Free plasma concentrations

True steady state is usually only achieved for a prolonged period with intravenous infusion. If we assume that we wish for a similar steady value after oral administration, then we need to balance our dosing frequency with the rate of decline of drug concentration and the rule of thumb referred to earlier (dosing interval equal to drug half-life) can be applied. Unbound clearance and free drug are particularly applicable to drugs delivered by the oral route. For a well-absorbed compound the free plasma concentrations directly relate to Cli (intrinsic unbound clearance). 

Tab. 8.3 Dose, total and free plasma concentrations for clinical CYP3A4 inducers.

Often PK/PD models are developed using classic PK models to describe plasma concentrations, which is often appropriate when P K samples are obtained during the PD assay so that plasma concentrations are most accurately simulated. A PBPK/PD model may be particularly useful when P K data are not available for a given PD assay, when a PD effect is not related to free plasma concentrations but instead is related to the free concentration in a target tissue, orwhena PK/PD model must be extrapolated to humans. 

E) The free plasma concentration of drug B would likely be markedly increased if drug A were given second rather than first. 

For FTIH trials, all applications should include a summary of projected free plasma concentrations of the new active substance (NAS) in humans and a brief description of any pharmacokinetic modelling programs used to generate the estimates. A comparison with the concentrations obtained in the nonclinical toxicity studies and projected safety margins should be given. In the same section, an estimate of the extent of the intended pharmacological or pharmacodynamic response at the expected plasma concentrations should be included, with a list of the assumptions used in deriving that estimate. 

For drugs that bind to serum proteins, equilibrium exists between the bound or ineffective portion and the unbound (free) or effective portion. For acidic drugs that are highly bound to albumin, the free plasma concentration may correlate best with pharmacologic effect. Although albumin levels decrease only slightly with age, they tend to decrease during periods of illness. This can result in elevated levels of... 

Pharmacokinetics Sildenafil is rapidly absorbed after oral administration, and peak plasma levels are achieved within one hour. Bioavailability is about 40 percent of the oral dose. Sildenafil enters tissues, and has an apparent volume of distribution of 1.5 L/kg. Both sildenafil and its major N-desmethylated metabolite are > 95 percent bound to plasma proteins. Both CYP3A4 (major route) and CYP2C9 (minor route) are responsible for the metabolism of sildenafil. The major metabolite, N-desmethyl sildenafil, is approximately 50 percent as potent as sildenafil in inhibiting PDE5. The major route of elimination for sildenafil and its metabolites is via the bile. Clearance is decreased in older individuals free plasma concentrations are 40 percent higher in healthy volunteers > 65 years old. Severe renal impairment (< 30 mL/min) increases the AUC (see p. 7) by two-fold. Similarly, cirrhosis of the liver also significantly increases the AUC. 

Albumin Maintains plasma oncotic pressure. Transports fat-soluble substances, e.g. bilirubin, drugs Reduced levels Low levels cause ascites and increase free plasma concentration of albumin-bound drugs, e.g. oestradiol, phenytoin Albumin is a useful clinical indicator of the liver s synthetic function. The liver produces and exports up to 12 g of albumin per day. Low levels are also seen in malnutrition, hypercatabolism and nephrotic syndrome. Half-life of 20 days, therefore indicator of chronic liver disease... 

Fluoxetine is highly protein bound and may affect the free plasma concentration and, thus, the pharmacological effect of other highly protein-bound drugs (e.g., warfarin sodium). 

The free drug hypothesis states that only the free unbound drug is available to drive efficacy and free drug is in equilibrium throughout the body. Hence the free plasma concentration can be used as a surrogate for the free concentration of the drug at its site of metabolism or activity. 

Abbreviations [I], inhibitor concentration C ax, maximum plasma concentration Cmax,fu, maximum free plasma concentration /max, maximum portal vein concentration /max,fu, maximum free portal vein concentration PBPK, physiologically-based pharmacokinetics. 

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