affiliations

Pharmacological Probes to Validate Biomarkers for Analgesic Drug Development

Johannes van Niel et al. Int J Mol Sci. .

Abstract

There is an urgent need for analgesics with improved efficacy, especially in neuropathic and other chronic pain conditions. Unfortunately, in recent decades, many candidate analgesics have failed in clinical phase II or III trials despite promising preclinical results. Translational assessment tools to verify engagement of pharmacological targets and actions on compartments of the nociceptive system are missing in both rodents and humans. Through the Innovative Medicines Initiative of the European Union and EFPIA, a consortium of researchers from academia and the pharmaceutical industry was established to identify and validate a set of functional biomarkers to assess drug-induced effects on nociceptive processing at peripheral, spinal and supraspinal levels using electrophysiological and functional neuroimaging techniques. Here, we report the results of a systematic literature search for pharmacological probes that allow for validation of these biomarkers. Of 26 candidate substances, only 7 met the inclusion criteria: evidence for nociceptive system modulation, tolerability, availability in oral form for human use and absence of active metabolites. Based on pharmacokinetic characteristics, three were selected for a set of crossover studies in rodents and healthy humans. All currently available probes act on more than one compartment of the nociceptive system. Once validated, biomarkers of nociceptive signal processing, combined with a pharmacometric modelling, will enable a more rational approach to selecting dose ranges and verifying target engagement. Combined with advances in classification of chronic pain conditions, these biomarkers are expected to accelerate analgesic drug development.

Keywords: PK/PD; analgesic; biomarkers; drug development; pain; proof of concept; proof of mechanism.

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Conflict of interest statement

O.C., L.G.L., I.T., N.M.A., I.F.T. and A.M. declare that they have no conflict of interest. P.B.F. was an employee of Grünenthal when she contributed to the conceptualisation and reports consultancy fees from Consultech. J.M.C. is an employee of Welab Barcelona but part of his work was done as an employee of ESTEVE Pharmaceuticals S.A. S.C.C. is an employee of Eli Lilly and Company. N.B.F. reports personal fees from Almirall, NeuroPN, Novartis Pharma, Merck and Mitshubishi Tanabe Pharma outside the submitted work. E.P.Z. reports fees from Mundipharma and Grünenthal outside the submitted work. K.P. is an employee of Eli Lilly and Company. J.V.N. was an employee of Grünenthal when he contributed to the Investigation and Methodology and reports personal fees from Medwis-extern GmbH & Co.KG outside the submitted work. AT received consulting fees or payment for lectures from Angelini, Grunenthal, Viatris and Eliem Therapeutics. R.D.T. reports personal fees from Bayer, Grünenthal, GSK and Sanofi outside the submitted work. In addition, he has a patent (DE 103 31 250.1–35) with royalties paid to MRC Systems. The statements and opinions presented here reflect the author’s view and neither IMI nor the European Union, EFPIA, or any Associated Partners are responsible for any use that may be made of the information contained therein.

Figures

Figure 1
Figure 1
The aim of the BioPain project of the IMI-PainCare consortium is to validate a set of pharmacodynamic biomarkers of nociceptive processing derived from non-invasive measures of nociceptive processing at the peripheral, spinal, brainstem and brain levels. Whereas some biomarkers are selective readouts for a given compartment of the nociceptive system (e.g., small-fibre perception threshold tracking as a readout of nociceptive processing at the level of the peripheral nervous system), other biomarkers are dependent on the state of nociceptive processing along the entire neuraxis (e.g., laser-evoked brain potentials that are sequentially processed and transmitted at peripheral, spinal cord and brain levels). These biomarkers will be tested across four parallel clinical studies (RCT1 [6,11], RCT2 [7,12], RCT3 [8,10] and RCT4 [9]) using three pharmacological probes (lacosamide, pregabalin and tapentadol) that are expected to predominantly affect nociceptive processing at peripheral, spinal and brain levels, respectively. Nonetheless, all three probes are active in multiple compartments. Hence, complex hierarchical modelling and estimation of latent variables will be used in addition to PK-PD modelling.
Figure 2
Figure 2
Flow diagram of Medline search.
Figure 3
Figure 3
Flow diagram of selection process.
Figure 4
Figure 4
Typical plasma pharmacokinetic profiles of four candidate pharmacological probes. Simulated plasma concentrations for a single dose, oral administration of 200 mg of lacosamide [20], 150 mg of pregabalin [21], 100 mg of tapentadol [22] and 300 mg of oxcarbazepine (including metabolites) [23] during a 24 h study period. Note the fast elimination of the oxcarbazepine parent compound (solid line) compared to the other pharmacological probes and the presence of two active metabolites, S-(+)-10-hydroxycarbazepine (dashed line) and R-(−)-10-hydroxycarbazepine (dotted line), making oxcarbazepine an unsuitable candidate for the planned experimental designs.
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