Maturation and size are key predictors of variability. A two-group polymorphism was identified based on phenotypic M1 formation clearance. Maturation of tramadol elimination occurs early (50 % of adult value at term gestation).

A theory-based PKPD model describes warfarin concentrations and clinical response. Expected PK and PD genotype effects were confirmed. The role of predicted fat free mass with theory-based allometric scaling of PK parameters was identified. R-warfarin had a minor effect compared with S-warfarin on PCA synthesis. INR is predictable from 1/PCA in vivo.

This tutorial defines the principles of the concentration -effect relationship which are the basis of pharmacodynamics. The two key parameters of pharmacodynamics are the maximum response (Emax) and the concentration producing 50% of Emax (C 50 ). The time course of effect is illustrated under the assumption that drug effects are immediately related to concentration in the central compartment e.g. plasma. The related idea of duration of drug action and its relationship to dose is shown to have a simple relationship with drug half-life. Pharmacokinetics and PharmacodynamicsThe time course of drug action combines the principles of pharmacokinetics and pharmacodynamics. Pharmacokinetics describes the time course of concentration while pharmacodynamics describes how effects change with concentration. There are 3 ways to think of the time course of effects:1. Drug effects are immediately related to observed drug con centration (e.g. in plasma) 2. Drug effects are delayed in relation to observed drug con centration 3. Drug effects are determined by the cumulative action of the drug This tutorial outlines the basic principles of the concentrationeffect relationship (pharmacodynamics) and illustrates the application of pharmacokinetics and pharmacodynamics to predict the time course of immediate drug effects. Drug concentration is not as easily observable as doses and effects. It is believed to be the linking factor that explains the time course of effects after a drug dose. The science linking dose and concentration is pharmacokinetics. The two main pharmacokinetic properties of a drug are clearance (CL) and volume of distribution (V).The science linking concentration and effect is pharmacodynamics. The two main pharmacodynamic properties of a drug are the maximum effect (Emax) and the concentration producing 50% of the maximum effect (C 50 ). The C 50 is also known as EC 50 but C 50 is preferred to make it clearer this is a concentration and not an effect scaled parameter.Clinical pharmacology describes the effects of drugs in humans. One way to think about the scope of clinical pharmacology is to understand the factors linking dose to effect. Clinical pharmacology may be defined as the science of understanding how to achieve a desired clinical effect by administering the right dose. This can be done by choosing a target effect, using pharmacodynamics to predict the target concentration which produces the effect and then using pharmacokinetics to predict the dose (Fig. 1).The time course of drug concentration can be described in terms of half-life. Table 1 shows an example of times and concentrations which can be used to find the half-life. The half-

The use of theory-based allometry with predictions of fat free mass has been able to separate the influences of weight and body composition and indicates that size-normalized clearance of dexmedetomidine is impaired in patients who are obese.

Germovsek and colleagues have recently concluded that a standard approach to modelling pharmacokinetics is not wrong and appears to be at least as useful as other ad hoc methods for describing drug concentrations. There are other advantages of this approach including learning about biology, comparing different studies, detecting errors and rationalizing dose prediction. A standard approach to size and maturation is not a panacea but provides the framework for challenging new ideas and supports a consistent method of dosing in patients of all ages.

The elimination of caffeine was investigated in a 1860 g, 31 week gestation neonate, following the accidental administration of a 160 mg.kg-1 dose. The first serum concentration measured was 217.5 mg.l-1 at 36.5 h after dosing. Fitting of time-concentration data was performed using non-linear regression with MKMODEL. A first order elimination model was superior to a mixed order model. Parameter estimates were: clearance 0.01 l.h-1 , volume of distribution 1.17 litres, elimination half-life 81 h. Toxic manifestations included hypertonia, sweating, tachycardia, cardiac failure, pulmonary oedema and metabolic disturbances (metabolic acidosis, hyperglycaemia and creatine kinase elevation). An unusual feature of this infant's illness course was gastric dilatation. These signs resolved by day 7 at a serum concentration of 60-70 mg.l-1. Caffeine clearance has traditionally been reported as either an absolute value or as directly proportional to body weight. The per kilogram model gives an erroneous impression that clearance is greatest in early childhood and then decreases with age until adult rates are reached in late adolescence. Age-related clearance values reported in the literature were reviewed using an allometric 3/4 power model. This size model demonstrates that clearance increases in infancy and reaches adult rates within the first three months of life.

The pharmacokinetics of paracetamol in adults after cardiac surgery have not been described. Twenty patients were randomized to receive either paracetamol 2 g through a nasogastric tube and as a suppository eight hours later or vice versa. Arterial blood samples were taken at 0.5, one, two, four, six and eight hours after dosing. Each patient was studied for 16 h. There were 16 males and three females. One patient was excluded because of sampling errors. The mean age was 59 (SD 8) years and the mean weight 84 kg (16).The time-concentration profiles for each individual were used to estimate pharmacokinetic parameters using a non-linear mixed effects model (NONMEM). Population parameter estimates with coefficient of variation (CV%), standardized to a 70 kg person, for a one-compartment model with first order input, lag time and first order elimination were volume of distribution 127 l (28) and clearance 26.4 l/h (29) Rectal paracetamol had an absorption half-life (T abs ) of 2.02 h (31) with a lag time of 0.28 h. The absorption half-life for the oral preparation was 1.49 h (81) with a lag time of 0.17 h. The relative bioavailability of the rectal compared to the oral formulation was 0.98 (18).Concentrations after either nasogastric or rectal paracetamol 2 g were below a target concentration of 10 mg/l, which is associated with analgesia. Absorption after nasogastric administration was slow compared to healthy adults (T abs 0.06 to 0.7 h) and the bioavailability was half that expected, due to nasogastric loss. Parameter estimates had large variability. Paracetamol is unlikely to have useful clinical impact in the majority of patients when standard doses (6 g/day) are given on day 1 after cardiac surgery.

Objectives 1) Appreciate how a target concentration (TC) strategy is essential for rational clinical use of medicines 2) Understand when and why individual patient monitoring can be used for dose individualisation 3) Distinguish target concentration intervention (TCI) from therapeutic drug monitoring (TDM)The target principle of dosing Therapeutics involves a two-step decision process. First, a suitable medicine is chosen to treat the disease process. Second, the right dose of the medicine must be administered to achieve the required effect to treat the disease.The target approach links pharmacokinetics (PK) with pharmacodynamics (PD) to predict the right dose for a patient.[1] Once a medicine has been chosen to achieve a desired clinical response, the target effect for the patient should then be established. The choice of target effect is always a balance between therapeutic benefit and toxicity and this requires clinical judgement along with comprehensive knowledge of the properties of the medicine. Once the target effect has been decided, the prediction of the right dose can then be done rationally based on knowledge of PD and PK.All drug effects are linked to concentration and that link is defined by a PD model. The most widely used is the E max model (Equation 1) which is described by the maximum response, E max , and the concentration producing 50% of E max , C 50 .[2]The E max model can be re-arranged to predict the target concentration required to achieve the target effect (Equation 2).With the target concentration in hand it is then simple to predict the loading dose to reach the target concentration (Equation 3) and the maintenance dose rate to keep the effect on target (Equation 4). [3,4] This tutorial reviews the principles of dose individualisation with an emphasis on target concentration intervention (TCI). Once a target effect is chosen then pharmacodynamics can predict the target concentration and pharmacokinetics can predict the target dose to achieve the required response. Dose individualisation can be considered at three levels: population, group and individual. Population dosing, also known as fixed dosing or "one size fits all" is often used but is poor clinical pharmacology; group dosing uses patient features such as weight, organ function and comedication to adjust the dose for a typical patient; individual dosing uses observations of patient response to inform about pharmacokinetic and pharmacodynamics in the individual and use these individual differences to individualise dose.