7B: Principles of Pharmacokinetics (PK) & Therapeutic Drug Monitoring for Antibiotics Flashcards
1
Q
Recall: What is Pharmacokinetics (PK)?
A
- The science investigating relationships between the movement of a drug [& its metabolites] through the body & the process affecting it’
- PK is about ‘What the body does to the drug’ whereas, PD might be defined as ‘What the drug does to the body’
PK describes the kinetic processes of a drug in the body
- Absorption
- Distribution
- Metabolism
- Excretion
2
Q
Absorption
A
- Process whereby the drug reaches systemic circulation from the site of drug administration
- For the same agent, different routes of administration & formulation give arise different bioavailability & PK profiles
3
Q
Distribution (V)
A
- Distribution describes the reversible transfer of drug from the bloodstream to the various tissues (such as fat, muscle & brain tissue)
- Each drug has a unique volume of distribution (V) – Unit L or L/kg
- A high V reflects wide distribution to various organs/tissues, rather than stay in blood
4
Q
Factors affecting drug distribution
A
Physiological / pathological factors:
- Blood perfusion
- Membrane permeability
- Transporters
- Special physiological barriers e.g. blood-brain barrier (BBB), blood-milk barrier
- Bacterial infections, meningitis, encephalitis & sepsis could cause BBB dysfunction, resulting in higher permeability
Drug properties:
- Lipid solubility (Log P)
- pKa (ionisation state) (& the pHs on both sides of a bio-membrane)
- Plasma protein binding
- Tissue binding
Most drugs do not spread evenly throughout the body:
- Water soluble drugs tend to stay within the blood & the fluid that surrounds cells (interstitial space)
- Fat-soluble drugs end to concentrate in fatty tissues
Protein bound drug leaves the bloodstream slowly - only unbound drug is distributed to tissues
5
Q
Examples of absorption
A
- Gentamycin – water soluble (log P = -1.88) & distributes mainly into ECF, V = 15 L
- Amoxicillin – log P = 0.87, V = 27 L (adults)
- Vancomycin – water soluble (HCl salt), log P = -3.1, V = 30 L (0.4 – 1 L/kg)
- Reference – Chloroquine (non-antibiotic) is highly lipophilic (log P = 4.5), distributes to fat tissues, V = 13,000 L
6
Q
Clearance
A
- ‘The volume of blood completely cleared of the drug per unit time’
- Units are in terms of volume per time
- Efficiency of irreversible elimination of a drug from the body such as urine, sweat, mostly by liver (metabolic conversion)
- Cltotal = Clrenal + Clhepatic + Clother
- The fraction or percentage of the total amount of drug removed at any time remains constant & independent of the dose
7
Q
Examples of clearance
A
- Vancomycin – Cltotal = Clrenal, is directly related to creatinine clearance 90 mL/min (=5.4 L/h)
- Gentamycin – 2.8 L/h (0.089L/h in infant)
- Amoxicillin – 10 L/h
8
Q
Elimination rate constant (Ke) & half-life (t1/2)
A
- Ke is the fraction of drug in the body that is eliminated per unit of time e.g. fraction/h (unit = h-1)
Ke = Cl / Vd
- Ke & elimination half life (t1/2)
t1/2 = 0.693 / Ke = (0.693 / Cl) x Vd
9
Q
Compartment models
A
- A simplified & idealised description of PK process
+ The body is represented as one or more compartments
+ The rate of drug movement between compartment is described by 1st order kinetics (inflow, outflow) - Gives a visual representation of various rate processes involved in drug disposition
- Useful in relating plasma drug concentration in efficacy & toxicity
10
Q
Compartment models: Examples
A
One single compartment model means the drug distributes instantaneously & uniformly in the body
- One-compartment model IV bolus injection
- One-compartment model with 1st order absorption
11
Q
Pharmacokinetic models:
A
2 compartment models:
- The drug distributes slowly to tissues in which case the drug equilibrates slowly
- Drug transfer between compartments is assumed to take place by 1st order process
12
Q
Therapeutic Drug Monitoring
A
- TDM is the clinical practice of measuring the drug concentrations at designated intervals in a patient’s bloodstream, thereby optimising individual dosage regimens
- To improve clinical outcomes from infections, one of the methods to improve antimicrobial dosing in individual patients is through application of TDM
- To individualise medicine – Getting the Dose Right!
+ Reduce toxicity & improved efficacy
+ Reduce the development of antimicrobial resistance - TDM plays important role in the dosing of antimicrobial agents to define the antimicrobial exposures necessary for maximising killing or inhibition of bacterial growth
13
Q
Definitions used in antibiotic dosing
A
- Minimum Inhibitory Concentration (MIC) – the concentration at which a chemical prevents visible growth of a bacterium
- Minimum Effective Concentration (MEC) – the minimum concentration at which a therapeutic response is obtained
- Maximum Recommended Concentration – the maximum effective concentration above which toxic side effects occur
14
Q
Multiple dosing & steady state
A
- Steady state (SS) is defined as the situation the rate of drug entering the body is equal to the rate of drug being removed from the body & the plasma
- At steady state, drug concentration in plasma remains constant over time (drug in = drug out)
Dose / Time = avg steady state concentration x Cl
15
Q
Time to reach steady state
A
- Attained SS needs ~5* T0.5 (97% of SS achieved)
- Time to reach 90% of Cpssav = 3.3* T0.5
- Time to reach 99% of Cpssav = 6.6* T0.5
- Time to reach SS is independent of dosing frequency
16
Q
Loading dose
A
- A higher dose of a drug that is given at the beginning of a course of treatment before dropping down to a lower maintenance dose
+ E.g. Doxycycline t1/2 = 18 h, 200 mg loading dose followed by 100 mg every 12 h - Loading doses to rapidly establish drug concentrations that are therapeutic
- Particularly useful for drugs with long half-lives
17
Q
Loading dose determination
A
The volume of distribution is used to calculate the loading dose:
Loading Dose = Vd x Cp desired
18
Q
Maintenance dose
A
- The maintenance rate [mg/h] of drug administration equal to the rate of elimination at steady state
- Provided the clearance & target concentration are known then it is possible to calculate the maintenance dose required to maintain that concentration as:
Rate ‘In’ = Rate ‘Out’
- Clearance (Drug ‘out’) is used to determine the maintenance dose required to maintain a target plasma concentration at steady state
19
Q
PK profile & therapeutic efficacy
A
PK profile influences the intensity, duration & termination of activity
20
Q
Antibiotic dosing strategies
A
Dosing will vary depending on their mode of action:
- Concentration-dependent antibiotics (e.g. aminoglycosides) – could be administered by extended interval regimens:
+ To maximise bactericidal effect & minimise toxicity
+ To allow time between doses for the drug to take effect - Time-dependent agents – the critical factor for time above the MIC
21
Q
TDM for antimicrobials: Predictors of efficacy
A
- ƒT>MIC (total time for C > MIC) – for time dependent antimicrobials
- Cmax/MIC – for concentration-dependent antimicrobials
- AUC0-24 / MIC – for BOTH concentration & time-dependent antimicrobials
- In some cases it may require peak (Cmax) or trough, or both to be measured at regular intervals
+ Peak – to monitor achievement of therapeutic concentration
+ Trough – to monitor drug clearance, to avoid toxicity
22
Q
Final comments
A
- The crucial PK parameters ‘V’ & ‘CL’ determine the extent & duration a compound remains in an organism
- A large V means a large loading dose is necessary, a large CL means a large maintenance dose is required
- For antibiotics, its efficacy may be concentration or time dependent or both, dosing methods should be adjusted as per the “Predictors of efficacy”
- TDM is often required to ensure the efficacy as well as the patient safety
