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3 :: ADVANCEMENTS IN PK

Pharmacokinetics

TIMELINE: 

RECENT ADVANCEMENTS

in Pharmacokinetics

clearance.png

Low Clearance Methods:

Clearance

  • A pharmacokinetic parameter representing the efficiency of drug elimination.

  • This is the rate of elimination of a substance divided by its concentration. The parameter also indicates the theoretical volume of plasma from which a substance would be completely removed per unit time.

​

(Ma et al., 2020)​

​Through development, there is an improvement in the detection of intrinsic clearance for low-clearance compounds. 

  • HEPATOCYTE RELAY METHOD: 

    • ​ Helps in this regard by extending incubation time → Better detection of intrinsic clearance for these types of compounds.

  • MICROPATTERNED & COCULTURE SYSTEMS: 

    • Maintain hepatocyte function for up to 7 days, enabling better low clearance and metabolite profiling prediction.

    • However, non-parenchymal cell metabolism can complicate data interpretation.

Source: ScienceDirect

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Transporter-Mediated Drug Disposition and Interactions: 

The FDA now recommends evaluating the DDI (Drug-Drug Interaction) potential for 9 key transporters.

Through development, there is an Increased recognition of transporters' role in drug efficacy, safety, and metabolism. 

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Advances include: ​​

  • CRISPR-Cas9 knockout models: 

    • ​Gene-editing technology.

    • "Knockout models" are created by using CRISPR-Cas9 to disable specific genes, often those that code for drug transporters or metabolising enzymes to allow researchers to understand the role of these genes in drug behaviour.

  • Quantitative proteomics: CRISPR-Cas9 knockout models: 

    • Measuring the amounts of different proteins in a cell or tissue. It can show how much of a particular drug transporter or metabolising enzyme is present and how this changes under different conditions. ​

  • IVIVE (in vitro-in vivo extrapolation): 

    • This is a way to predict how a drug will behave in the body (in vivo) based on experiments done in the lab (in vitro).

      • REF method: Used to extrapolate in vitro to in vivo transporter-mediated clearance.

Source: MDPI

Intestinal Elimination (IE): 

  • ​Intestinal elimination is the active removal of drugs (or their metabolites) from the systemic circulation directly into the intestinal lumen, where they are ultimately excreted in faeces.​

​

  • IE is emerging as a significant non-hepatic clearance mechanism.

    • Hepatic clearance is the loss of drug during its passage through the liver. Hepatic clearance results from hepatic metabolism and biliary excretion and is a function of the hepatic blood flow, the drug plasma protein binding and the activity of liver enzymes and transporters.

      • Good for drugs that are not well metabolised by the liver, subject to efflux transport & involved in enterohepatic recycling.

      • Can help explain why some drugs have unexpectedly low systemic concentrations.

Bio-Analytical Strategies for New modalities:

particularly Antibody-Drug Conjugates (ADCs)

  • Antibody–drug conjugates (ADCs) are a class of biopharmaceutical drugs designed as a targeted therapy for treating cancer.

    • Unlike chemotherapy, ADCs are intended to target and kill tumor cells while sparing healthy cells.

​

  • Key Components of an ADC: 

    • Cytotoxic Drug (Payload): 

      • ​A powerful chemotherapy agent that damages or kills cancer cells.

    • Monoclonal Antibody (mAb): 

      • ​The antibody is designed to bind specifically to a protein found on the surface of the cancer cells.

    • Chemical Linker: 

      • ​A molecule that connects the antibody to the cytotoxic drug.

​

  • Bioanalytical Complexities: ​

    • ADCs require multiparametric analysis, as they exist as heterogeneous mixtures with varying drug-to-antibody ratios (DARs).

    • Analytical methods must assess total antibody, conjugated drug, free drug, and DAR distribution.

Schematic-representation-of-antibody-drug-conjugate-ADC.png

(Santiagola, 2022)

TECHNOLOGICAL ADVANCEMENTS

Microdosing: 

Why use microdosing? 🔍

  • Traditional drug testing starts with animal studies and later moves to human trials (Phase I), which are expensive and take a long time.

    • Sometimes drugs work in animals but fail in humans, wasting time and resources.

  • Microdosing allows researchers to test in humans much earlier (called Phase 0), but with extremely low doses that don’t cause any pharmacological effect.

    • Gathers human PK data without full trials.

    • Gather preliminary data on safety and potential therapeutic benefits. 

    • Identifies poor candidates early. 

    • Minimises risk of side effects.

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Source: Genetic Engineering & Biotechnology News

​Disadvantages: 

  • However, ultrasensitive and specific analytical methods capable of measuring drug and metabolite concentrations in the low picogram to fentogram range are required.

    • Liquid chromatography coupled with tandem mass spectrometry (LC-MS-MS)

      • Common and widely used in labs

      • It has a good sensitivity and can detect very small drug levels (picogram range)

      • Separates drug and its metabolites and then measures them precisely

    • Accelerator Mass Spectrometry (AMS)

      • Much more sensitive than LC-MS/MS (can detect levels in femtograms!)

      • Used when drug concentrations are extremely low

      • Requires the drug to be labeled with a radioactive isotope like Carbon-14.

        • However, the dose of radiation used is extremely tiny (100 nanocuries), so it's safe for humans. 

        • DOWNSIDE: More expensive and complicated because of the radiolabeling

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