Multi-factorial pharmacokinetic interactions: unraveling complexities in precision drug therapy

ABSTRACT

Introduction: Precision drug therapy requires accounting for pertinent factors in pharmacokinetic (PK) inter-individual variability (i.e., pharmacogenetics, diseases, polypharmacy, and natural product use) that can cause sub-therapeutic or adverse effects. Although each of these individual factors can alter victim drug PK, multi-factorial interactions can cause additive, synergistic, or opposing effects. Determining the magnitude and direction of these complex multi-factorial effects requires understanding the rate-limiting redundant and/or sequential PK processes for each drug.

Areas covered: Perturbations in drug-metabolizing enzymes and/or transporters are integral to single- and multi-factorial PK interactions. Examples of single factor PK interactions presented include gene-drug (pharmacogenetic), disease-drug, drug-drug, and natural product–drug interactions. Examples of multi-factorial PK interactions presented include drug-gene-drug, natural product-gene-drug, gene-gene-drug, disease-natural product-drug, and disease-gene-drug interactions. Clear interpretation of multi-factorial interactions can be complicated by study design, complexity in victim drug PK, and incomplete mechanistic understanding of victim drug PK.

Expert opinion: Incorporation of complex multi-factorial PK interactions into precision drug therapy requires advances in clinical decision tools, intentional PK study designs, drug-metabolizing enzyme and transporter fractional contribution determinations, systems and computational approaches (e.g., physiologically-based pharmacokinetic modeling), and PK phenotyping of progressive diseases.

KEYWORDS:

• complex interactions
• disease-drug interaction
• drug-drug interaction
• multi-factorial
• natural product-drug interaction
• pharmacogenetics
• pharmacokinetics
• precision medicine
• transporter-mediated drug interaction

Article highlights

• Genetics (i.e., pharmacogenetics), environment (i.e., diseases and polypharmacy), and lifestyle (i.e., diet and natural product use) are factors that contribute to inter-individual variability in pharmacotherapy.

• Combinations of these factors cause additive, synergistic, or opposing effects on drug PK.

• Functionally redundant and/or sequential PK processes dictate the direction and magnitude of these effects on drug disposition.

• Advances in clinical decision tools, drug-metabolizing enzyme and transporter fractional contribution determinations, PBPK modeling, and PK phenotyping of progressive diseases will facilitate precision drug therapy.

This box summarizes key points contained in the article.

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.

Additional information

Funding

JD Clarke was supported in part by National Center for Complementary and Integrative Health (NCCIH) grants U54 AT008909, R21 AT011101, R56 AT010650 and National Institute of Environmental Health Sciences grant R00 ES024455. BJ Bechtold was supported in part by NCCIH grant R21 AT011101.