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4 :: Personalised Medicine

Drug Dosing & Response Predictions

Model-Informed Precision Dosing (MIPD): 

  • MIPD combines pharmacokinetic-pharmacodynamic (PK-PD) models with individual patient data (e.g. weight, renal function, genotype) to optimise dosing.

    • Bayesian Forecasting uses prior knowledge and patient-specific data to estimate optimal dose.​

  • Applied in narrow therapeutic index drugs:

Antibiotics (e.g. vancomycin), antifungals, immunosuppressants (e.g. tacrolimus) and chemotherapy agents.

  • Extends to pharmacodynamic (PD) markers:

​e.g. INR monitoring for warfarin dosing, especially when genetic variants like CYP2C9 and VKORC1 are present. ​

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  • MIPD is particularly useful for:

    • Special populations

      • (e.g. paediatrics, elderly, organ dysfunction)​

  • Polymedicated patients

    • ​​

​​(e.g. transplant recipients, cancer patients)​

(Darwich, A. S., et. al, 2021).  Source: Frontiers 

NARROW THERAPEUTIC INDEX

Medications with a small margin between a safe, effective dose and an ineffective or toxic dose.

 

The larger the therapeutic index (TI), the safer the drug is. If the TI is small (the difference between the two concentrations is very small), the drug must be dosed carefully and the person receiving the drug should be monitored closely for any signs of drug toxicity

PD MARKERS

Molecular indicators of drug effect on the target in an organism.

POLYMEDICATED

The administration of many drugs simultaneously, or the administration of an excessive number of drugs to a patient. 

Genetic Factors that affect Drug Metabolism:

Pharmacogenomics

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Pharmacogenomics

PHARMAGENOMICS (PGx) looks at how an individual’s response to drugs (pharmacology) is affected by their genetic information (genomics).

  • Drug transporters (e.g. P-glycoprotein)

  • Drug targets (e.g. receptors, enzymes)

  • Drug-metabolising enzymes

Source: StoryMD

Pharmacogenomic testing enables pre-emptive identification of patients at risk of adverse drug reactions (ADRs) or non-response, improving safety and therapeutic outcomes across fields like oncology, psychiatry, and cardiology. 

​

MUTATIONS

can affect drug metabolism, efficiency, and safety.  Even small genetic differences may cause enzymes to degrade or oxidise a drug too quickly, making it ineffective or even harmful to patients.

For example, the CYP450 family genes can reduce, absent, or increase enzyme activity.

CYP450 family

The CYP450 family is a large group of heme-containing enzymes primarily found in the liver, playing a crucial role in metabolising drugs and other substances. These enzymes are classified into families and subfamilies based on their structural and sequence similarities, with CYP1, CYP2 and CYP3 being the most important in drug metabolism. 

(Tjorvi E. Perry, Charles D. Collard, 2013)

CYP2D6_structure.png

CYP2D6

  • Metabolises ~25% of drugs

  • Poor metabolisers: ineffective prodrug activation

    • (e.g. codeine → morphine)

  • Ultrarapid metabolisers: overdose risk

CYP2C9_1OG2.png

CYP2C9

  • Metabolises ~15% of drugs

  • Variants require lower doses; increased bleeding risk with NSAIDs.

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CYP2C19

  • Activates antiplatelet drugs

  • Loss-of-function alleles lead to therapeutic failure

  • Warfarin (CYP2C9 & VKORC1)

  • Genetic polymorphisms: 

Affects warfarin metabolism & sensitivity.

​​​​

  • Demonstrates integration of PGx and PK to enhance therapeutic precision.

    • Pharmacokinetic studies incorporating genetic data have led to the development of genotype-guided dosing algorithms, improving the safety and efficacy of warfarin therapy.

​

  • Clopidogrel (CYP2C19)

    • Genetic polymorphisms in CYP2C19 can result in reduced drug metabolism, leading to diminished therapeutic effects.

      • Pharmacokinetic studies in different populations have elucidated the prevalence of these variants, prompting personalised dosing recommendations to optimise the antiplatelet effects of clopidogrel.

​

  • Codeine (CYP2D6)

    • A prodrug activated by CYP2D6 to morphine. Genetic polymorphisms in CYP2D6 can result in:

      • Poor metabolisers, which lead to insufficient pain relief.

      • Ultrarapid metabolisers, which can lead to risk of respiratory depression and toxicity.

    • Pharmacogenomic insights have influenced dosing recommendations for codeine, highlighting the importance of tailoring treatment based on individual genetic profiles. 

      • Clinical guidelines recommend avoiding codeine in CYP2D6 ultrarapid metabolisers, especially in paediatrics.

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(Julesbick, 2024) (Kamali, F., & Wynne, H., 2010) (Lee, M. T. M., & Klein, T. E., 2013) (Wadelius, M., & Pirmohamed, M., 2006) 

(Frére, C., Cuisset, T., et. al, 2009) (Gasche, Y, et. al,  2004) 

GENETIC POLYMORPHISMS

The presence of multiple forms (alleles) of a gene within a population, where each allele occurs with a relatively high frequency (typically 1% or more). 

 

These variations in the DNA sequence can lead to different traits and characteristics among individuals. 

The most common type of polymorphism involves variation at a single nucleotide (also called a single-nucleotide polymorphism, SNP).

 

(Munir Pirmohamed, B.Kevin Park, 2001)

Real-World Drug Examples of PK Improving Treatment:

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