Pharmacokinetic-Pharmacodynamic Analysis’ Role in Design of Phase ⅠClinical Trials of Anticoagulant Agents: A Systematic Review

ABSTRACT

Introduction

There remains an unmet need for better anticoagulants. The phase I clinical trial is of great significance in the development of anticoagulants, and the design is special. This system review aims to provide insights for the design of future phase I clinical trials of anticoagulants.

Areas covered

We searched the database PubMed and ClinicalTrail.gov website, to collate the phase I clinical trial of anticoagulants in healthy people. The study protocol, inclusion-exclusion criteria, safety, and pharmacodynamic indexes were reviewed.

Expert opinion

New anticoagulants under development focused on inhibiting one or more than one serine proteases within the coagulation cascade. Agents targeting intrinsic factors are in the pipeline of the drug development. The enrollment eligibility criteria have more restrictions on laboratory tests, medical history, or medication history related to bleeding and coagulation; more precautions were taken to assess and minimize the risk of hemorrhagic events. Pharmacodynamics markers were evaluated as a surrogate marker of anticoagulation potency to guide further dose selection in drug’s development. In future, the positive control study can be applied in phase I studies of new anticoagulants with appropriate pharmacodynamics markers, which can provide more favorable information on making ‘go/no’ decision in drug development.

KEYWORDS:

• Anticoagulant
• factor Ⅱ
• factor Ⅷ
• factor Ⅸ
• factor Ⅹ
• factor Ⅺ
• factor Ⅻ
• pharmacokinetics
• pharmacodynamics
• safety

Article highlights

• New anticoagulants under development focused on inhibiting one or more than one serine proteases within the coagulation cascade. Various agents targeting intrinsic coagulation factors were hotspots.

• Special considerations of trial design should be taken in phase Ⅰ clinical trial of anticoagulants, such as criteria of inclusion/exclusion, safety monitoring, participant withdrawal, termination criteria, and pharmacodynamic test.

• The enrollment eligibility criteria have more restrictions on laboratory tests, medical history, or medication history related to bleeding and coagulation; more precautions were taken to assess and minimize the risk of hemorrhagic events.

• A panel of pharmacodynamic markers were evaluated in most studies. The relationship between pharmacodynamics markers and drug exposure can provide more information for drug development.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants, or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplementary material

Supplemental data for this article can be accessed here.

Additional information

Funding

This paper was funded by the National Science and Technology Major Projects for ‘Major New Drugs Innovation and Development’ under Grant No. 2017ZX09304028-006 and Beijing Municipal Science & Technology Project under Grant No. Z191100007619038.