Therapeutic Drug Monitoring 5.

A drug interaction is or maybe

● It involves the analysis, assessment occurring
and evaluation of circulating 6. It helps in monitoring patient
concentrations of drugs in serum, compliance
plasma, or whole blood.
● A quantitative procedure performed Route of administration:
for drugs with a narrow therapeutic - The circulatory system is a
index. convenient route that can effectively
● It allows for the safe use of drugs deliver most drugs to its site of
that would otherwise be potentially action.
toxic . - Intravenous route of administration
● TDm ensures that a given drug is associated with 100%
produces maximal therapeutic bioavailability; all drugs enter the
benefit and minimal side effects: blood stream (1.0 bioavailable
achieves a constant serum level of fraction)
the drug that will be therapeutic. - Orally administered drug should
● Most drugs have a half life achieved 0.7 availability fraction
independent of their concentrations. - When drugs are intravenously (most
● The half life of the drug determines immediate route) administered, the
the time to reach the steady- state or distribution and eliminations rates
average concentration . are constant
● Only the free fraction of the drugs - Routes: intravenous , oral ,
can interact with the site of action intramuscular, subcutaneous,
and result in a biologic response. inhalation, suppository, and
● Mixed function oxidase (MFO) transcutaneous
system is the biochemical pathway
responsible for the greatest portion FIVE PHARMACOLOGICAL
of drug metabolism. PARAMETERS THAT DETERMINES
SERUM DRUG CONCENTARTIONS:
INDICATIONS OF TDM
1. The consequences of overdosing 1. Liberation: release of the drug
and under-dosing are serious. 2. Absorption: transport of the drug
2. There are small difference between from the site of administration to the
therapeutic and toxic dose. blood
3. There is poor relationship between 3. Distribution: refers to the delivery of
the dose of the drug and circulating the drug to the tissues
concentrations but a good 4. Metabolism: process of chemical
correlation between circulating modifications of the drug by cells
concentrations and therapeutic toxic 5. Excretion: process by which the drug
effects and its metabolites are excreted
4. There is a change in the patients from the body
physiologic state that may
unpredictably affect circulating drug Absorption
concentrations
 - For a drug to achieve therapeutic Excretion
dose, it must be at the proper - The rate at which a particular drugs
concentrations at its site of action cleared from the circulation is
- Most drugs are absorbed by passive dependent not only on the type of
diffusion- the drug must be in drug itself, but also on a patient’s
hydrophobic state (nonionized) capacity to metabolize and excrete
- Some drugs require uptake by it.
transport mechanism intended for - All drugs are excreted- either
dietary constituents unchanged in the urine, or excreted
- Drugs absorbed from the intestine as metabolites of the parent drug.
enter the hepatic portal system- all - Conversion of a parent drug to its
blood from the GIT is routed through metabolites occurs in the liver (extra
the liver before it enters the general mitochondrial microsomal system of
circulation the hepatocytes-cytochrome p450
- Tablets and capsules requires enzymes.)
dissolution before being absorbed; - Some drugs enter the enterohepatic
liquid solutions are rapidly absorbed circulation and excreted in the stool.
- Weak acids are absorbed in the
stomach; weak bases in the intestine Causes of Drug toxicity:
- Changes in the absorptive 1. Elevated concentration of free drug
characteristics of the drug may be 2. Abnormal response of the drug
due to age, pregnancy or pathologic administration
conditions 3. The presence of active drug
- Factors affecting absorption: metabolites
changes in intestinal movement, ph,
inflammation, and the presence of Terminologies:
food or other drugs
1. Bioavailable fraction (f)- is the
Distribution fraction of the dose that reached the
- The location where the drugs are blood
effective are in the body tissues, not 2. Vd of a drug- represents the dilution
generally in the blood. of the d rug after it has been
- Drugs diffuse widely through the distributed in the body. It is used to
body frequently reaching higher estimate the peak drug blood level
concentrations in tissues than in expected after a loading dose is
blood. given, it is the principal determinant
- The relationship between tissue and of the dose.
blood levels is termed as the 3. First-pass hepatic metabolism-
distribution space. drugs that are transported to the
- A large distributions space indicates liver lost a fraction of its
that much of the drug moving into bioavailability before the drug
the tissues than staying in the reaches the general circulation.
circulation 4. First-order elimination- represents a
linear relationship between the
 amount of drug eliminated per hour ● Class III ( K+ channel blockers) -
and the blood level of the drug. amiodarone
5. Half -life (t1/2)- the time required to ● Class IV (calcium channel blockers)-
reduce a drug level to half of its verapamil
initial value.
6. Peak concentration- is the highest
concentration of a drug obtained in 1. Digoxin
the dosing interval - It is a cardiac glycoside for
7. Pharmacodyamics- is the treatment of atrial arrhythmia
relationship between the drug and CHF.
concentration at the target site and - The therapeutic actions and
response tissues toxicities can be influenced
8. Pharmacogenemics- refers to the by serum electrolytes
study of genes that affect the - Inhibits membrane Na-K
performance of a drug in an ATPase, thus it decreases K+
individual and Mg+, and increases Ca+
9. Pharmacokinetics- is the (cardiac contractility
mathematical expression of the -inotropic effect, 0.8-2ng/mL.)
relationship between the drug dose - 25% is protein bound; free
drug blood level (non bound) form is
10. Therapeutic index- the ratio between sequestered into muscle
the minimum toxic and maximum cells.
therapeutic serum concentration - GIT absorption is variable ;
11. Therapeutic range- the difference change in GFR affect serum
between the highest and lowest concentration
effective dosages - Hyperthyroid individuals are
12. Through concentration- is the resistant to the action of
lowest concentration of a drug digoxin
obtained in the dosing interval - The timing of the blood
collection after last dose can
A. CARDIOACTIVE DRUGS be critical to interpretation of
- These drugs are used for the drug levels
treatment of arrhythmias and - Elimination: renal filtration of
congestive hear failure the plasma free form
(CHF). - Peak serum level: 8 hours
CLASSIFICATION OF CARDIOACTIVE after an oral dose
DRUGS: - Half life: 38 hours (average
adult)
● Class I (rapid sodium channel - Therapeutic level:
blockers) - Quinidine, procainamide, 0.5-2ng/mL
Lidocaine - Toxic level: > 2ng/mL
● Class II (beta receptors blockers)- - Toxic effects: nausea,
propranolol vomiting, visual disturbances,
premature ventricular
 contractions and - Peak serum level: 2 hrs after
atrioventricular node an oral dose ( sukfate); 4-5
blockage. hrs (gluconate)
- Therapeutic level:
2. Lidocaine (xylocaine) 2.3-5ug/mL
- Used to correct ventricular - Toxic levels: >5ug/mL
arrhythmia for treatment of - Toxic effects: cinchonism,
acute myocardial infarction blood dyscrasia, and
- Administered by continuous hepatitis
IV infusion after a loading
dose. 4. Procainamide (pronestyl)
- Can be used as local - Used to treat ventricular
anesthetic arrhythmia
- Bound to album and AAG - GIT absorption is rapid and
- Cannot be administered complete
orally due to almost complete - 20% protein-bound;
hepatic removal of the eliminated by renal filtration
absorbed drug. adn hepatic metabolism
- Elimination: by hepatic - Common route: oral
metabolism; changes in renal - Hepatic metabolite: N-acetyl
function have little effect procainamide (NAPA)
- Primary product of hepatic - Peak serum level: one hr
metabolism: after the dose
monoethylglycinexylidie - Therapeutic level: >12ug/mL
(MEGX) - Toxic effects: reversible
- Therapeutic level: 1.5 4.0 lupus-like syndrome (ANA),
ug/mL nephrotic syndrome, urticaria
- Toxic effect: CHF and heart
block 5. Disopyramide
- Used to treat cardiac
3. Quinidine arrhythmias; used as a
- It is a naturally occurring substitute fro quinidine
drug for the treatment of - Administered orally; GIT
arrhythmia absorption is complete and
- 85% protein-bound; GIT rapid
absorption is complete and - Has anticholinergic effects-
rapid for the sulfate dry mouth and constipation
- Elimination: hepatic (.4.5ug/mL)
metabolism - Elimination: renal filtration
- Route of delivery: oral - therapeutic level: 10ug/mL
administration - Toxic effects: bradycardia
- Common formulations: and atrioventricular node
quinidine sulfate and blockage
quinidine gluconate
 6. propranolol - Used for treatment of
- Beta-receptor blocking drug; gram-negative bacterial
used in the tratment of infections; not given to
angina pectoris, outpatients
hypertension, coronary artery - It is administered IM or IV; it
disease is not well absorbed from the
- Supressesthe ocnversion of GIT
T4 to T3- - it is used in the - May cause damage to 8th
treatment of thyrotoxicosis cranial nerve at toxic levels
- Therapeutic range: 50-100 (hearing loss)
ng/mL - Requires through and peak
- Toxic effects: bradycardia, measurements
arterial insufficiency - Elimination: renal filtration
(raynaud’s type) , platelet - Toxic level: >30ug/mL (
disorder and pharyngitis amikacin and kanamycin)-
peak levels
7. Amiodarione (cordarone) - Toxic effects: nephrotoxicity
- Blocks potassuim channe;s and ototoxicity
in the cardiac muscle; use for
treatment for ventricular 2. Vancomycin
arrhythmias - Gkycopeptide effective
- Iodine-containing drug which against gram-positive cocci
can cause hyperthyroidism or and bacilli
hypothyroidism - Poor oral absorption;
- Therapeutic level: .2.5ug/mL administered IV infusion
- Toxic effects: bradycardia, - Toxic side effects occur in the
hepatitis, photodermatitis, therapeutic range (5-10
and thyroid dysfunction ug/mL)
- Only the trough levels are
8. verapamil monitored to ensure the
- Used for treatment of angina, serum drug concentration is
hypertension and within the therapeutic range
supraventricular arrhythmias - Elimination: renal filtration
- Therapeutic range: 80-400 and excretion
ng/mL - Toxic effects: “ red man
- Toxic effects: hypotension, syndrome” nephrotoxicity
peripheral edema and and ototoxicity
ventricular fibrillation - Toxic levels: >10ug/mL-
nephrotoxicity
B.ANTIBIOTICS - >40ug/mL - ototoxicity
1. Aminoglycosides (gentamicin,
tobramycin,amikacin,kanamycin, 3. Chloramphenicol
Neomycin, streptomycin) - Distributes to all tissues, and
it concentrates in the CSF
 - 50% protein bound: rapidly - It controls seizures (
absorbed in the GIT tonic-clonic, simple partial
- Toxic effects: blood seizures); a short-term
dyscrasia, cytoplasmic prophylactic agent in brain
vacuolation (erythroid & injury
myeloid cells) - Not used for petit mal and
- Toxic level: >25 ug/mL atomic seizures
- Decreases sodium and
C. ANTIEPILEPTIC DRUGS calcium influx into
1. Phenobarbital hyperexcitable neurons
- Long acting barbiturate that - IV administered ; GIT
controls mal tonic-clonic absorption is incomplete
seizure and focal epileptic ; - 87-97% protein bound; free (
not used for petit mal seizure unbound) form is the
- Used for treating withdrawal biologically active portion
symptoms in infants-mothers - Toxicity may be seen at the
that are addicted to opiate or level of therapeutic range
barbiturate. - Elimination: hepaticpathway
- Used to treat cases of (zero-order kinetics)
congenital hyperbilirubinemia - Major toxicity: initiation of
(this drug enhances bilirubin seizures; teratogenic action
metabolism (cleft lip and palate ) and
- Absorption is slow but nystagmus
completes; 50% - Therapeutic range: 10-20
protein-bound ; majority is ug/mL; 1-2 ug/mL ( free form)
stored in the brain - Toxic level: >20 ug/mL
- Renal impairment slows - Injectable proform:
down elimination process fosphenytoin
- Elimination: hepatic
metabolism 3. Valproic acid (depakene)
- Inactive proform: primidone - Used for treatment of petit
(mysoline); half life: 70-100 mal (absence seizure),
hrs atomic seizure and grand
- Peak serum level: 10 hrs mal
after an oral dose - Orally administered; GIT
- Therapeutic level: 20-40 absorption is rapid and
ug/mL (phenobarbital) / 5-12 complete
ug/mL (primidone) - Highly protein bound (93%)
- Toxic effects: nystagmus, - Hepatic dysfunction is
stupor,ataxia,and respiratory observable which requires
depression monitoring after 6 mos of
therapy
2. Phenytoin ( dilantin) - Elimination: hepatic
metabolism
 - Therapeutic level: 50-100 6. Gabapentin (neurontin)
ug.mL - Chemically similar to
- Toxic level: >100 ug/mL neurotransmitter gamma
(nausea, lethargy and weight aminobutyric acid (GABA)
gain), >200 ug/mL - Used for partial seizures; for
(pancreatits, hallucinations adjunctive therapy
and hyperammonemia) - Administered orally, unbound
to plasma proteins
4. Carbamazepine (tegretol) - Excreted unchanged in the
- Tricyclic compound related to urine, not metabolized in
imipramine (TCA) humans
- Effective for grand mal - Adverse effects: dizziness,
seizures and treating ataxia, fatigue, and
seizures accompanied by nystagmus
pain - Therapeutic level: 2-15
- Has antineuralgic action; ug/mL
70-80% protein- bound - Toxic effects: ataxia and
- Has serious toxic effects and somnolence (drowsiness)
not frequently used: orally
administered 7. Topiramte- used as adjunct drug
- Elimination: hepatic forpartial seizures
metabolism 8. Lamotrigine (lamictal)- used as an
- Idiosyncratic effects- rashes, adjunct drug for patial seizures
leukopenia, nausea, vertigo, 9. felbamate
febrile reactions
- Therapeutic level: 4-16 ug/ml D.PSYCHOACTIVE DRUGS
- Toxic level:. 12 ug/mL 1. Lithium
- Toxic effects: hematologic - Used for treatment of
dyscrasias, aplastic anemia, manic-depressive illness
and pancytopenia (bipolar disorders)
- Drug of choice for the
5. Ethosuximide (zarcontin) prevention of chronic cluster
- Drug of choice for controlling headache
petit mal (absence seizure); - Inhibts thyroid hormone
orally administered synthesis and release-
- It is free in the serum and not inhibits iodine uptake
protein bound - Cationic metal that does not
- Therapeutic level: 40-100 bind to proteins
ug/mL - Orally administered;
- Toxic level: > 100ug/mL absorption is rapid and
- Toxic effects: GI complete
disturbances, ataxia,SLE, - Distribution of this drug is
aplastic anemia, and uniform througout the body of
pancytopenia water
 - Subject to reabsorption - Blocks the re-uptake of
- Lithium and demeclocylcine serotonin in centra;
inhibit the effect of ADH ion serotonergic pathways
the kidney - Also used for treatment of
- Elimination: renal filtration obsessive-compulsive
- Therapeutic range: 0.8-1.2 disorders
mmol/L - Toxic effects: attempted
- Toxic effects: severe suicide, decreased libido and
dehydration, nephrotoxicity, sexual function
and hypothyroidism - Therapeutic level: 90-300
- Toxic level: 1.2-3 mmol.L- ng/mL
apathy, lethargy, speech
difficulties E. Bronchodilator
>2 mmol/L- seizures, muscle Theophylline
rigidity and coma - Belongs to methylated xanthine
class
2. Tricyclic antidepressants (TCAs) - Action is specific to the relaxation of
- Used for treatment of bronchial smooth muscle
depression, insomia,extreme - Used for asthma treatment and
apthy and loss of libido chronic obstructive pulmonary
- Orally administered with disease
variability in absorption ( slow - Drug for primary apnea of
gastric emptying and prematurity (absence of respiratory
intestinal motility) effort in newborn infants)
- Examples: imipramine, - Its action is inhibitory to the release
amitriptyline, doxepin, of histamine and other pro
nortriptyline, trazodone inflammatory agents
- Elimination: hepatic - 50% protein bound ; initially
metabolism administered intravenously then
- Toxic effects: drowsines, orally
blurred vision, memory loss, - Crosses the placenta and may be
seizure, cardiac arrhythmia, teratogenic in pregnant females
parkinsonian - Best predictor of toxicity is the blood
- Syndrome and level of the drug and not early signs
unconsciousness it symptoms of toxicity
- Peak serum concentration: - Elimination: renal filtration and
2-12 hours hepatic metabolism
- Therapeutic level: 100-300 - Therapeutic level : 10-20 ug/mL
ng/mL - Toxic level: >20 ug/mL
- Major metabolite: - Toxic effects: GI bleeding, seizures,
desipramine tachycardia. And syncope

3. Fluoxetine (prozac)
F. IMMUNOSUPPRESIVE DRUGS - Toxic effects: thrombus
1. Cyclosporine formation, nephrotoxicity and
- Inhibits the cellular immune neurotoxocity
response by blocking
production of interleukin-2 3. Rapamycin (sirolimus)
- Used to prevent rejection of - Similar to tacrolimus; major
allogenic organ transplants side effects are lipid
- Used for suppression of abnormalities and
acute graft- versus host thrombocytopenia
disease (GVHD)
- The organs such as the 4. Mycophenolate mofetil
heart, liver, and pancreas - It decreases renal allograft
requires high dosage (300 rejection
ng/mL) 5. Leflunomide (LFM)
- Has marked affinity with - Inhibits lymphocyte
RBC; RBC-cyclosporine is proliferation; for treatment of
temperature dependent rheumatoid arthritis
- Orally administered with
5-50% absorption G. ANTINEOPLASTIC DRUGS
- Elimination: hepatic 1. Methotrexate
metabolism - An effective therapy for a
- Specimen of choice: whole variety of neoplastic
blood (with lysis of RBC to conditions; also an
yield the total amount) immunosuppressive agent
- Toxic level: >500 ng/mL - Inhibits DNA synthesis in all
- Toxic effects: renal tubular cells, by blocking
and glomerular dihydrofolate reductase
dysnfucntions, GI - Leucovorin is used to reverse
distrubances, hirsutism and the action of methotrexate -
hematologic dyscrasia leucovorin rescue
- Toxic level: 0.01 umol/L
2. Tacrolimus (Progaf/ Fk-506) - Toxic effects: leucopenia, GI
- Is 100x more powerful than ulceration,thrombocytopenia,
cyclosporine cirrhosis
- Take Macrolide lactone
antibiotic; GIT uptake is 2. Busulfan
variable - It is an alkylating agent used
- Elevated levels are observed to treat leukemias and
in cholestasis lymphomas prior to bone
- Elimination: hepatic marrow transplantation
metabolism
- Specimen of choice: whole H. ANTI-INFLAMMATORY/ ANALGESICS
blood 1. salicylates/ aspirin (acetysalicylic
acid)
 - Commonly used analgesic, - Method; HPLC
antipyretic and
anti-inflammatory drug 3. ibuprofen
- Direct stimulator of the - Has analgesic and
respiratory system and anti-inflammatory actions
inhibitor of the kreb’s cycle - Has lower risk of toxicities
- Has an anticoagulant than salicylates and
property (anti platelet activity) acetaminophen
by inhibiting the action of - Toxic effects: nausea,
cyclooxygenase vomiting, blurred vision,
- Function: decreases abdominal pain, edema
thromboxane and - Therapeutic level: >100
prostaglandin formation ug/ml
through inhibition of I. Neuroleptics (antipsychotic major
cyclooxygenase tranquilizers)
- Acute aspirin intoxication: - Blocks the action of
common cause of fatal drug dopamine and serotonin in
poisoning in children the limbic system
- Side effects: gastrointestinal - Used in the treatment of
disturbance and interference acute schizophrenia
with platelet aggregation - Monitoring of these drugs in
- Therapeutic level: 5mg/dL serum is difficult due to
(treatment of headache) abundant metabolites for
- Toxic level: >30mg/dL each drug resulting to
- Toxic effects: mixed extensive metabolism in the
acid-base disturbance liver
(metabolic acidosis and - 2 classes: phenothiazines
respiratory alkalosis), (chlorpromazine) and
hypoglycemia and reye’s butyrophenones (haloperidol)
syndrome - Examples: risperdal,
- Method: Trinder assay; olonzapine (zyprexa),
enzymatic assay (salicylate quetiapine (seroquel),
hydroxylase); HPLC; EMIR aripiprazole (abilify)
- Toxic effects:
2. Acetaminophen (tylenol) cholestasis,orthostatic
- Inhibitor of prostaglandin hypotension, aplastic
metabolism anemia, muscle rigidity
- Commonly used as analgesic
and antipyretic drug Methods for TDM:
- Overdosage of this drug - Specimen of choice: serum or
leads to hepatoxicity plasma
- Therapeutic level: >50ug/mL - Whole blood EDTA sample is
- 100-300 ug/mL (hepatic required for cyclosporine and
necrosis) tacrolimus test
 - Timing of specimen collection is the - Acetaminophen in urine is detected
single most important factor in TDM by boiling to form p-amphenol which
- TDM samples should not be then reacts with o-cresol to form
collected in tubes with gel indophenol blue.
separators or SST- some gels - Trinder assay for salicylate using
absorb certain drugs (phenytoin, ferric nitrate forming a (+) colored
phenobarbital, lidocaine, quinidine, complex
and carbamazepine) causing a
falsely low result. 2. Immunoassay methods
- No changes occurred in theophylline - Provides rapid analyses of blood
and salicylate levels when blood is and urine samples
collected in serum separator tube - Can detect drug levels in the
(SST) nanomolar range; sensitive and
- Measurement of serum specific methods
concentrations should be done only - Uses antibody specifically reactive
after steady state has been with a particular drug- the drug must
achieved. bind to antibody before it is identified

Specimen considerations: a. Enzyme- mediated ( multiplied)

1. Trough concentrations are drawn immunologic technique (EMT)
immediately (or 30 minutes) before - The amount of enzyme activity is
the next dose directly proportional to the amount of
- The trough level is affected by the drugs present in the sample
drug clearance rate- if clearance
increases, then through level b. Flourescence polarization
decreases Immunoassays (FPIA)
- Trough concentrations reflects the - The binding of the marker
lowest level of drug in the blood drug to antibody can be
2. Peak concentrations are drawn one quantitated by the angle at
hour after an orally administered which the emissions occur
dose (except digoxin ) - The drug is attached to a
- The peak blood sample ( sample fluorescent label or
after absorption and distribution is fluorophore
complete) is the best specimen for
initial investigation of therapeutic 3. Chromatographic methods
drug toxicity- it is most likely to Best specimen: urine
exceed the upper therapeutic limit a. Thin layer chromatography
- For IV drugs, peak levels are - Uses serum, urine , or gastric fluid
determined after the infusion is for analysis ( for toxicology testing)
completed - Can demonstrate the presence of
- Increasing the dose rate may result multitude abuse of drugs
in peak drug levels in the toxic range - Qualitatively identifies drugs by
mean means of their Rf values
1. colorimetry
 - Drugs are identified according to physiologically active and the
how far they have traveled or presence of a higher than expected
separated and to how they appear concentration of free dug.
with each of the stains - Some drugs with wide therapeutic
- Extraction of drugs is pH dependent- index are potentially toxic because
acidic drugs at pH 4.5 and alkaline they may be ingested in great
drug at pH 9.0 excess with little or no initial toxicity
- Most drugs follows first- order
b. High performance liquid pharmacokinetics- the clearance of
chromatography (HPLC) the drug is linearly related to the
- Highly quantitative procedure dose of the drug
- Measurement depends on the type - Trough and peak levels are
of column used, the solvent and characteristics of intermittent dosing
detector systems regiments
- Ideal for separation of tricyclic anti - Steady- state drug level is reached
depressants and its metabolites when drug in the next dose is
sufficient only to replace the day
c. Gas chromatography- Mass eliminated since the last dose
spectrophotometry (GC- MS) gold - Steady- state drug level can be
standard measured after five drug half lives
- Used for the quantification of many bacuase blood levels will have
drugs reached 97% of steady state
- Drugs must be volatile in form or can - If the steady- state is too high,
be chemically derivatized into decrease the dose
volatile form
- MS can be added onto effluent and
of GC, enhancing its capability to FORMULA:
quantify drug 1. BIOAVAILABLE FRACTION FOR
ORAL ADMINISTRATION
Note: for complete explanation on the - F = peak blood concentration after
above- mentioned chromatography oral administration/ peak drug
principles, please refer to the previous concentration after IV
discussions on analytical methods administration
2. ESTIMATE DOSAGE TO GOVE A
Notes to remember: STEADY-STATE BLOOD LEVEL
- Individual differences alter - Dose/ hr = clearance (mg/hr) x
pharmacokinetics, causing lack of average concentration at steady
correlation between dose and drug state ) / f
level 3. Vd = Xo / Ca
- Altered pharmacokinetics may result 4. Peak blood level = (Dose) (f) (Vd)
in toxicity even when the dose o 5. K = 0.693 / half life (t1/2)
drug is within accepted therapeutic 6. DOSAGE ADJUSTMENT TO
range - cause by the presence of ACHIEVE THE DESIRED BLOOD
unmeasured metabolites that are LEVEL
New dose = current dose /
concentration at steady state (
desired concentration )