1. Case 9 Amikacin in an elderly CKD patient Block 9 : Divine Ramos, Remonte, Reyes, Rivera A, Rivera K, Rivera M, Rogelio, Sagayaga, Santiago, See, Siy, Sotalbo, Soyangco, Tagayona, Tagomata, Talan

2. Case 9 AT, 35 yo male, 60 kg Diagnosed with chronic renal disease Admitted for sepsis

3. Case 9 Started on Amikacin at 7.5mg/kg IV q12 Subsequent daily serum creatinine determination showed rising levels of creatinine as follows: Day 1: 400 umol/L Day 2: 554 umol/L Day 3: 665 umol/L

4. What was causing rising levels of creatinine? Amikacin Aminoglycoside Nephrotoxic (trough > 10mg/L) Regular dosage: 15 mg/kg/day divided IV/IM q8-q12

5. What was causing rising levels of creatinine? Doses for patients with renal impairment: CrCl/AgeDosing Interval >90 mL/min, <60 years oldq8 60-90 mL/min, >60 years oldq12 25-60 mL/minq24 10-25 mL/minq48 <10 mL/minq72

6. What was causing rising levels of creatinine? Creatinine clearance of AT: Day 1: 19.34 mL/min Day 2: 13.96 mL/min Day 3: 11.63 mL/min Worst case scenario: The patient’s CrCl was 19.34 at the start, thus should have been dosed every 48 hours only.

7. What medical issue relevant to pharmacovigilance are we dealing with? c/o Nico

8. What is your plan of management?

9. Aminoglycosides potent tubular toxin reduces GFR; thought to be an indirect effect on the glomerulus predominant sites of toxicity: S1 and S2 segments of the prox tubule known to bind to phospholipids  internalization with the cell via megalin  concentrated within lysosomes within proximal tubular cells  disorganization of lysosomes: “myeloid bodies” Toxicity best correlates with peak concentration of drug

10. Our patient Two considerations in our patient: elderly and with CKD

11. Renal function and the Elderly After age 50: number of nephrons progressively declines Decreased renal blood flow Further distress on renal function: higher incidence of vascular disease, hhypertension, DM, smoking, high protein diet The age-dependent alterations to renal anatomy and physiology in older adults make kidneys more susceptible to environmental and pathologic nephrotoxins

12. 5 steps for dosage adjustment

13. Step 1: Medical Hx and PE With thorough medication history should be obtained to identify drug allergies or intolerances Comorbidities BMI and ideal body weight Volume status (since shifts in EC fluid volume may change the volume of distribution of many drugs)

14. Step 2: Renal Function Assessment Cockroft-Gault: 24 h creatinine clearance is an approximation of GFR limitation in the elderly because it may overestimate renal function and mask the early stage of renal dysfunction prod and elimination of creatinine decreases with age Modification of Diet in renal Disease formula may be a better estimate Other limitations: drugs which can increase creatinine or urea production (eg GCs), agents interfering with creatinine tubular secretion (eg cimetidine), ketosis, hyperbilirubinemia Iohexol currently just in the clinical research setting

15. Step 3: Loading Dose Determination In Pts with normal renal function, steady-state drug concentration is reached after approximately five half-lives The half-life of drugs that are excreted renally may be significantly prolonged in CKD patients A smaller loading dose may be required Loading dose LD = Vd (L/kg) x IBW (kg) x Cp Cp = desired plasma concentration (mg/L) IBW, men = 50 kg + 2.3 kg for every 2.5 cm over 152 cm IBW, women = 45.5 kg + 2.3 kg for every 2.5 cm over 152 cm

16. Step 4: Maintenance Dose Determination Dosage modification in older adults with kidney disease can be accomplished by dose reduction dosing interval prolongation both methods For drugs whose clinical efficacy correlates with adequate peak concentrations (aminoglycosides, cephalosporins) the dosing interval should be adjusted Combined method also done

17. Intramuscular Administration for Patients with Impaired Renal Function Normal Dosage at Prolonged Intervals: If the creatinine clearance rate is not available and the patient’s condition is stable, a dosage interval in hours for the normal dose can be calculated multiplying the patient’s serum creatinine by 9 ex. if the serum creatinine concentration is 2 mg/100 mL, the recommended single dose (7.5 mg/kg) should be administered every 18 hours.

18. Step 5: Drug Level Monitoring Important in older patients with renal impairment Because of inter- and intraindividual pharmacokinetic vari- abilities, comorbid conditions, and drug interaction

19. Step 5: Drug Level Monitoring Whenever possible, amikacin concentrations in serum should be measured to assure adequate but not excessive levels It is desirable to measure both peak and trough serum concentrations intermittently during therapy Peak concentrations (30-90 minutes after injection) above 35 micrograms per mL and trough concentrations (just prior to the next dose) above 10 micrograms per mL should be avoided Dosage should be adjusted as indicated.

20. Points to remember Review patients past medical history and medication profiles for any possible drug–drug interactions For GFR <50 ml/min, renally excreted drugs should be adjusted according to the renal function Dosage modification can be accomplished by dose reduction, dosing interval prolongation, or both methods If needed, consider therapeutic drug monitoring (TDM) in older patients with renal impairment