Pharmacokinetic parameters: Half-

life (t1/2)

1. By definition t1/2 is the time required for the concentration to fall by one half. For drugs with first order kinetics this is a constant. 2. Half-life allows the calculation of the time required for plasma concentrations to reach steady-state after starting (or changing) a dosing regimen. 3. It also allows us to estimate the time required for a high dose to fall back within the therapeutic range after an overdose. Hence it allows us to determine when to re-start therapy after such an event. 4. Dosing intervals can also be determined using half-life. i.e. If the half-life is longer than expected (as shown by drug accumulation) the dosing interval can be extended, rather than decreasing the dose (see aminoglycosides later). PK Parameters - Bioavailability (F).

Absolute bioavailability is the fraction of the dose that reaches the systemic circulation and is usually determined by comparing the AUC of an oral dose (F<1) with that of an IV dose (F = 1).

Oral doses of drugs that are cleared by the liver have an absolute bioavailability of less than one as the portal circulation from the gut passes through the liver before going to the systemic circulation. This is known as the first-pass effect.

Drugs absorbed through the buccal cavity pass directly into the systemic circulation. This route of administration therefore has a higher bioavailability than the oral route for many drugs.

Comparative Bioavailability is the ratio of the area under the curves (AUC’s) of two formulations of the same drug.

Example - Aminoglycoside Therapy (Gentamicin & Tobramycin)

Therapeutic Aim: To maximise efficacy with minimum toxicity. This is achieved by; 1. Achieving a high peak concentration (i.e. 10 x MIC) to maximise the concentration dependent killing and post-antibiotic effect (post antibiotic effect is proportional to the peak concentration and is the period of time that bacterial growth is suppressed after the plasma concentration has fallen below the MIC). 2. To achieve a low concentration or “drug free” period at the end of the dosing interval to assist in the reversal of adaptive resistance, and to minimise drug accumulation and toxicity. Summary of A/G’s PK’s

1. Linear (first order) pharmacokinetics

2. Half-life: approx 3-6 hours in adults (normal renal function)

3. Other factors of importance: The aminoglycosides are water soluble, therefore dosing regimens are based on lean body weight.

Pharmacokinetics - first-order.

Cpt = Cp0- K.t (Elimination) LnC = lnC.e –Kt

Also known as: Linear Kinetics (plasma concentration is directly proportional to the dose). Summary of A/G’s PK’s

1. Linear (first order) pharmacokinetics

2. Half-life: approx 3-6 hours in adults (normal renal function)

3. Other factors of importance: The aminoglycosides are water soluble, therefore dosing regimens are based on lean body weight.

TDM of Phenytoin - Zero order (Michaelis –Menten) Pharmacokinetics. Most drugs are cleared predominantly by the liver. The liver enzyme systems usually have excess capacity to metabolise drug presented to them. This results in first order kinetics where increases in dose result in proportional increases in circulating concentration. If the concentration of drug approaches (or exceeds) the ability of the liver enzyme system to metabolise it, we have zero order (MM) pharmacokinetics. Under these conditions any increase in dose will result in a disproportionately high increase in concentration. If the capacity to metabolise the drug is exceeded, the concentration will continue to rise until the therapy is ceased. – potentially dangerous situation!

TDM of phenytoin - PK’s.

Non-Linear (Zero order) pharmacokinetics. 1. (Apparent) half-life is approximately 40 hours and is variable both within and between patients. 2. Primarily cleared by hepatic metabolism. 3. Volume of distribution is approximately 0.65 L/kg 4. Induction of liver enzymes influences metabolism. 5. Vm is variable but within the range 100-1000 mg/day. 6. Km is variable within the range of 1-15 mg/L. 7. Initial doses usually established from protocols/ guidelines.

TDM of phenytoin - protein binding and free drug concentrations. 1. Many drugs are reversibly bound to proteins in the plasma. 2. Basic drugs such as amitriptyline bind predominantly to alpha one acid glycoprotein (AAG) and acidic drugs such as phenytoin bind to albumin. AAG is an acute phase reactant and its production is increased in relation to stresses such as surgery or disease, hence the concentration of free drug compared to the total drug concentration can vary substantially when the protein concentration varies. This is true for variation in albumin concentrations also. 3. In vitro studies demonstrated the ability of drugs to displace each other from the binding sites. It was thought that drug- drug displacement interactions would therefore have a significant impact on PK’s 4. In most cases however clearance and volume of distribution mechanisms rapidly adjust for binding alterations and they have little, if any, impact on PK’s, with a couple of notable exceptions. Phenytoin is one such exception. TDM of phenytoin – dose adjustment. Usually doses are adjusted by cautious increments (titration) by around 10 % of the existing dose for smaller adjustments, with monitoring to watch rate and direction of change (i.e. don’t wait for steady-state). For toxic concentrations – cease therapy until symptoms cease and concentration in plasma is within the therapeutic range. Then re-start therapy at a reduced dose with monitoring until plasma concentrations and symptoms are appropriate. RFTDM - interpretation.

Time after starting therapy – How many doses to date? (i.e. at steady state?) Correct sample collection time wrt dosing (i.e. where in dosing cycle are we?). Knowledge of dosing details (i.e. drug & dose). RFTDM – Timing of collection of samples Steady state required (4-5 half-lives) for monitoring (in most cases). Trough levels used in most cases as:

 Equilibrium with tissue concentrations.

 More accurate as change with time is less. (Collection time not as critical).

 Data wrt efficacy and/or toxicity usually related to trough (predose) concentrations because of first two points.

RFTDM - Importance of correct information. (eg Tobramycin AUC’s). 5 yo female. CF. 320 mg tobra iv daily.

Time (h) AUC (0.5 hr inf) AUC (1.0 hr inf) 1.0 79 68 1.5 87 74 2.0 99 83 2.5 115 95

AUC range = 80-100, Target AUC = 95. Importance of correct information (Adult patient on tobramycin). Date Dose AUC Se Creat (mg) (mg.L/hr) (µmol/L) 31/3 280 63 62 03/4 320 70 71 07/5 320 59 67 13/5 400 53 59 15/6 320 90 61 Where can things go wrong?

Blood collection – contamination from central lines/skin. - Special protocols.

 Cyclosporin (central lines)

 Tobramycin (central line &/or inhalers)

 Other? Times – details of time dose given and time sample taken. Doses - need correct dosing details. Complete and correct information needed in patients’ charts. Dose Individualisation - Bayesian PK Modelling (eg. TCIWorks ®) New patient – predicts Concentration/Time curve (i.e. PK profile) based on population PK model and patient demographics. Estimating initial dose from demographics and proposed dose. Add dosing/concentration data Establishing individual model Predicting a new dose. TCIWorks® – input patient demographics TCIWorks® – population estimation TCIWorks® – individual model TCIWorks® – dose prediction TCIWorks® – PK prediction based on proposed dose TCIWorks® - report Therapeutic Drug Monitoring fundamentals and emerging trends - Focus on Antimicrobials.

Thursday 6th December 2012. University of Sydney.

This meeting will bring together all healthcare professionals involved in Therapeutic Drug Monitoring, especially those involved in the use of antimicrobial agents. The meeting is aimed at Medical Scientists, Chemical Pathologists, Pharmacists, Clinical Pharmacologists and Infectious Diseases Physicians. The principles of therapeutic drug monitoring will be introduced and discussed, illustrated with antimicrobial drugs. Current practices and issues of analysis, interpretation and delivery will be covered. Emerging trends in target concentration interventions will be presented using antimicrobial examples. Speakers include prominent national speakers and our international speaker is Dr Michael Neely from the Keck School of Medicine, University of Southern California and the Laboratory of Applied Pharmacokinetics, Los Angeles. Dr Neely is an infectious diseases physician and will be presenting from his substantial clinical application of computer based pharmacokinetic modelling in clinical practice.