PHAR44002: Individualized Dosing Notes PT 1

Introduction to Individualised Dosing

Intended Learning Outcomes

• Describe the importance of concentration in clinical pharmacology.

• Explain the concept and importance of variability in PK and PD.

• List sources of variability.

• Describe approaches to individualised dosing.

• Carry out calculations for dose adjustment using covariate information.

Clinical Pharmacology

• Dose -> Plasma Concentration -> Effect Site Concentration -> Effect -> Clinical Outcome

• PK (Pharmacokinetics): relates concentration to dose.

• PD (Pharmacodynamics): relates effect to concentration.

• PK/PD: combines PK and PD to build a bridge between dose and effect.

• PK and PD target levels can be used as feedback to modify dose.

• Start with dose- drug administered to body- drug distributes into different places in body to get to site of action and produce effect, which gives the desired outcome.

• If can detrmine target conc that will produce desired effect, can use this to inform dose need to administer. This may need modifhying between individual patients.

Importance of Concentration in Drug Monitoring

• Effects are caused by concentration and not by dose. therefore individual dosing can help to reach these desired concentrations.

• Dose -> C_{ss,min}

Therapeutic Window in Clinical Pharmacology

• Therapeutic window is the range of dose or concentration of a drug that provides safe and effective therapy.

• It's the difference between the minimum effective concentration and maximum safe concentration.

• The therapeutic window can be wide or narrow.

• It is usually determined during drug development.

• The range of dose or conc of a drug that provides safe and effective therapy.

• Difference between minimum effective and maximum safe.

• Can be wide/narrow

• Usually determined during drug development.

When increase concentration, side effects begin to change also- this will affect clinical outcome, so need window where getting best efficacy with minimal harmful side effects. Window varies between drugs which is important in drug development.

Key Parameters

• E: Effect

• C: Concentration

• t: time

• Minimum effective concentration

• Maximum safe concentration

• Onset of action

• Peak effect

• Duration of action

Balance of Efficacy and Toxicity During Drug Development

• Utility is the balance of efficacy and toxicity, represented as a multi-dimensional surface of drug and patient-related factors

• Randomised Clinical Trials (RCTs) capture only a small area of this surface.

• Dose optimisation is performed during RCTs to determine the licensed dose.

• genetics impact this. It is impossible to incorporate all individual differences in clinical trials.

• Look beyind clinical trials when drugs are used in practice.

Variability in PK and PD

Different sources of variability; intrinsic and extrinsic.

• Genetics and demographics are important sources of variability in PK and PD.

• Genetics: e.g., polymorphism in drug metabolising enzymes

• Demographics: e.g., body size metrics, age etc.

• Polymorphism is verying levels of enzymes in the body which leads to different clinical outcomes.

High Variability Example

• High variability in 5-Fluorouracil PK

• C_{ss} (mg/L) = 0.16 – 1.65

• Wide range of drug conc with narrow therapeutic window. Will affect individual patients differently depending on levels.

• AUC = 7-fold difference

Hierarchy of Variability in PK and PD

• Within subject variability:

  • Total (VUW)

  • Predictable (VTP)

  • Unpredictable (VUP)

• Between subject variability (VUB)

  • Body weight, genetics, sex

  • Genetics, disease conditions, race

  • Food effect, environment

• Genetics is predictable variability- also body size, weight, sex, renal function ….

• Most of the time you cannot explain all variability- this is unpredictable variability, can’t account for this because it cant’t be measured but it is there.

• Between subject variability and within subject variability are types of unpredictable variability.

• Between subkect includes stuff like individual differenes ie empty stomach etc.

5-Fluorouracil (5-FU) Example - Exposure-Effect Relationship

• Used in the treatment of various types of cancer – colorectal, oesophageal etc.

• It has a very narrow therapeutic window

• The toxicity can be very severe and life threatening – diarrhoea, stomatitis, mucositis, myelosuppression, and neurotoxicity

• It can be cardiotoxic, directly linked to plasma concentration

• Variability in PK makes dosing/monitoring complicated

• Narrow therapeutic window and risk of toxicity makes it very important to look at variability.

5-FU Biotransformation

• 5-FU biotransformation is complex.

• Dihydropyrimidine Dehydrogenase (DPD) enzyme is the major enzyme for elimination.

• DPYD is the gene that encodes DPD.

• There is genetic polymorphism in DPYD gene.

• Reduced or absence of DPD activity.

• Significant contribution to variability.

• Implication for toxicity.

• DPD responsible for almost 80% of its elimination. So if there is a problem with this enzyme, concentration of drug will increase- so more likely to experience toxicity.

• Reduced activity of PDYD can contribute to variability in plasma 5fu conc - big implication for toxicity.

DPD Activity and Polymorphism in DPYD Gene

• Variants in DPYD gene correlate to DPD enzyme function.

• DPYD genotype tests are available and guidelines for interpretation have been published by Clinical Pharmacogenetics Implementation Consortium (CPIC).

• DPYD genotype results are linked to phenotype by activity score to guide dosing.

• There are racial differences in the frequency of the DPYD genotypes.

• can look at this gene in individuals to help predict the action of the drug.

DPYD Genotype, Phenotype and Activity Score

• Assignment of likely DPD phenotypes based on DPYD genotypes

• Likely phenotype

  • DPYD normal metabolizer

  • DPYD intermediate metabolizer

  • DPYD poor metabolizer

• Activity scores

  • 2

  • 1 or 1.5

  • 0 or 0.5

• If an individual carries 2 fucntional alleles- can be categorised as NORMAL METABOLISER.

• 1 normal allele and one dec functional allele= INTERMED metaboliser

• 2 non functional alleles or 0 alleles= poor metaboliser - drug will not benefit this patient.

5-FU – FOLFIRI (Colorectal Cancer)

• 400mg/m2 bolus + 2400mg/m2 (46h infusion)

• C_{ss} (mg/L) = 0.16 – 1.65

• Therapeutic window (mg/L) = 0.43 -0.65

  • Within = 42%

  • Above = 25%

  • Below = 33%

• ?

5-FU – PK Guided Dosing

• Heterozygous mutant has some levels of enzyme in body, but not normal amount- inc exposire to drug so modify dose.

• Clinical pharmacogenetics implementation consortium- guidelines

• Normal metabolisers- do not change dose

• Intermediate metabolisers- look at activity score , if 1- reduce dose by 50%

• Poor metaboliser and activity score 0.5 = avoid drug.

5-FU - PK Guided Dosing (Sex Effect)

• Strong sex effect

• AUC- female higher exposure than males, suggesting males have higher levels od enzyme and are able to metabolise 5FU more quickly. Therefore will have reduced levels in the body.

• Sex is v important variation in therapeutic monitoring and dosing od some drugs.

• Subtherapeutic, Therapeutic, Supratherapeutic

5-FU – PK Guided Dosing

Focus on concentration to control efficacy and toxicity.

•    Look at total variability

• explained variability + PKPD target for first dose, then based on this look at unexplained variability + PKPD target for second dose onwards to give individualised precision dosing.

• Individualised/Personalised/Precision dosing

  • Individual specific information- look at plasma conc after first tode and get specific info about them- so get right level and use this to inform next dose- gives individualised dosing but is expensive.

  • Therapeutic drug monitoring (TDM) or Target concentration intervention (TCI)

5-FU – PK Guided DosingKnikmam et al (2020), CPT 109(3): 591 - 604

Types of Dosing

• Stratified dosing- does not look at unexplained variability.

• Individualised/ Personalised/ Precision dosing

Gentamicin Dosing Stratification – Morbidly Obese Individuals (Special Population)

• Covariates that affect the PK of gentamicin have been defined.

• Dose stratification based on body weight and renal function (CKD-EPI) for gentamicin.

• Dose for morbidly obese individuals with renal dysfunction.

• Can be nephrotoxic in obese population - need to take renal function into consideration if increasing dose to account for body weight.

• Gentamicin – an antibiotics that is commonly used for severe infection.

• Gentamicin is renally cleared.

• Narrow therapeutic window – concentration correlated well with efficacy and toxicity.

  In renal dysfunction, dose interval can be extended to reduce toxicity.

• Body weight and renal function have been identified as covariants that affect peal concs of gent.

Precision Dosing Software

• InsightRX, MwPharm, DoseMe, iDose, BestDose

• Web-based platforms - NextDose, TCIWorks, TDMx

• these are used to determine individual dosing.

5-FU PK Guided Dosing

• When 5FU is used, first cycle with standard licenced dosing - see if plasma conc is within therapeutic window- then alter 2nd dose onwards according to explained variability etc to use individualised dosing to improve therapeutic outcomes.

• Drug concentration is important for drug response – efficacy and toxicity.

• therapeutic success

• Variabilities from different sources contribute to differences in exposure and response.

• Good understanding is required for dose optimisation.

• Genetic factors are important sources of variability in PK and PD.

• Once quantified and explained in PK/PD = explained variability.

• Tests prior to dosing can be used to optimise dosing (dose stratification).

• Precision dosing (target concentration intervention) required information from an individual.

• E.g. plasma concentration from a cycle of treatment.

• There are commercial and web-based applications for individualised dosing.

References

• CPIC Guideline for Fluoropyrimidines and DPYD (https://cpicpgx.org/guidelines/guideline-for-fluoropyrimidines-and-dpyd/)

• Amstutz et al 2018, Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update, Clinical Pharmacology and Therapeutics, 103(2): 210 – 216

• Tyson et al 2020, Precision Dosing Priority Criteria: Drug, Disease, and Patient Population Variables, Frontiers in Pharmacology 11: 1 – 18