Marie Varela, Pharm.D., BCPS Sherene Samu, Pharm.D. Pediatric Dosing of Aminoglycosides and Vancomycin Based on Pharmacokinetic Concepts Marie Varela, Pharm.D., BCPS Sherene Samu, Pharm.D.

Objectives Describe basic pharmacokinetic parameters for vancomycin and aminoglycosides in pediatric patients Outline dosing strategies for aminoglycosides based on pharmacokinetic principles Outline dosing strategies for vancomycin based on pharmacokinetic principles Select a monitoring plan for vancomycin and aminoglycosides in pediatric patients Select an adjusted dosing regimen based on serum concentrations for vancomycin and aminoglycosides in pediatric patients

Pharmacokinetics Definition: The study of the time course of a drug and its metabolites in the body The study of the ADME of a drug and its metabolites in the body Absorption Distribution Metabolism Excretion Varies greatly with age groups (pediatrics, geriatrics)

Volume of Distribution As a review, this illustration represents volume of distribution. It demonstrates that if you give the same amount of drug (in this case 100 mg) to someone with a small volume of distribution, the serum concentration would be higher than giving the same amount to someone with a larger volume of distribution. Volume of distribution is affected by body mass, but also possibly by percentage of body water (for aqueous drugs) or fat (lipophilic drugs).

Excretion Because of the PK and PD characteristics of vancomycin and aminoglycosides, the clearance of these drugs is closely correlated to creatinine clearance

Estimation of Creatinine Clearance Schwartz Estimate Estimates creatinine clearance from serum creatinine, the patient's height, and a proportionality constant CrCl = (k * Ht) / Cr (Caution: formula tends to overestimate the actual creatinine clearance and should be used with caution.) http://www-users.med.cornell.edu Ht height in centimeters Cr serum creatinine K Constant: (see below) Infant (LBW < 1 year) 0.33 Infant (Term < 1 year) 0.45 Child or Adolescent Girl 0.55 Adolescent Boy 0.70 Designed to be used in children 1 to 18 years but appears to be less accurate in children < 100 cm tall. This formula tends to overestimate the creatinine clearance First couple of days of life, crcl is reflective of mother’s crcl. So we should base renal function on urine output

Elimination Half-life (t½) Associated with first-order kinetics (serum concentration diminishes logarithmically over time) Time it takes for plasma concentration to reach half of a previous concentration Affected by metabolism and excretion Most drugs follow first-order kinetics (including aminoglycosides and vanco) This is specific to vancomycin and gent

% of Steady State Achieved Equilibrium reached: Rate of drug in=Rate of drug out Time to reach steady state is a function of t½ t½ % of Steady State Achieved 1 50% 2 75% 3 87.5% 4 93.75% 5 100%

Graph of Multiple Dosing Q6h dosing t½ = 6 hours

Pharmacodynamic Concepts Affecting Dosing and Monitoring of Aminoglycosides and Vancomycin Organism (Gram + vs. Gram -) MIC of organism Site of infection Dose-response relationships of Abx Concentration vs. time dependent bactericidal activity PAE

Concentration Dependent Aminoglycosides CONCENTRATION dependent killing Maximize INTENSITY of exposure As concentration at site ↑, antimicrobial action ↑ More pronounced responses to dosage adjustments

Gentamicin/Tobramycin Initial Dosing Pediatrics Conventional Dosing Extended Interval Dosing 2-2.5 mg/kg/dose q8h 4.5-7.5 mg/kg/dose q24h CF: 3.3 mg/kg/dose q8h CF: 10-12 mg/kg/dose q24h Gram + synergy: 1 mg/kg/dose q8h N/A Lexicomp 1978-2013

Gentamicin/Tobramycin Initial Neonatal Dosing SBUH PMA (weeks) Postnatal (days) Dose (mg/kg) Interval (hours) ≤ 29 0 to 7 8 to 28 > 28 5 4 48 36 24 30 to 34 > 7 4.5 ≥ 35 ALL Postmenstrual age (PMA) = GA + PNA Reference: Neofax

Gentamicin/Tobramycin Expected Half-Life (Population Statistics) Age t½ Neonates < 1wk 3 to 11.5 hrs Neonates 1wk-1mo 3 to 6 hrs Infants 4 ± 1 hrs Children 2 ± 1 hrs Adolescents 1.5 ± 1 hrs Adults Normal Renal Function: 2 to 3 hr Functionally Anephric: 30 to 60 hr Clearance approximately equal to CrCl (≈ 5% metabolized)

Aminoglycosides Target Goals Tobramycin/Gentamicin Target Serum Concentrations Parameter Serum Concentration Condition Peak 4-5 mcg/mL UTI Gram (+) synergy 6-8 mcg/mL Pneumonia (within 24 to 48 hours) Trough <2 mcg/mL to minimize toxicities

Time Dependent Vancomycin TIME dependent killing Maximize DURATION of exposure More pronounced responses to interval adjustments

Vancomycin Initial Dosing Pediatrics 10-15 mg/kg/dose q6-8 hours Renal impairment GFR 30-50: 10 mg/kg/dose q12h GFR 10-29: 10 mg/kg/dose q18-24 hours GFR < 10: 10 mg/kg/dose; re-dose based on serum concentrations Lexicomp 1978-2013

IV Vancomycin Initial Neonatal Dosing SBUH PMA (weeks) Postnatal (days) Interval ≤ 29 0 to 14 > 14 18 12 30 to 36 8 37 to 44 0 to 7 > 7 > 44 All 6 Dose: 10 to 15 mg/kg/dose* (*This dosing strategy targets a trough of 5-15, therefore 15 mg/kg/dose is preferred.) Reference: Neofax

Vancomycin Expected Half-Life (Population Statistics) Age t1/2 Neonates 6 to 10 hrs Infants 3 to 4 hrs Children 2.2 to 3 hrs Adults Normal renal function: 5-11 hr End stage renal: 5 to 7 days Clearance approximately equal to CrCl (≈ 5% metabolized)

IV Vancomycin Target Serum Concentrations Trough Goal Condition 10-15 mcg/mL General 15-20 mcg/mL Peritonitis Osteomyelitis MRSA pneumonia CNS infections Maintain trough in therapeutic range; peak inconsequential

IV Vancomycin Dosing Strategies Due to pharmacodynamic characteristics, optimal give more frequently Want trough to remain in therapeutic range; peak inconsequential For renal impairment, reduce frequencies

Why Monitor? Constant changes in Vd and clearance Optimize therapeutic effects Minimize toxicity

When to Monitor? At presumed steady state Upon initiation of therapy After a dosage/frequency adjustment Upon significant change in weight, fluid status, renal function After addition of a medication that may affect renal function (i.e. Ibuprofen) Every week after achieving therapeutic serum concentrations For vancomycin doses of > 15 mg/kg/dose q6h or > 3 g per day, recheck first therapeutic trough in 2-3 days. (Then follow above monitoring strategy thereafter.)

Time to Draw Peak (aminoglycosides only) Trough (all drugs) 30 minutes after dose completely infused Trough (all drugs) 30 minutes before the next dose is due Peak time to draw varies with the drug and is based on the distribution time. Vancomycin peak would be drawn one hour after dose is infused IF we had the need to draw one (because it’s lipophilic and it takes 1 hour for it to distribute).

How to Interpret Lab Results Questions to ask yourself Was the initial dosing appropriate? (considering renal function etc.) Was the trough drawn at presumed steady state? For unexpected high concentrations, was it possible the trough was drawn after the start of the infusion or from a line that may not have been flushed? Was it actually drawn at the time documented in the system? Should the level be redrawn?

Gentamicin Conventional Dosage Adjustment Guidelines If Peak is High (>10 mcg/mL) Trough is High Proportional DECREASE in DOSE to bring peak to desired number. Check to see how this change affects trough. If trough is still high (above range) with this dosage decrease, DECREASE the FREQUENCY. Trough is in range Proportional DECREASE in DOSE to bring peak to desired number. Trough is low (<0.5 mcg/mL) Proportional DECREASE in DOSE to bring peak to desired number and INCREASE the dosing frequency. If Peak is Low (less than target) Proportional INCREASE in DOSE to bring peak to desired number. Must also DECREASE the dosing frequency Trough is in Range Proportional INCREASE in DOSE to bring peak to desired number. Check to see how this change affects the trough. If the change will cause the trough to be high (above range), also DECREASE the FREQUENCY. Proportional INCREASE in DOSE to bring peak to desired number. Check to see how this change affects trough.

Gentamicin Dosage Adjustment Guidelines If peak is in desired range and trough is high, DECREASE THE FREQUENCY. After rechecking serum concentrations, may be necessary to increase dose with next adjustment. If peak is in desired range and trough is low, most likely no adjustment is necessary.

Vancomycin Dosage Adjustment Guidelines If trough comes back HIGH If trough is in toxic range, hold and draw random serum concentrations until below 15 mcg/mL. May calculate patient half-life using formula if there are 2 concentrations after a dose and one value is at least twice the other. When concentration is below 15 mcg/mL, recalculate dose and restart. If half-life is greater than dosing interval, increase dosing interval to greater than or equal to one half-life If trough comes back LOW If trough is less than half of target, increase the frequency. If the frequency is already Q6H, increase the dose to 15 mg/kg. If trough is still low, increase the dose in small increments (i.e. 2 mg/kg per dose) If trough is more than half of target, increase the dose based on a linear relationship; calculate as a proportional ratio to trough. Maximum increase of 50% at one time. Note: Q6h hours in the maximum frequency

Common Myth Adjust the dose by 10% Is this an appropriate recommendation? In what situation, if ever, would this apply? Since vancomycin follows linear kinetics, increasing/decreasing the dose by 10% would only affect the level by 10%. If your goal is to go from 10 to 11, then you would increase by 10%. Recommending a blanket statement of “increase the dose by 10%” is not accurate. For example, if the trough is 7 and your goal is 15-20, increasing the dose by 10% will not help you reach your goal. Adjusting the frequency would be an appropriate change.

Calculating Actual Half-Life to choose best dosage interval K = ln C1 C2 Δ Time t½ = 0.693/K K=elimination rate constant Δ Time = hours Can be done from random levels if spaced far enough apart (one number at least twice the other) Can be done from peak and trough if at steady state

Communication Verbal Progress notes Sign outs

Case 1 Reason for visit Started on vancomycin Patient Specific Data Female 20 years old ABW 76.6 kg IBW 52.4 kg SCr 0.6 CrCl 123 mL/min Case 1 Reason for visit Chronic CSF leak Comes to ER with symptoms of bending down, having rhinorrhea Started on vancomycin Trough goal = 15-20 mcg/mL

Case 1 Date Dosing Schedule Dose Received Time 2/3/10 1 g x1 STAT 1 g 1629 2/4/10 1.5 g Q12H 1.5 g 0400 1 g Q12H 1520 2/5 /10 VANCOMYCIN TROUGH 10.1 mcg/mL 0330 1530 This was the dosing regimen and the times at which the drug was administered. What do you think of this level? What dosing does this level reflect? Would you recommend an adjustment based on this level? Why or why not?

Case 1 Pharmacy recommendation on 2/5/10 Draw a level on 2/6/10 AM If level ≤ 10 mcg/mL, give 1 g Q8H If level 11-12 mcg/mL, give 1.5 g Q12H If 13-15 mcg/mL, give 1.2 g Q12h

VANCOMYCIN TROUGH 11 mcg/mL Case 1 Date Dosing Schedule Dose Received Time 2/6/10 VANCOMYCIN TROUGH 11 mcg/mL 0300 1 g Q12H 1 g 0330 1.5 g Q12H 1.5 g 1530 2/7/10 2/8/10 VANCOMYCIN TROUGH 17.5 mcg/mL

Case 2 Reason for admission Started on gentamicin Lethargy Patient Specific Data Female 2 years old ABW 17.5 kg IBW 17.3 kg SCr 0.3 CrCl 177 mL/min Case 2 Reason for admission Lethargy Mental status changes Fever Started on gentamicin R/O sepsis (gram negative coverage)

Case 2 Target Serum Concentrations Gentamicin Dose: 2.5 mg per kg q8h Peak: 6-10 mcg/mL Trough: < 2 mcg/mL Gentamicin Dose: 2.5 mg per kg q8h

Case 2 Date Dosing Schedule Dose Received Time 1/27/10 43 mg Q8H 43 mg 22:00 1/28/10 06:00 14:00 Gentamicin Peak 5.2 mcg/mL 15:00 Gentamicin Trough 1.3 mcg/mL 21:30 What do you think of these levels? How would you adjust this dose?

Case 2 Dosage Adjustment Want peak 6 or greater If 43 mg yields peak of 5.2, what dose would bring it to 6? Use linear proportion as long as interval is unchanged

Case 2 Dosage Adjustment Continued What effect would that have on trough (if dose was increased to 49 mg q8h)? If 43 mg yields a trough of 1.3 mcg/mL, 49 mg would bring it to what trough? Now you have to ask yourself, if I just increased the dose to get a higher peak, how much of an effect would it have on my trough? Would I still remain under 2?

Case 2 What if trough calculated to greater than 2? Answer: increase the interval Monitoring After dosage change, repeat peak and trough around 3rd dose of the new regimen

Case Study Term neonate DOB: 1/25/12 Diagnosis: chorioamnionitis Weight 3.65 kg Start antibiotics: ampicillin gentamicin

Case 3 ( 1) Gentamicin Gentamicin ordered: 14.6 mg q 24 hours Dosed at 4 mg per kg

Questions: Was this dosed properly? What criteria are used to determine if this was dosed properly? What level(s) will be drawn to properly monitor this drug? What serum concentrations are we targeting? Dosed properly? (YES. Over 36 weeks is term and is dosed at 4 mg per kg q 24h). Premenstrual age, post natal age, weight and renal function must be considered. Evaluation of renal function is based on urine output; the serum creatinine of a neonate will reflect that of the mother for the first few days of life, and is therefore not useful in determining renal function. Monitor peak and trough around the third dose. Targeting of serum concentration is based on indication and bug coverage.

Gentamicin Dosing PMA (weeks) Postnatal (days) Dose (mg/kg) Interval (hours) ≤ 29 0 to 7 8 to 28 > 28 5 4 48 36 24 30 to 34 > 7 4.5 ≥ 35 ALL PMA= post menstrual age PMA is the equivalent to Gestational Age plus Postnatal Age

Case 3 (2) Gentamicin Dose given each morning for 3 doses

Question: What time should the peak be drawn? What time should the trough be drawn? Around the third dose

Case 3 (3) Gentamicin

Case 3 (4) Gentamicin This screen shows the time the specimen is documented as being collected.

Question: What is your evaluation of this peak? How do we proceed from here? Peak is extraordinarily high. Much higher than expected. Must question if this result is “believable” and what may have happened… Nurse started infusing the drug and then remembered to draw a level? Nurse drew it from a line that was previously used for that drug but never flushed? Decreasing renal function? Pharmacy accidentally drew up the concentrated stock solution? Need additional serum concentration to confirm or dispute the lab result.

Aminoglycoside Pharmacokinetic Monitoring Drug: Gentamicin Date Dosage Regimen Admin Time Time of Blood Draw Peak, Trough or Random Result Serum Creat Comments 1/25/12 Gent 14.6 mg q24 9:00 No serum creatinine. Wt= 3.65 kg 4 mg/kg 1/26/12 “ 8:08 1/27/12 (11:09) Peak 33.7 Mcg/mL If you “believe” these numbers, t ½ =1.88 12:39 (12:55) Random 9.3 Expected t ½ in neonate=3-6 hours No dose has been given since 8:08 on 1/27. Order a trough for AM on 1/28. No need to hold dose since drug clearance appears to be adequate (At least 19 hours between random level drawn and next dose due. Even if t ½ is 6 hours, 3 half-lives can transpire before next dose is due, which would bring trough down to approximately 1.2 mcg/mL).

Case 3 (5) Gentamicin Trough is in target range. Calculate half-life: K= [natural log (9.3 /1.6)] /19 = 0.093 T ½= 0.693/k = 7.5 hours.

Aminoglycoside Pharmacokinetic Monitoring Drug: Gentamicin Date Dosage Regimen Admin Time Time of Blood Draw Peak, Trough or Random Result Serum Creat Comments 1/25/12 Gent 14.6 mg q24 9:00 No serum creatinine. Wt= 3.65 kg 4 mg/kg 1/26/12 “ 8:08 1/27/12 (11:09) Peak 33.7 Mcg/mL If you “believe” these numbers, t ½ =1.88 12:39 (12:55) Random 9.3 Expected t ½ in neonate=3-6 hours 1/28/12 8:15 Trough 1.6 Whole picture of all the monitoring we have so far.

Question: Next step? Give a dose (4 mg/kg dose) now (9AM) and draw a peak 30 minutes after it is infused Give a dose (4 mg/kg dose) now (9AM) and draw a peak 30 minutes after it is infused.

Case 3 (6) Peak and trough are both in range to treat gram negative organisms as well as providing gram positive synergy.

Evaluation Check initial dosing for correctness Evaluate the credibility of the laboratory values Identify possible reasons for serum concentration to be different than what is expected Confirm that all doses were given as scheduled Confirm that blood was drawn at the correct time Repeat lab work if necessary Make adjustments based on pharmacokinetic relationships

Case 4 (1) Vancomycin Premature infant is 3 weeks old when vancomycin is added.. This is a premature neonate that was dosed appropriately at every 8 hours as per Neofax. The patient’s weight is 2.63 kg and the dose is 26 mg which is 10 mg/kg (rounded off). This is within the recommended dosage range. Dosed at 10 mg/kg per dose every 8 hours.

Case 4 (2) Vancomycin Current practice is to ensure that trough is at least 10 mcg/mL. Since 10 mg/kg targets a trough of 5 to 10 mcg/mL, it is not uncommon for 10 g/kg/dose to result in under-dosing.

Case 4 (3) Vancomycin 4th dose Trough would need to be drawn on 1/31/12 at 16:00.

Case 4 (4) Vancomycin It appears that trough was drawn correctly.

What is the next step? Evaluate the initial dosing strategy Evaluate the lab result Target trough? Adjust dose or change the frequency? Again, dosing at 10 mg/kg often results in under-dosing. The trough appears to have been drawn correctly with respect to the dose and to time relative to the dose. A trough of 6.6 is below the desired range, so dosage adjustment is necessary. Change the dose proportionately to target a trough of 10 mcg/mL, or go to 15 mg/kg/dose and keep the frequency the same. Draw another trough prior to the fourth dose of the new dosing strategy.

Summary Basic knowledge of pharmacokinetics will optimize prescribing by insuring: Maximal therapeutic benefits Minimal adverse effects Cost effectiveness Decreased blood sampling

CE Question #1 A patient is on vancomycin every 8 hours and his half life is 6 hours. What is the earliest you would expect him to be at steady state? 12 hours 6 hours 18 hours 24 hours

CE Question #2 A patient is on gentamicin being treated for a gram negative pneumonia. What is the target serum concentrations? Peak 4; Trough <2 Peak 15; Trough <2 Peak 7; Trough <2 Peak 5; Trough <2

CE Question #3 A 4 year old female child with normal renal function (Wt = 18 kg; Ht = 40 inch) is admitted for presumed meningitis. What would be the appropriate starting dose of vancomycin? 1g q12h 15 mg/kg/dose q6h 5 mg/kg/dose q8h 750mg q6h

CE Question #4 There is a 10 kg patient that is on vancomycin 150mg q8h being treated for cellulitis. The trough comes back at 5 at presumed steady state with all doses given at the appropriate times. The resident calls down to the pharmacy and asks you for a dosage adjustment. What would be an appropriate recommendation? Increase the dose by 10% Change the frequency to q6h at the same dose Increase the dose to 170mg at the same q8h frequency Switch to linezolid because you don’t know how to adjust vancomycin

Questions?

References Harriet Lane Handbook. 17th ed. Robertson, J and Shilkofski, N Editors. Philadelphia: Mosby, Inc., 2005. Shargel L, Yu ABC. Applied Biopharmaceutics and Pharmacokinetics. 3rd ed. Appleton & Lange, 1993. Thomson MICROMEDEX. 1974 - 2008 MICROMEDEX(R) Thomson Healthcare Winter ME. Basic Clinical Pharmacokinetics. 4th ed. Baltimore: Lippincott Williams & Wilkins, 2004. http://www-users.med.cornell.edu www.merck.com. Merck Manual on-line Young, TE and Mangum, B. Neofax. 18th ed. Acorn Publishing, Raleigh, 2005. Taketomo, Hoddong and Kraus. Pediatric Dosage Handbook. Lexi-comp. 2003-2004.