PK Final Cumulative Notes
ADME: absorption, distribution, metabolism, excretion
- Absorption and distribution may dictate/be affected by route of admin (can dictate or be
exploited)
- Permeation mechanisms
Aq diffusion: water compartments, paracellular diffusion
Lipid diffusion: rate limiting, cross membranes
Carriers/transporters: active transport, facilitated diffusion, large insoluble molecules
Endo/exocytosis: uptake/excretion
- Fick’s law: passive flux across membranes-important for drug absorption/distribution
- Bioavailability: extent/rate drug/metabolite enters systemic circulation and is available at
site of action determined by dosage form and physicochemical properties
IVF=1
- Chemical equivalence: same compound, same amount, inactive ingredients may differ
- Bioequivalence: same patient, same regime gives equivalent Cps
- Therapeutic equivalence: same patient/same regimen, same therapeutic/adverse effects
- Therapeutic index: ratio of min toxic conc to median effective conc
- First pass metabolism (liver/intestinal wall): metabolism of drug before it reaches
systemic circulation ( can reduce F)
PO v IV dosing
Only unbound drug can be metabolized by liver (but remember protein binding is an
equilibrium)
- High extraction drugs: rapid/extensive metabolism/extraction on first pass throughliver
- Distribution at stead state: [drug tissue]=[drug plasma]
- Vd= v of fluid drug dose would have to be diluted to to produce plasma concentration
(inversely related)-independent PK parameter-related to measurable drug concentration
in plasma compared to total amount in body determined by the relative strength of
drug binding in tissue compared to plasma proteins
Loading dose: rapid drug accumulation to quickly fill up the Vd
- Metabolism:
i. Phase I: CYTP450s, redox reactions to expose functional group
ii. Phase II: UGTs, SULTs, conjugation reactions
- Prodrug: inactive/weakly active drug with active metabolite
- First order elimination: increased metabolic rate with increased drug concentration
metabolized drug rate a constant fraction of drug remaining in body
- Zero order metabolism: saturated, fixed amount of drug metabolism per time
- Clearance: efficiency of irreversible elimination of a drug from the system (independent
PK parameter)- volume of blood cleared of drug/time
main parameter determining maintenance dosing rate req to achieve Cp target (Css
elim rate= dosing rate)
Renal clearance: urine excretion rate and blood concentration measured at same
time
- Elimination: excretion of unchanged drug
- Extraction ratio: proportion of drug entering liver which is irreversibly removed
- Half life: constant proportion of drug eliminated per unit time
First order exponential elimination
, Dependent on Vd and CL
Determinant of duration of drug action after single dose, time required to reach Css
w cts dosing
4/5 T1/2s to reach Css with complete elimination: mean Css one dose of drug
eliminated per dosing interval
- AUC: measure of total drug exposure taken from time 0 to last Cp sample (mghr/L)
At Css=AUCsingle dose
Model independent
Increase Vd no loss of AUC, increase CL loss of AUC
One Compartment IV Bolus Dosing
- Instantaneous distribution, immediate elimination
- Assumptions:
i. One compartment: blood drug equilibrium w extravascular tissue drug
ii. Rapid mixing: blood/plasma instant mix
iii. Linear model: first order elimination-monoexponential decay
- May ONLY regress to Y axis for IV BOLUS DOSE with LOGGED y axis
Multiple IV Bolus Dosing
- Higher Cp w subsequent doses due to accumulation limit to accumulation because as
Cp increases, the amount of drug elimination during dosing interval will also increase
- Waiting for plateau suitable for: not fast remedy, differences in drug effect are large
- Cpmax and Cpmin equations can ONLY be used at mean Css
IV Infusion Dosing
- 0 order process, 1st order elimination
- Ko= infusion
- At Css, rate of elimination=rate of infusion
- Combined infusion w IV bolus: LD by rapid IV and after Cp target reached, use slower
infusion as mtn dose
- Kel can be measured using slope lnCp/t proportion of drug eliminated per unit time
Pharmacokinetic Monitoring
- Assume that Cp mirrors tissue drug concentrations at drug site
- Used when: pharmacological response not readily assessable, narrow therapeutic
range, good correlation bw concentration and response, wide interPT variability in ADME
- Factors to consider when interpreting Cp:
i. Drug: dose, ROA, dosage, dosing history, accuracy of prep, admin error
ii. Cp: exact time collected, post dose time, inappropriate documenting time, assay
error
iii. PT info: demographic, history, lab data, clinical parameters (non responsive:
altered receptor sensitivity, interaction at site)
iv. Other drug therapy: interactions
- Therapeutic range is a probability table-to not treat the level, treat the patient
- Drug assays: specific (measure without interference), sensitive (smallest conc that can
be measured), accuracy (closeness), precision (reproducibility
ADME: absorption, distribution, metabolism, excretion
- Absorption and distribution may dictate/be affected by route of admin (can dictate or be
exploited)
- Permeation mechanisms
Aq diffusion: water compartments, paracellular diffusion
Lipid diffusion: rate limiting, cross membranes
Carriers/transporters: active transport, facilitated diffusion, large insoluble molecules
Endo/exocytosis: uptake/excretion
- Fick’s law: passive flux across membranes-important for drug absorption/distribution
- Bioavailability: extent/rate drug/metabolite enters systemic circulation and is available at
site of action determined by dosage form and physicochemical properties
IVF=1
- Chemical equivalence: same compound, same amount, inactive ingredients may differ
- Bioequivalence: same patient, same regime gives equivalent Cps
- Therapeutic equivalence: same patient/same regimen, same therapeutic/adverse effects
- Therapeutic index: ratio of min toxic conc to median effective conc
- First pass metabolism (liver/intestinal wall): metabolism of drug before it reaches
systemic circulation ( can reduce F)
PO v IV dosing
Only unbound drug can be metabolized by liver (but remember protein binding is an
equilibrium)
- High extraction drugs: rapid/extensive metabolism/extraction on first pass throughliver
- Distribution at stead state: [drug tissue]=[drug plasma]
- Vd= v of fluid drug dose would have to be diluted to to produce plasma concentration
(inversely related)-independent PK parameter-related to measurable drug concentration
in plasma compared to total amount in body determined by the relative strength of
drug binding in tissue compared to plasma proteins
Loading dose: rapid drug accumulation to quickly fill up the Vd
- Metabolism:
i. Phase I: CYTP450s, redox reactions to expose functional group
ii. Phase II: UGTs, SULTs, conjugation reactions
- Prodrug: inactive/weakly active drug with active metabolite
- First order elimination: increased metabolic rate with increased drug concentration
metabolized drug rate a constant fraction of drug remaining in body
- Zero order metabolism: saturated, fixed amount of drug metabolism per time
- Clearance: efficiency of irreversible elimination of a drug from the system (independent
PK parameter)- volume of blood cleared of drug/time
main parameter determining maintenance dosing rate req to achieve Cp target (Css
elim rate= dosing rate)
Renal clearance: urine excretion rate and blood concentration measured at same
time
- Elimination: excretion of unchanged drug
- Extraction ratio: proportion of drug entering liver which is irreversibly removed
- Half life: constant proportion of drug eliminated per unit time
First order exponential elimination
, Dependent on Vd and CL
Determinant of duration of drug action after single dose, time required to reach Css
w cts dosing
4/5 T1/2s to reach Css with complete elimination: mean Css one dose of drug
eliminated per dosing interval
- AUC: measure of total drug exposure taken from time 0 to last Cp sample (mghr/L)
At Css=AUCsingle dose
Model independent
Increase Vd no loss of AUC, increase CL loss of AUC
One Compartment IV Bolus Dosing
- Instantaneous distribution, immediate elimination
- Assumptions:
i. One compartment: blood drug equilibrium w extravascular tissue drug
ii. Rapid mixing: blood/plasma instant mix
iii. Linear model: first order elimination-monoexponential decay
- May ONLY regress to Y axis for IV BOLUS DOSE with LOGGED y axis
Multiple IV Bolus Dosing
- Higher Cp w subsequent doses due to accumulation limit to accumulation because as
Cp increases, the amount of drug elimination during dosing interval will also increase
- Waiting for plateau suitable for: not fast remedy, differences in drug effect are large
- Cpmax and Cpmin equations can ONLY be used at mean Css
IV Infusion Dosing
- 0 order process, 1st order elimination
- Ko= infusion
- At Css, rate of elimination=rate of infusion
- Combined infusion w IV bolus: LD by rapid IV and after Cp target reached, use slower
infusion as mtn dose
- Kel can be measured using slope lnCp/t proportion of drug eliminated per unit time
Pharmacokinetic Monitoring
- Assume that Cp mirrors tissue drug concentrations at drug site
- Used when: pharmacological response not readily assessable, narrow therapeutic
range, good correlation bw concentration and response, wide interPT variability in ADME
- Factors to consider when interpreting Cp:
i. Drug: dose, ROA, dosage, dosing history, accuracy of prep, admin error
ii. Cp: exact time collected, post dose time, inappropriate documenting time, assay
error
iii. PT info: demographic, history, lab data, clinical parameters (non responsive:
altered receptor sensitivity, interaction at site)
iv. Other drug therapy: interactions
- Therapeutic range is a probability table-to not treat the level, treat the patient
- Drug assays: specific (measure without interference), sensitive (smallest conc that can
be measured), accuracy (closeness), precision (reproducibility
