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 conc-dependent 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 Pharmacokinetic Dosing Method Hull & Sarubbi Nomogram Hartford Nomogram Literature-based Recommended Dosing 1 2 3 4

1. Pk Dosing Method 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 =0.00293*(CrCl)+0.014 =0.00293*(43 mL/min)+0.014 = 0.140 h–1 t1/2 = 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.