Basic PharmacokineticsIntroduction Flashcards
Dose
predetermined amount of the drug administered at one time to produce a certain degree of biological response. E.g., Analgesic dose of aspirin for headache is 300-600 mg
Dosage
predetermined amount and rate of administration of a drug for a patient. E.g., 200 mg ibuprofen once daily.
Dosage form
the physical form in which a precise mixture of API (active pharmaceutical ingredient) and excipients are presented to help administration, deliver to sites of action, achieve rapid onset of action, and improve bioavailability etc. E.g., 200 mg ibuprofen tablet.
Dosage regimen
The schedule of doses of a therapeutic agent per unit of time, including: the time between doses, or the time when the dose (s) are to be given,and theamount of a medicine to be givenat each specific time. E.g.,aspirin 300 mg, 4 times daily repeated every 6 hours according to the response for mild to moderate pain and fever. In other words, the specific way a therapeutic drug is to be taken, it may include formulation, route of administration, dose, dosing interval, and treatment duration
Medicine or Medicinal product
A substance or combination of substances that is intended to treat, prevent or diagnose a disease, or to restore, correct or modify physiological functions by exerting a pharmacological, immunological or metabolic action. E.g., Panadol Actifast®
Active ingredient
the substance in amedicinal productthat is biologically active i.e.producesthe desired effect. Also referred to as active pharmaceutical ingredient (API) or active substance. The international non-proprietary name (INN) is the globally recognized name used to identify the active ingredient in a medicine. E.g., paracetamol is the INN for paracetamol and acetaminophen (USA)
Excipient
A constituent of a medicine other than the active substance. E.g., In Panadol Actifast: Sodium Bicarbonate. Soluble Starch. Povidone. Maize Starch. Potassium Sorbate (E 202). Microcrystalline Cellulose. Magnesium Stearate. Carnauba Wax. Titanium Dioxide (E 171). Polydextrose. Hypromellose. Glycerol Triacetate. Polyethylene Glycol
How to establish a dosage regimen?
In the past: trial and error
dose,
interval between doses, and
route of administration
were changed empirically until a satisfactory therapy was achieved, but: large number of patients and experimentation no understanding (Why right? Why wrong?)
What do you need to know to design a dosage regimen?
Potency? Smaller doses for potent drugs!
Concentration for efficacy / toxicity?
Oral administration? Bioavailability?
Intravenous infusion? How fast?
Time and extent of distribution to target?
How quickly is the drug eliminated?
Elderly or paediatric patient? Pregnancy?
Renal or hepatic insufficiency?
And many more…. How do we connect / integrate all these factors?
Why pharmacokinetics?
Pharmacokinetics: the study of the (dynamics) movements of foreign chemicals (xenobiotics) during their passage through the body and as such encompasses the kinetics of absorption, distribution, biotransformation/metabolism and excretion (ADME)
Since the 60s the development of pharmacokinetics (PK) has contributed to:
understanding drug ADME
understanding “dose – concentration - effect” relationship
selection of best drug candidates
a rational development of drug therapy
establish dosage regimens
PK is part of:
preclinical studies and clinical (phase I, II and III) studies in drug development
post-marketing surveillance (phase IV)
regulatory marketing submissions.
The science of the kinetics of drug absorption, distribution and elimination
The pharmacokinetic phase
The PK phase covers the relationship between drug input and the drug concentration achieved with time
Biopharmaceutics
Science that studies the inter-relationships between:
the physicochemical properties of the drug,
the dosage form, and
route of administration with the
the rate and extent of absorption
and
the disposition of the drug
Remember: Disposition = Distribution + elimination
The pharmacodynamic phase
The PD phase covers the relationship between concentration and both the desired and adverse effects produced with time.
Therapeutic window
A basic assumption in pharmacotherapy is that the magnitude of both
therapeutic and
toxic
responses is a function of the drug concentration at the site(s) of action (usually measured at plasma).
If the drug concentration is:
Too low: no therapeutic effects
Minimal concentration (Cmin, eff.)
Too high: toxicity
Maximum concentration (Cmax, tox.)
The range of concentrations* between Cmin, eff. and Cmax,tox is the therapeutic window associated with therapeutic success.
(*also defined as the: optimal range of exposure to the drug)
The objective of a dosage regimen is to keep the drug concentration inside the therapeutic window
Cmin,efficacy < Cdrug < Cmax,toxicity
Understanding the PK getting the right dosage regimen
Pharmacokinetic models
Drug absorption and drug disposition processes are complex
Drugs are “moving continuously around” the body.
Events and ADME processes happen simultaneously.
A model is a set of mathematical expressions that describes quantitatively the processes involved in ADME and their relationships/links.
A model is a hypothesis, its utility depends on:
How well “it has been built” that is, on the right:
selection of processes that govern the ADME for each drug/dosage form
description of these processes with mathematical functions.
How well it describes the experimental/clinical observations
PK models can be used to:
describe the complexity of ADME
predict plasma, tissue, urine levels thus, efficacy/toxicity.
estimate drug / metabolite accumulation
establish dosage regimens
measure and compare rate/extent of absorption (bioavailability and bioequivalence)
describe and predict variability in drug therapy:
effects of disease, changes in physiology (e.g., pregnancy), age, sex, pharmacogenetics… on ADME processes
predict and explain drug interactions
