TDM aminoglycoside (2022)

30/09/65 Therapeutic drug monitoring :Aminoglycosides By Assistant Prof. Karunrat Tewthanom RPh., PhD. Silpakorn University 1

Objectives After study this topic, the student should be able to  Explain the overall properties of Aminoglycosides.  Explain the reason and advantages of therapeutic drug monitoring of aminoglycosides and the factors affect drug level monitoring  Explain the principle of aminoglycosides monitoring  Calculate dose and design appropriate interval in Aminoglycosides monitoring  Explain the pharmacist role and update research in aminoglycosides monitoring 30/09/65 2

Scope (Topic) 1. Introduction (Case based study) - overview in aminoglycosides 2.Therapeutic drug monitoring of aminoglycosides: rationale and clinical application 3. Future research 4. Conclusion 5. Question and assignment 30/09/65 3

Case Study • MK ( 60 yo F Scr = 1.15 mg/dL, weight = 60 kg) is initiated on Amikacin 250 mg every 12 hours for a MDR P. aeruginosa pneumonia (MIC = 8). Patient has been on therapy for 2 days and you would like to assess her Amikacin concentration. 30/09/65 4

Introduction • Introduction • Aminoglycosides antibiotics was introduced at 1940’s. • The indication were eliminate the sensitive bacterias and available of aminoglycosides are presented in Table 1 • The common of clinical use of aminoglycosides is presented in Table 2. The chemical structure of these group is presented in Figure 1 30/09/65 5

Table 1 Available aminoglycosides Drug Trade name Available Amikacin dosage form Gentamicin Akacin inj® , Various such as Injection Tobramicin Injection Netilmicin Genta-oph, Cream Gentamicin cream, Eye drops 30/09/65 Getamicin inj Injection Injection Netromycin® 6

Table 2 Common clinical uses of aminoglycosides Serious life threatening gram negative infection  Complicated skin , bone or soft tissue infection  Complicated urinary tract infection  Septicemia  Peritonitis  Other severe intra-abdominal infections  Severe pelvic inflammatory disease  Endocarditis  Mycobacterium infection  Neonatal sepsis  Ocular infection  Otitis media (topical) 30/09/65 7

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Summary of antibiotics action on ribosomes 30/09/65 10

http://pharmaxchange.info/press/2011/05/mechanism-of-action-of- aminoglycosides/ 30/09/65 11

Summary of Pharmacokinetic Profile Absorption Most aminoglycosides have low bioavailability (less than 1%). Therefore, the preparation mostly in parenteral forms. 30/09/65 12

Summary of Pharmacokinetic Profile Distribution  Aminoglycosides predominantly distributed into body water, extracellular fluid.  The distribution volume may be altered by any comorbidity condition that involve fluid balance.  Distribution volume will be greater in patient with ascites, edema, pleural effusion, peritonitis, pregnancy, hypoalbuminimia, HIV, in perioperative condition. It is similar in dehydrated condition. 30/09/65 13

Summary of Pharmacokinetic Profile • Elimination Aminoglycoside are eliminated mainly via glomerular filtration with active secretion. Clearance approximates with creatinin clearance, which can be used for approximately calculation 30/09/65 14

Summary of Pharmacokinetic Profile https://apps.pharmacy.wisc.edu/courses/728656/vancomycin/presentation_content/ external_files/handouts.pdf 30/09/65 15

Resistance http://narst.dmsc.moph.go.th/ 30/09/65 16

Resistance http://narst.dmsc.moph.go.th/ 30/09/65 17

Resistance 30/09/65 http://narst.dmsc.moph.go.th/ 18

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Resistance Chemotherapy 2013;59:379–384 23 30/09/65

Resistance 30/09/65 24

Drug Interactions and Adverse Effects Nephrotoxicity Ototoxicity 30/09/65 25

Drug Interactions and Adverse Effects  Non-oliguric azotemia due to proximal tubule damage; increase BUN and serum creatinine, reversible if caught early.  Risk factor: prolonged high trough, long duration of therapy (> 2weeks), underlying renal dysfunction, elderly, other nephrotoxins 30/09/65 26

Drug Interactions and Adverse Effects 8th Cranial nerve damage- vestibular and auditory toxicity; irreversible and saturatble Vestibular: dizziness, vertigo, ataxia  Auditory: tinnitus, decreased hearing  Risk factors: same as for nephrotoxicity 30/09/65 27

Drug Interactions and Adverse Effects 30/09/65 28

Drug Interactions and Adverse Effects Risk factors, predisposing to aminoglycoside nephrotoxicity Potentially Alterable factors Unalterable factors Use of diuretics* Age Radiographic Pre-existing renal diseases contrast exposure Effective circulating volume depletion Use of ACE inhibitors† Use of NSAIDs† Use of other nephrotoxic medications Concomitant use of amphotericin (Fungizone IV) Use of cisplatin (Platinol) 30/09/65 29

Drug Interactions and Adverse Effects 30/09/65 30

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Drug Interactions and Adverse Effects In order to minimize toxicity, it should remember a few key considerations. (1) Aminoglycosides should be used only when their unique antibiotic potency is needed, such as treatment of infection in critically ill patients, and in nosocomial infections or infections with organisms resistant to less toxic therapies. (2) The clinician should change to a potentially less toxic antibiotic as soon as the infecting organism and its antibiotic sensitivities have been determined. (3) Potential risk factors that predispose to nephrotoxicity should be identified and, when possible, corrected 33 30/09/65

Therapeutic Drug Monitoring of Aminoglycosides Why aminoglycosides is appropriate for therapeutic drug monitoring?  Too much aminoglycosides may dangerous. It may cause ototoxicity and nephrotoxicity.  Too little of aminoglycosides may not sufficient to control infection.  Targeted concentration of aminoglycosides improve outcome and nephrotoxicity* 30/09/65 34

Therapeutic Drug Monitoring of Aminoglycosides Population Data Key parameters Volume distribution : between 0.06 – 0.84 L/kg Since aminoglycosides are difficult distribute in to adipose tissue, therefore, lean body weight should be provide more accurate volume of distribution In obese patients Vd = (0.25 L/kg) (IBW) + 0.1 (TBW-IBW) IBW: Male = 50+ 2.3 (high in Inch > 60) 35 Female = 45 + 2.3 (high in Inch >60) 30/09/65

Therapeutic Drug Monitoring of Aminoglycosides  For ascites, edema, or enlarge third space Vd = (0.25 L/kg x non obese, non excess fluid weight) + 0.1 (excess adipose tissue weight) + excess third space weight  For children (1-5 years) Vd  (0.5 L / kg)  (Agein5 yearsx 0.25) x (weightin kg) The pharmacokinetic of the aminoglycosides antibiotics has been describes by 2-3 compartment model. However, in clinical practice one compartment model has been use widely. 30/09/65 36

Therapeutic Drug Monitoring of Aminoglycosides  The error encountered when using a single- compartment model for aminoglycosides can be minimized if plasma drug concentrations are obtained at times that avoid the first and third distribution phases and at 24 hrs after therapy had been initiated.  Aminoglycoside concentration < 1 mg/L should be evaluated with caution because the influence of the large third compartment will become greater at these low concentrations. 30/09/65 37

Therapeutic Drug Monitoring of Aminoglycosides The equation that usually use in clinical practice for aminoglycosides 30/09/65 38

Therapeutic Drug Monitoring of Aminoglycosides The algorithm for selection the equation At steady state? NO Non-steady state /Duration of therapy (iterative search) > 3-5 t1/2? Yes In put continuous Css max= Cave= Css min or Is  < t1/2? Yes NO Continuous infusion 30/09/65 39

Therapeutic Drug Monitoring of Aminoglycosides The algorithm for selection the equation Is -tin < 1/3 t1/2? No Is tin < 1/6 t1/2? No ( ) ) Yes () Short infusion model 30/09/65 40

Therapeutic Drug Monitoring of Aminoglycosides The algorithm for selection the equation Bolus model 30/09/65 41

Therapeutic Drug Monitoring of Aminoglycosides The algorithm for selection the equation Non steady state NO Csum= (S)(F)(Dose1)(e-kt1)+ (S)(F)(Dose2)(e-kt2) dose and are + …Etc consistant? Sum of individual dose Yes ������������������������ = ( )( )( ) +… Yes Is tin < 1/6 t1/2? In put continuous Sum of individual bolus or model Is  < 1/3 t1/2? Yes ( )( )( )(1-������ ) NO ������1 = Non steady stae continuous infusion Yes 30/09/65 42

Therapeutic Drug Monitoring of Aminoglycosides The algorithm for selection the equation No Yes Is tin < 1/6 t1/2? Is -tin < 1/3 t1/2? No Yes ( )( )( )( ) ) (1 − ������ )(������ ) Non-steady state short infusion model ( )( )( ) ������������������2 = (1-������ ( ) )(������ ) ( ) Non-steady state bolus model 30/09/65 43

Therapeutic Drug Monitoring of Aminoglycosides • Step for aminoglycosides monitoring  Calculate IBW  Sometimes it needs to calculate clearance to evaluate renal function By using Cockcroft-Gault equation CL cr ( Female )  0.85 x (140  age)x weight (72 / Scrss ) CLcr(Male)  (140 age)x weight (72/Scrss ) 30/09/65 44

Therapeutic Drug Monitoring of Aminoglycosides Calculate ke  For 1 concentration received population Vd should be use for calculate ke ; sometimes infusion model should be used and try to caution about t 30/09/65 45

Therapeutic Drug Monitoring of Aminoglycosides For 2 concentrations k  ln C p1  ln C p2 (t) Then you can calculate Vd by the following equation 30/09/65 46

Therapeutic Drug Monitoring of Aminoglycosides  If you have only 1 point of concentration you may calculate Cp2 by the following equation Then you can calculate the dosage which giving desire targeted concentration 30/09/65 47

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Example • PK is a 50 year-old, 70 kg , 178 cm (70 inch) man with gram negative pneumonia. His serum creatinine is 2.5 mg/dL, which has been stable over the last 5 days since admission. Gentamicin 160 mg every 24 hr was prescribed and expected to achieve steady state peak and trough concentrations at 20 mcg/mL and < 2 mcg/mL, respectively. After the third dose, steady state peak and trough concentration were measured and were 25 mcg/mL, 3.5 mcg/mL, respectively. Calculate a new gentamicin dose that will provide a steady state peak of 20 mcg/mL and trough < 2 mcg/mL 30/09/65 49

Example 1. Estimate creatinine clearance CLcr(Male)  (140 age)x weight (140 − 50������)������ 70������������ (72/Scrss ) = (72/2.5������������/������������) ������������ ( ) = 35 mL/min = 2.1 L/h 2. Estimate elimination rate constant (ke) and half-life (t1/2) k  ln C p1  ln C p2 (t) 30/09/65 50