Pharmacokinetics: Concerned with the study and characterization of the time course of drug absorption, distribution, metabolism and excretion, and with the mathematical relationships required to develop models to interpret such date.
Clinical pharmacokinetics:A health science discipline dealing with the application of pharmacokinetics to the safe and effective therapeutic management of the individual.
Volume of Distribution (Vd)
(a) Non-physiologic volume into which the drug disperses after it is absorbed.(b) Does not represent a real body space. Vd may be affected by:
1. Body size and composition-fat, muscle, total body water, extracellular water.
2. Physical-chemical characteristics of drugs-pka, molecular weight, solubility.
Bioavailability (F) = 0 to 1
(a) Extent to which drug reaches the general circulation or becomes systemically available.
(b) Vancomycin & aminoglycosides given intravenously: F=1 (100%). <Top>
(a) 5 half-lives to be approximately 97% of steady state.
(b) At steady state the rate of drug administration is equal to drug
elimination and the mean concentration remains constant. <Top>
Elimination Rate Constant (kel)
(a) The fraction of the amount of drug in the body eliminated per unit time.
(b) For drugs eliminated by first-order kinetics<Top>
(a) Time required for serum concentration to decrease by one-half the original value.(b) T1/2 = 0.693/kel
Creatinine Clearance (ml/min)
(a) Creatinine is a metabolic by-product of muscle and an individual's
muscle mass or lean body weight primarily determines its rate
(b) Cockcroft and Gault equation:
CrCl: (140 - age) x IBW / (Scr x 72) (x 0.85 for females)
IBW (Ideal body weight)
Males: IBW = 50 kg + 2.3 kg for each inch over 5 feet.
Females: IBW = 45.5 kg + 2.3 kg for each inch over 5 feet.<Top>
First Order Elimination
(a) Rate of biotransformation is proportional to the amount of drug in the
apparent compartment in which the site of biotransformation is located.
(b) A direct proportionality exists between drug concentration at any specified
time and the size of the dose.
(c) Kel (elimination rate constant) is equal to the slope of the line of
[Log conc vs time plot].
(d) One-compartment model: Immediate and uniform, complete drug
distribution into a single compartment followed by elimination.
(e) Two-compartment model: Distribution initially into a central compartment,
followed by a gradual equilibration with a peripheral compartment.<Top>
<Top> Overview: Aminoglycosides: not absorbed orally; IV route primary route of administration-occasionally given IM; quite hydrophilic-distributes primarily in extracellular fluid~25% of body weight; relatively poor tissue penetration; protein binding (20-30%)-not clinically significant; well distributed except for the eye, CNS, CSF. Must be given intrathecally for CNS infections. Increased Vd seen in CHF, peritonitis, ascites, acute burn injury, s/p surgery, immediately post partum patients. Exhibits concentration dependent bactericidal activity. MIC: (Tobra/Gent): Susceptible: < 4 mg/l Intermediate: 8 Resistant: >16. Increasing the peak, will result in an increased post-antibiotic effect.Vancomycin: Given IV only (IM very painful). Exhibits time-dependent or concentration independent bactericidal activity. MIC's: Susceptible: <4 mcg/ml. Intermediate: 4-16 mcg/ml. Resistant: > 16 mcg/ml. Protein binding: 30-55%; Vd (range): 0.5 to 0.9 L/kg. Follows a two-compartment model (prolonged distribution-well distributed).
Mechanism of Action (a) Aminoglycosides are rapidly bactericidal. They irreversibly bind to the
30 s bacterial ribosome; protein synthesis is thereby inhibited and cell death
ensues. Uptake into bacterial cells is facilitated by cell wall inhibitors
(Vancomycin and beta-lactams).(b) Vancomycin is bactericidal against most sensitive organisms except
enterococci. Vancomycin inhibits bacterial cell wall synthesis by interfering with
Distribution Aminoglycosides enter most body fluids well approximating extracellular fluid. (excluding pulmonary tissue, fatty tissue, abscess).Vancomycin is widely distributed throughout the body.
The volume of distribution of the aminoglycosides and vancomycin can be quite variable and can vary widely from patient to patient. It is one of the key factors in the determination of the peak and trough concentration.
Any factor that can alter the extracellular fluid can affect the volume of
*Dehydration: Decreased Vd.
*Chronic renal failure, CHF, ascites, obesity: Increased Vd. <Top>
Is the drug appropriate?
Is the dose appropriate?Specific patient parameters
(a) Age, sex, height, weight, IBW.
(c) Current antibiotic therapy
(d) Infectious diagnosis
(e) Renal and hepatic function
(f ) Concurrent disease states/diagnoses that may impact therapy
(eg. cachexia, diabetes mellitus, bilateral AKA, etc.)
(g) Clinical signs and symptoms (Temp, RR, HR etc)
(h) Laboratory tests: gram stains, culture and sensitivity results, CBC & diff,
Scr, BUN, WBC, I/O (past 24 hours)
(i ) Determination of optimal blood levels based on diagnosis.
Is the drug working?
Is the patient experiencing any adverse effects from the drug?Treatment failure:
Temperature or WBC increasing; symptoms increasing.
Note: changes in renal function may not reflect nephrotoxicity.
Other causes of acute renal failure occurring
in hospitalized patients, include:
- Severe or prolonged hypotension (decreased renal perfusion)
- Other nephrotoxic drugs: amphotericin, cisplatin, etc.
- Acute cardiovascular dysfunction
<Top>Is the patient responding to treatment?
Look for reversal of initial signs and symptoms.
-Is the patient's temperature decreasing?
Culture results negative?
-Heart rate and respiratory rate returning to normal?
-Is the white blood cell count decreasing?
-Normalization of blood gases?
Is the current regimen appropriate?
Is the patients renal function stable?
Are current serum levels (peak and trough) appropriate?
Is the drug still required?
Major: Vestibular toxicity; auditory toxicity;
renal toxicity (reversible); neuromuscular toxicity (post-synaptic
Minor: skin rash; drug induced fever.
What to look for: Changes in urine output; BUN,
creatinine, ototoxicity (hearing tests).]
Red man syndrome (histamine-like reaction characterized by flushing,
tingling, pruritis, tachycardia, and a red rash on the face,neck,upper
torso, back and arms.
Management: slow rate of infusion, dilute drug in sufficient diluent,
anti-histamine prophylaxis); Nephrotoxicity (reversible)-incidence
(<5%); ototoxicity (may be irreversible); neutropenia; thrombophlebitis;
skin rash.<Top>Monitoring for toxicity:
1. Auditory and neuromuscular toxicity are not evaluated in most patients.
If prolonged courses of aminoglycosides are anticipated, baseline and
periodic assessment of hearing with audiometry are recommended.
Neuromuscular toxicity is most likely in patients with preexisting
neuromuscular disease or patients with hypocalcemia.
2. Serum creatinine and BUN determinations 2-3 times/week should monitor
renal toxicity. More frequent determinations are advised for patients with
changing renal function. Creatinine clearance, I/O's, urinalysis, when
available will help to identify patients with possible nephrotoxicity.
3. Risk factors for Nephrotoxicity: Age, renal insufficiency, elevated trough concentrations, total daily dose, cumulative dose, concurrent nephrotoxic
drugs, prior aminoglycoside exposure, duration of treatment.
4. Toxicity usually takes 5-7 days to develop. Mechanism: damage occurs
to the cells lining the proximal tubules.
5. The process of nephrotoxicity (uptake by cells) is saturable and the
number of insults determines toxicity. It is imperative to minimize the
number of insults and allow the tubular cells a relatively drug free
period in which to regenerate cells.
Criteria for Selecting the Appropriate times for Collecting
Serum Drug levels
<Top> Indications for serum concentration monitoring: (1) Patients with compromised renal function (CrCl <50 ml/min) and/or
unstable renal function (an increase or decrease in serum creatinine
> 0.3 mg/dl).
(2) Projected courses of therapy of > 7 days.
(3) Suspected treatment failures.Patients not requiring levels include those in whom the assessed
dosage regimen is adequate and (1) CrCl >50 ml/min and stable
(< 0.3 mg/dl changes in serum creatinine) and
(2) Projected course of therapy is < 7 days, and infections are unlikely
to be complicated.
Frequency of serum level determinations:
A. Weekly levels are advised for patients with stable renal function
as noted above.
B. Levels may be advised more frequently than once weekly in patients
exhibiting conditions predisposing them to pharmacokinetic variability
(1) Fluid overload or dehydration
(2) Rises in serum creatinine above baseline of > 0.3 mg/dl
(3) Acute cardiac, and/or renal decompensation.
(4) Severe hypotension (decreased renal perfusion)
(6) Ascites (increased Vd)
(7) Burn patients (usually see increases in kel)
(8) Cystic fibrosis patients (increases in kel)
(9) Surgery patients
Draw levels off the third dose for:
-Patients with normal renal function based on Creatinine/Bun, I/O's,
medical history; concomitant drug therapy, and hydration status. When to draw levels: Aminoglycoside: Peak/trough: 30 minutes before
and after a 30 minute infusion. Vancomycin: Peak: 60 minutes after the infusion. Trough: 30
minutes prior to next dose. <Top>
Draw levels off the first dose for:
- Patients with abnormal renal function based on BUN/SCR; I/O's,
edema, history of renal or cardiac disease.
- Patients receiving other nephrotoxic drugs.
- Patient is neutropenic, febrile, and/or unstable.
- Patient has unstable or increasing serum creatinine. When to draw levels: 1st level: aminoglycoside: 30 minutes post infusion. Vanco: 60 minutes post
infusion. 2nd level: at least one
half-life (depending on drug) after the 1st level.
Aminoglycoside / Vancomycin Worksheet
(Step by Step)
(1) Obtain baseline data:
Patient age, sex, height, weight, allergies, diagnosis, infection site, current
drug therapy, I/O's for past 24 hours, Tmax, WBC with diff, albumin,
Past medical history, Lab work-up: Scr, Bun, cultures etc. (2) Estimate Ideal body weight in (kg)
Males: IBW = 50 kg + 2.3 kg for each inch over 5 feet.
Females: IBW = 45.5 kg + 2.3 kg for each inch over 5 feet.
(3) If the actual body weight is greater than 25 - 30% of the calculated
IBW, calculate the adjusted body weight (ABW):
ABW = IBW + 0.4(Total body weight - IBW)
(4) Estimate Creatinine Clearance: (ml/min)
Cockcroft and Gault equation:
CrCl: (140 - age) x IBW / (Scr x 72) (x 0.85 for females)
Note: if the ABW (actual body weight) is less than the IBW use the
actual body weight for calculating the CRCL. If the patient is >65yo and
creatinine<1, use 1 to calculate the creatinine clearance.
<Top>(5) Estimate kel (Elimination rate constant):
Amikacin /Gentamicin/Tobramycin: Kel = (0.00285 x CrCl) + 0.015
May also use: (0.003 x CrCl) + 0.01
Vancomycin: kel = 0.0016 x Crcl
The above equations provide an estimate of the elimination rate
constant based on population kinetics. The following may decrease
the usefulness of these equations:
*Renal failure, CHF, Burn patients, cystic fibrosis, severe hypotension, rapidly changing renal function. (Burn victims
and patients with cystic fibrosis usually have increased
rates of elimination. Patients with CHF or severe hypotension
will have decreased rates of elimination due to decreased
Kel determination from reported levels:
kel = (Ln C1 / C2) / (t2 - t1)
C1= actual or extrapolated Peak; or post peak level
C2= actual or extrapolated trough; or random level
Drawn at least 1.5 x estimated half-life after first level.
(t2 - t1) = Time difference between levels.
(6) Estimate half-life (T1/2) in hours:
T1/2 = 0.693 / Kel
(7)Estimate Volume of Distribution (Vd): (Liters) Aminoglycosides:
Use IBW unless obese, then use ABW= 0.4 x (TBW-IBW) + IBW
Vd (Normal) = 0.25 to 0.3 L/kg
Bun/Cr ratio 10 to 15:1 (nml). Patient normally hydrated or a
patient that will return rapidly to normal status.
Vd (overhydrated) = 0.35 to 0.4 L/kg.
Bun/Cr ratio < 10:1 , patients with ascites; edema, chronic renal
failure, severe hypalbuminemia (less than 2.5 gm/dl)-promotes
[Use actual body wt unless obese (> 30% over IBW)-then use adjusted
body weight = 0.4(TBW- IBW) + IBW.]
Vd (Normal): 0.6 to 0.7 L/kg (usually 0.65)
(dehydrated): 0.5 to 0.6 L/kg
(overhydrated): 0.7 to 0.85 L/kg
<Top> Volume of distribution calculation based on actual or
extrapolated peak and trough concentrations:
Vd = MD x (1-e-kti) / (k) (ti) [Cmax - (Cmin e-kti)]
Rybak M, Lomaestro B, Rotschafer JC, et al. (2009). "Therapeutic monitoring of vancomycin in adult patients: A consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists". American Journal of Health-System Pharmacy 66 (1): 82–98.
Direct quotes from this reference (Rybak et al.):
"Further, data derived from more recent studies appear to suggest that vancomycin has little potential for nephrotoxicity or ototoxicity when used at conventional dosages (e.g., 1 g every 12 hours [15 mg/kg every 12 hours]), unless it is used concomitantly with known nephrotoxic drugs or at very high dosages."
Recommended TDM Parameters- Optimal monitoring parameter: "Trough serum vancomycin concentrations are the most accurate and practical method"
Timing of monitoring: "Troughs should be obtained just prior to the next dose at steady-state conditions (approximately after the fourth dose)."
Optimal trough concentration (see also Optimal trough concentration—complicated infections) : "Minimum serum vancomycin trough concentrations should always be maintained above 10 mg/L to avoid development of resistance. For a pathogen with an MIC of 1 mg/L, the minimum trough concentration would have to be at least 15 mg/L to generate the target AUC:MIC of 400."
Criteria for monitoring: "Data do not support using peak serum vancomycin concentrations to monitor for nephrotoxicity."
"Trough monitoring is recommended for patients receiving aggressive dosing (i.e., to achieve sustained trough levels of 15–20 mg/L) and all patients at high risk of nephrotoxicity (e.g., patients receiving concurrent nephrotoxins). Monitoring is also recommended for patients with unstable (i.e., deteriorating or significantly improving) renal function and those receiving prolonged courses of therapy (more than three to five days)."
Summary and recommendations:
"Vancomycin dosages should be calculated on ABW. For obese patients, initial dosing can be based on ABW and then adjusted based on serum vancomycin concentrations to achieve therapeutic levels. Continuous infusion regimens are unlikely to substantially improve patient outcome when compared with intermittent dosing. (Level of evidence = II, grade of recommendation = A.)"
"Trough serum vancomycin concentrations are the most accurate and practical method for monitoring vancomycin effectiveness. Trough concentrations should be obtained just before the next dose at steadystate conditions. (Level of evidence = II, grade of recommendation = B.) (Note: Steady-state achievement is variable but occurs approximately after the fourth dose.)"
"Based on evidence suggesting that S. aureus exposure to trough serum vancomycin concentrations of <10 mg/L can produce strains with VISAlike characteristics, it is recommended that trough serum vancomycin concentrations always be maintained above 10 mg/L to avoid development of resistance. (Level of evidence = III, grade of recommendation = B.)"
"Based on the potential to improve penetration, increase the probability of optimal target serum vancomycin concentrations, and improve clinical outcomes for complicated infections such as bacteremia, endocarditis, osteomyelitis, meningitis, and hospital acquired pneumonia caused by S. aureus, total trough serum vancomycin concentrations of 15–20 mg/L are recommended. Trough serum vancomycin concentrations in that range should achieve an AUC/MIC of 400 in most patients if the MIC is 1 mg/L. (Level of evidence = III, grade of recommendation = B.) In order to achieve rapid attainment of this target concentration for seriously ill patients, a loading dose of 25–30 mg/kg (based on ABW) can be considered. (Level of evidence = III, grade of recommendation = B.) A targeted AUC/MIC of 400 is not achievable with conventional dosing methods if the vancomycin MIC is 2 mg/L in a patient with normal renal function (i.e., CLcr of 70–100 mL/min). Therefore, alternative therapies should be considered. Vancomycin dosages of 15–20 mg/kg (based on ABW) given every 8–12 hours are required for most patients with normal renal function to achieve the suggested serum concentrations when the MIC is 1 mg/L. It should be noted that currently available nomograms were not developed to achieve these targeted endpoints. Individual pharmacokinetic adjustments and verification of serum target achievement are recommended. When individual doses exceed 1 g (i.e., 1.5 and 2 g), the infusion period should be extended to 1.5–2 hours. (Level of evidence = III, grade of recommendation = B.)"
"Available evidence does not support monitoring peak serum vancomycin concentrations to decrease the frequency of nephrotoxicity. (Level of evidence = I, grade of recommendation = A.) Monitoring of trough serum vancomycin concentrations to reduce nephrotoxicity is best suited to patients receiving aggressive dosing targeted to produce sustained trough drug concentrations of 15–20 mg/L or who are at high risk of toxicity, such as patients receiving concurrent nephrotoxins. (Level of evidence = III, grade of recommendation = B.) Monitoring is also recommended for patients with unstable renal function (either deteriorating or significantly improving) and those receiving prolonged courses of therapy (over three to five days). (Level of evidence = II, grade of recommendation = B.) All patients receiving prolonged courses of vancomycin should have at least one steady-state trough concentration obtained (approximately after the fourth dose). Frequent monitoring (more than a single trough concentration before the fourth dose) for short-course therapy (less than five days) or for lower-intensity dosing (targeted to attain trough serum vancomycin concentrations below 15 mg/L) is not recommended. (Level of evidence = II, grade of recommendation = B.)"
(9). Select Time of Infusion (ti):
(a) Aminoglycosides: 30 minutes (0.5 hrs)
(b) Vancomycin: 0-500 mg/ 0.5 hrs ; 501 to 1250 mg/ 1 hour ;
1251 to 1750/ 1.5 hrs ; >1750/ 2 hours. (10) Calculate Loading Dose:___________(mg).
Gentamicin/Tobra: 1.5-2.5 mg/kg x ABW (usually 2 mg/kg)
Amikacin: 6-7.5 mg/kg x ABW
Vancomycin: Loading doses may be administered to moderately to severely ill patients requiring rapid attainment of therapeutic levels.
<Top>(11) Calculate Dosing Interval (T)hrs.
T = Ln (Cmax/Cmin) / kel + ti or estimated T = 3 x T1/2
(12) Calculate Maintenance dose (MD):_____mg.
MD = [(kel) x (Vd) x (ti) x (Cpeak desired) x (1 - e-kT)] / (1 - e-kti)
or MD = (Cpeak desired) x Vd (eg: C = D/V, therefore D=C*V)
(13). Calculate Predicted Peak and Trough at Steady State.
Cmax = [Dose * 1-e-kti] / (kel)(Vd)(ti) 1-e-kT
Summary: Chart Documentation
(All documentation should follow this format).
(1) Identify service: "Pharmacokinetic dosing service" or "Clinical
(2) Record time and date.
(3) List day of therapy for all antibiotics<Top>Pharmacokinetic Dosing Service -Gentamicin Day #2
O: (Objective) Patient is an 86yo, M, 5'6" , 140# (65kg), IBW= 65kg.
(Pt has S/Sx of pneumonia). Dx: PneumoniaBUN: 12
Creat: 1.2 WBC =16.1 Tmax: 102.2 I/O= 3850/ 3640 (24hrs)
Current antibiotic regimen: Ancef 1 gram ivpb q8h and
Gent 80mg ivpb q12h.
* (Normally include patient age, sex, admission diagnosis, medical
history, allergies, current drug therapy, and reason for
placing pt on the consult drug).
A: (Assessment) Estimated CrCl= 34 ml/min yielding a Gent T1/2 of
7.2 hrs suggesting an 18hr dosing interval. A gent peak of 8 mcg/ml
is desirable for adequate pulmonary penetration. Bun/Scr =22:
Somewhat dehydrated-should result in smaller Vd. Albumin wnl.
*(Under assessment-may include: Ht, Wt, IBW, BUN/Cr, I/O's,
albumin, other pertinent lab data, pharmacokinetic parameters,
and predicted drug concentrations. Should also include specific
data relating to infectious process: WBC, cultures & sensitivities,
chest X-ray etc.)
(1) Change gent to 100mg q18h for
estimated peak of 7.7 and trough of 0.9.
(2) Obtain Peak and trough on
Friday around 0600 dose (30 min before and 30min post infusion).
(3) Decrease Ancef to 1gram q12h
(4) Monitor BUN and creat 3 x weekly.
Thank you for the consult, will continue to follow.
John Doe R.Ph.
<Top>(Overview of recommendation: Based on patient data and disease state
recommend a dosing regimen on the consult drug. Indicate the predicted
concentrations. Recommend the appropriate times to measure drug
concentrations. Evaluate the patient's other medications and recommend
dosing adjustments as necessary. Contact the physician and verbally
state the recommendations and document this in the patient's medical
Mr. Smith is a 43 yo male. Diagnosis : aspiration pneumonia. Social history:
chronic alcoholic. Height: 6'2" Weight: 70kg. Scr: 0.7 mg/dl. Bun: 12 mg/dl.
Patient is started on Piperacillin 3 grams q4h and gentamicin 140 mg load.
Physician requests consult.
(1) Estimated IBW= 50 kg + (2.3 x 14) = 82.2 kg(2) Estimated Crcl = (140-age) x IBW / 72 x SCR =
[(140- 43) x 70] / 72 x 1.0 = 94.3 ml/min
(Note: used ABW because ABW<IBW. Also rounded SCR to 1,
in order to compensate for "cachectic" nature of patient.)
(5) Estimate Vd: BUN/Scr = 17 (assume nml hydration).
Vd= 0.25 L/kg x 70 kg = 17.5 liters. (may use 0.25 to 0.3)
(6) Select infusion time: Use 0.5 hrs for aminoglycosides.
(7) Determine desired peak and trough concentrations:
For the treatment of pneumonia, higher levels are req'd in order to
to get adequated pulmonary penetration.
Desired Cpeak: 8-10 mcg/ml Cmin<1 mcg/ml ideally.
(8) Calculate dosing interval (T):
(a) Quick method: T = 3 x T1/2 = 3 x 2.44 = 7.3 hrs (Interval =8hrs)
(b) Longer method: T= Ln (Cmax/Cmin) / Kel + ti
= Ln(8/1)/0.284 + 0.5 = 7.82 hrs (Interval = 8 hrs)
(10) Determine if the regimen is appropriate by plugging the values into
the Cmax and Cmin equations. These equations will predict the
concentrations that will be achieved at steady state.
Cmax = [140mg x 1- e- (0.284 x 0.5)] /
[0.284 x 17.5 x 0.5 x 1 -e-(0.284 x 8hr)]
= 8.3 mcg/ml (Expected peak)
Cmin= Cmax x e-kel(T-ti) = 8.3 x e- 0.284 (8 - 0.5) = 0.99= ~1.0
(Exclusions: Check all that apply: If there are any checks do not use
once-daily dosing-use conventional dosing.
(1) Patient has febrile neutropenia
(2) Burn patient
(3) Spinal cord injury
(4) R/O meningitis or endocarditis
(5) CrCl < 40 ml/min
(6) Age < 18 or >70
(7) History of ototoxicity
(9) Being used for synergy for staph or strept infection.<Top>
Calculation of Dosing weight
If not obese, Use IBW. ( If actual wt is < IBW use actual instead.)
If obese use the adjusted body weight.
Patient Total body weight (TBW)=___________kg
Calculate Ideal body weight=_______________kg
IBW (male) = 50 kg + 2.3 kg for each inch over 60"
(Female)= 45.5 kg + 2.3 kg for each inch over 60"
Calculate Adjusted body weight (ABW) for obese patients.
(Use if TBW >20% over IBW)=______kg.
ABW = 0.4(TBW - IBW) + IBW
Goals of therapy: Desired trough for once daily dosing
Trough concentration: The trough may be measured at 18 or 24 hours.
If measured after 18 hours, the trough concentration must be less< 1
or < 0.5 mcg/ml if measured after 24 hours. If these goals are not met,
initiate standard dosing.
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