Transcript AMGs Antibiotics

Clinical
Pharmacokinetics of
Aminoglycosides
Dr. Muslim Suardi
Faculty of Pharmacy
University of Andalas
2013
AMG ANTIBIOTICS
• Widely used for the treatment of severe
gram (-) infections such as
pneumonia/bacteremia, often in
combination with a β-lactam antibiotic.
• AMGs are also used for gram (+)
infections such as infective endocarditis in
combination with penicillins when antibiotic
synergy is required for optimal killing.
AMGs Antibiotics
Common use include:
Gentamicin
Tobramycin
Netilmicin
Mikacin
AMGs Antibiotics
• Bactericidal, & the drugs exhibit conc
dependent bacterial killing
• Kill bacteria at a faster rate when drug
conc are higher.
• Have a conc-dependent postantibiotic
effect.
The Postantibiotic Effect
• The phenomenon of continued bacterial
killing even though Cs have fallen below
the MIC.
• Because the postantibiotic effect is conc dependent for the AMGs, higher drug conc
lead to a longer postantibiotic effect.
Mechanism of Action
Binding to the 30S ribosomal subunit
inhibiting protein synthesis & misreading of
mRNA causing dysfunctional protein
production.
THERAPEUTIC & TOXIC
CONCENTRATIONS
• The conventional method of dosing AMG
antibiotics is to administer multiple daily
doses (usually every 8h).
• In order to take advantage of concdependent bacterial killing & the
postantibiotic effect, extended-interval
(usually the total daily dose given 1x per
day) AMG administration is also a dosing
option
Conventional Dosing
• AMG antibiotics are given as short-term
(1/2–1h) infusions.
• If a 1-h infusion is used, max end of
infusion “peak” conc are measured when
the infusion is completed.
• If a 1/2-h infusion is used, Cs exhibit a
distribution phase so that drug in the blood
& in the tissues are not yet in equilibrium.
Toxicity
• Ototoxicity: auditory & vestibular, & the
damage is permanent.
• AMGs accumulate in the lymph of the
inner ear causing ongoing damage to
cochlear or vestibular sensory cells
BASIC CLINICAL PK PARAMETERS
• AMGs are eliminated almost completely (≥90%)
unchanged in the urine primarily by GF.
• Usually given by short-term (1/2-1h) intermittent
iv infusions, although they can be given im-ly.
• They exhibit very good BA of ~100% im-ly &
rapidly absorbed with max conc occurring about
1h after inj.
DRUG INTERACTIONS
• Most important drug interactions are PD, &
not PT
• VANCO, amphotericin B, cyclosporin, &
furosemide the nephrotoxicity of the
AMGs
• SCr conc should be monitored on a daily
basis.
INITIAL DOSAGE
DETERMINATION METHODS
1
Pharmacokinetic Dosing Method
2
Hull & Sarubbi Nomogram
3
Hartford Nomogram
4
Literature-based Recommended Dosing
1. Pk Dosing Method
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Ke & Vd estimate
Selection of appropriate Pk Model & Eq
Css Selection
Dosage Computation
RoA Single Dose Multiple dose SS
Route of dosage interval MD (D or k0) &
LD Eq
• Special Dosing Considerations
• Hemodialysis Dosing
2. Hull & Sarubbi Nomogram
Method
• For patients who do not have disease
states/conditions that alter Vd, the only 2
patient-specific factors that change when
using the Pk dosing method is:
BW & CrCl.
• Because of this, it is possible to make a
simple nomogram to handle
uncomplicated patients with a standard Vd
(Table 4-3)
2. Continued
• Hull & Sarubbi AMG dosing nomogram is
a quick and efficient way to apply
pharmacokine & dosing concepts without
using complicated Pk Eq. With a simple
modification, it can also be used for obese
3. Hartford Nomogram Method
• For Extended-Interval Dosing
• Extended-interval dosing is now a
mainstream method used to administer
AMG antibiotics.
• Conventional dosing is still preferred for
endocarditis patients because the AMG is
usually used for antibiotic synergy.
3. Continued
• The Hartford nomogram includes a
method to adjust doses based on GENTA
Csr.
• This portion of the nomogram contains
average Csr/time lines for GENTA in
patients with Crcl of 60, 40, & 20 mL/min.
4. Literature-Based
Recommended Dosing
• Because of the large amount of variability
in AMG Pk, even when concurrent disease
states/conditions are identified, many
clinicians believe that the use of standard
AMG doses for pediatric patients is
warranted.
4. Continued
• In general, the expected AMG serum Css
used to compute these doses were similar
to those for adults given conventional
dosing.
• Suggested initial AMG doses for various
pediatric patients are listed in the Effects
of Disease States & Conditions on AMG
Pk & Dosing section
• Expected Peak Serum
• AMG Usual LD Concentrations
Sawchuk-Zaske Method
• Standard SAWCHUK-ZASKE METHOD
• AUC Method
• Pk Computer Programs
AUC Method
Problem
• JM is a 50-yo, 70-kg (5 ft 10 in) male
with gram (-) pneumonia.
• His current Scr is 0.9 mg/dL, & it has been
stable over the last 5d since admission.
• Compute a GENTA dose for this patient
using conventional dosing.
1. Estimate Scr
• Patient has a stable Scr & not obese.
• The Cockcroft-Gault eq can be used to
estimate Clcr:
• CrClest
= [(140−age)BW]/(72*SCr)
= [(140−50y)70kg]/(72*0.9 mg/dL)
= 97mL/min
2. Estimate ke & t1/2
• ke vs Crcl relationship is used to estimate
the GENTA ke rate for this patient:
• ke
= 0.00293(CrCl) + 0.014
= 0.00293(97 mL/min) + 0.014
= 0.298 h−1
• t1/2
= 0.693/ke
= 0.693/0.298 h−1 = 2.3 h
3. Estimate Vd
• The patient has no disease states or
conditions that would alter the Vd
from the normal value of 0.26 L/kg:
• V = 0.26 L/kg (70 kg) = 18.2 L
4. Choose Desired Serum Css
To avoid toxicity
• Gram (-) pneumonia patients treated with
AMG require:
SS peak conc (Cssmax) : 8–10μg/mL
SS trough conc (Cssmin) : <2μg/mL
• Set
Cssmax = 9 μg/mL
Cssmin = 1 μg/mL
5. Use Intermittent iv Infusion Eq. to
Compute Dose (Table 4-2)
See Table 4-2 Bauer
5. Calculate Required τ Using
a 1h Infusion
• τ
= [(lnCssmax−lnCssmin)/ke] + t′
= [(ln 9 μg/mL−ln 1μg/mL) / 0.298 h−1] + 1h
= 8.4h
• Τ should be rounded to clinically
acceptable intervals of 8, 12, 18, 24, 36,
48, 72h, & multiples of 24h thereafter,
whenever possible.
• Τ would be rounded to 8h
5. Continued
• Also, Cssmax are similar if drawn
immediately after a 1h infusion
• or 1/2h after a 1/2h infusion, so the dose
could be administered either way.
• k0 = Cssmax*keV[(1−e−keτ)/(1−e−ket′)]
= (9 mg/L*0.298 h−1*18.2 L){[1−e−(0.298 h−1)
(8h)] / [1−e−(0.298 h−1)(1h)]}
= 172 mg
5. Continued
• AMGs doses should be rounded to the
nearest 5–10 mg. This dose would be
rounded to 170 mg.
• The prescribed MD would be 170 mg
every 8h.
Problems
• A 75yo, 62kg (5ft 9in) male with gram(-)
sepsis. His current SCr is 1.3 mg/dL, & it
has been stable since admission.
• Compute a GENTA dose for this patient to
provide a Cssmax & a Cssmin sing
conventional dosing.
Solution to Problem
The initial GENTA dose for patient PQ
would be calculated in several steps as
follows.
1. Estimate CrCl
Patient has a stable SCr & not obese.
Cockcroft-Gault eq can be used
to estimate CrCl:
CrClest
= [(140–age)*BW] / (72*SCr)
= (140–75)*62 kg]/ (72*1.3 mg/dL)
= 43 mL/min
2. Estimate ke & t1/2
ke vs CrCl is used to estimate the GENTA
• Ke
• t1/2
=0.00293*(CrCl)+0.014
=0.00293*(43 mL/min)+0.014
= 0.140 h–1
= 0.693/ke
= 0.693/0.140 h–1
= 4.9h
3. Estimate Vd
• Patient has no disease states or
conditions that would alter the Vd from the
normal value of 0.26 L/kg:
• Vd = 0.26 L/kg*(62 kg) = 16.1 L
4. Choose Desired Css
Gram (-) sepsis patients treated with AMG
antibiotics require:
• Cssmax equal to 8–10 µg/mL
• Cssmin should be <2µg/mL to avoid toxicity
• Set Cssmax = 8 µg/mL & Cssmin = 1.5 µg/mL
5. Use Intermittent iv Infusion
eq. to Compute Dose
• Calculate required τ using a 1h infusion
• τ = [(ln Cssmax - ln Cssmin)/ke] + t′
= [(ln8µg/mL-ln1.5µg/mL)/0.140 h−1]
+1h
= 12.9 h.
5. Continued
• τ should be rounded to clinically
acceptable intervals of 8h
• 12, 18, 24, 36, 48, 72h, & multiples of 24 h
thereafter, whenever possible.
• τ would be rounded to 12h
5. Continued
Also, Cssmax are similar if drawn
immediately after a 1h infusion or 1/2h
after a 1/2h infusion, so the dose could be
administered either way.
k0 = Cssmax*ke*V[(1-e−ke*τ) / (1-e-ket′)]
k0 = (8mg/L*0.140 h−1 *16.1 L){[1 - e−(0.140
h−1*(12 h)] / [1 - e−(0.140 h−1)(1 h)]}
= 112 mg
5. Continued
AMG doses should be rounded to the
nearest 5–10 mg.
This dose would be rounded to 110 mg.
The prescribed MD dose would be 110
mg every 12h.
6. Compute LD, If Needed
• LD should be considered for patients with
CrCl values below 60 mL/min.
• The administration of a LD in these
patients will allow achievement of
therapeutic peak concentrations quicker
than if MD alone are given.
6. Continued
• However, since the Pk parameters used to
compute these initial doses are only
estimated values & not actual values, the
patient’s own parameters may be much
different than the estimated constants &
SS will not be achieved until 3–5t1/2 have
passed
• LD = k0/(1 − e−keτ)
= 110mg/[1−e−(0.140 h−1)*(12h)] =135mg
References
• Bauer, LA. (2008). Applied Clinical
Pharmacokinetics. New york: McGraw Hill.