PHA2022 Chap.2 Pharmacokinetics, Exposure and Dosing

Pharmacokinetics, Exposure and Dosing

Pharmacokinetics describes how the body handles a drug through absorption, distribution, metabolism and excretion. The useful object is concentration over time in a defined compartment, not a list of four words. Dose and route shape input; distribution relates amount to measured concentration; clearance relates concentration to elimination rate.

Together they determine onset, peak, duration, accumulation and the time required to approach a new steady state.

Bioavailability is the fraction of a dose reaching systemic circulation in an available form. Intravenous dosing is the reference for complete systemic input, while oral exposure can be reduced by incomplete absorption and first-pass metabolism.

A lower oral concentration can reflect bioavailability rather than faster clearance. Area under the concentration–time curve is proportional to systemic exposure under the appropriate linear assumptions.

Volume of distribution is an apparent proportionality between amount in the body and measured plasma concentration.

A large value suggests extensive distribution or binding outside plasma; it is not a literal anatomical container. Loading dose is influenced by the target concentration, volume and bioavailability. Maintenance dosing replaces what clearance removes over the dosing interval.

Clearance is not the amount eliminated. It relates elimination rate to concentration and can combine renal, hepatic and other routes.

Under first-order elimination, a constant fraction is removed per unit time and half-life is constant when clearance and distribution remain stable. Zero-order behaviour removes a roughly constant amount and can make small dose increases produce disproportionate accumulation.

The familiar relation t1/2 ≈ 0.693 × V/CL shows that half-life increases when distribution volume increases or clearance falls, within the model.

It does not say why clearance changed. Renal impairment, enzyme inhibition, liver function, blood flow and transporter effects require mechanism-specific analysis. A concentration measurement also needs timing relative to dose and knowledge of whether distribution equilibrium is plausible.

Repeated dosing accumulates until average input rate matches average elimination rate.

A longer half-life means more time to steady state and washout, commonly several half-lives. It does not by itself specify the eventual average concentration; maintenance input relative to clearance does. Changing the dosing interval changes peak–trough fluctuation even when average input is similar.

Worked renal case: a drug is mostly cleared unchanged by the kidney.

Clearance falls by half while dose and interval remain unchanged. Under linear kinetics, average steady-state exposure approximately doubles, elimination half-life lengthens and accumulation increases.

A defensible response may reduce maintenance dose, extend the interval, monitor exposure or choose an alternative, while loading dose may be less affected if distribution is unchanged.

Effect can lag behind plasma concentration because distribution to the effect site or downstream signalling takes time. Active metabolites can extend action after parent concentration declines.

High protein binding changes free concentration and interactions, but total concentration alone can mislead when binding changes. Match the measured analyte and sampling time to the pharmacological question.

For calculation practice, write units before substitution. Ask whether the relationship assumes linear kinetics and steady parameters.

State the direction before the number: lower clearance raises exposure; larger distribution volume changes loading requirement and often half-life; lower bioavailability raises the oral dose needed for the same systemic input. The number is the final check, not the reasoning.

Drug interactions can be organised by the parameter they change.

Altered absorption changes input, enzyme inhibition or induction changes clearance, protein-binding displacement changes free fraction and pharmacodynamic co-action changes response at a given exposure. Predict the concentration–time effect before the clinical effect. If two sedatives act at different targets, plasma concentrations can remain unchanged while combined impairment rises.

This prevents every interaction from being mislabeled as metabolism and directs the appropriate monitoring strategy.

When a regimen changes, specify the expected peak, trough, average exposure and time to the new steady state rather than saying levels change.

What this chapter covers

• 01

  bioavailability

• 02

  clearance

• 03

  half-life

• 04

  reason from absorption, distribution, metabolism and excretion to concentration over time and dosing decisions

• 05

  Plasma concentration is a useful exposure measure but may not equal concentration at the effect site or determine response alone.

Adjust for lower clearance

Key terms

bioavailability

The fraction of an administered dose reaching systemic circulation in an available form.

clearance

The proportionality term relating elimination rate to drug concentration.

half-life

The time for concentration or amount to fall by half under the stated kinetic conditions.

Pharmacokinetics, Exposure and Dosing FAQ

Exam move

Retrieve the target or decision, trace concentration and time, work one changed case, then write the translational boundary.

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