Saturday, November 21, 2015

The Dark Arts of Pharmacokinetics

It’s ok to give 1 gram of vancomycin. As long as they’re obese and the dosing interval is adjusted to follow the two compartment distribution model of vancomycin.
Single, double or triple? In terms of vancomycin dosing kinetics, it’s an important question.  Pharmacokinetic teachings tell us to select the simplest model and fewest compartments necessary to describe the data adequately. Thus the single compartment model is frequently used in initial dosing of vancomycin.  For the most part, vancomycin dosing teachings include solving patient cases using one compartment pk formulas such as the Sawchuck-Zaske.1

However, this simple view ignores the need of vancomycin to distribute into tissue where the infection exists (ie, skin, lung, bone, CNS, etc.).  It has been established that vancomycin demonstrates a two phased distribution; alpha, lasting about 30min to 1hour after the end of an infusion, and beta, the terminal elimination half-life. Simplified single compartment models don’t fully (or at all) take this into account. Never the less, we get away with the assumption of adequate distribution in most situations involving dosing vancomycin, but in models with altered volumes of distribution or clearance such as in obesity (> 30% above IBW) this model falls apart where troughs cannot be predicted accurately.
A two compartment model acknowledges the distribution of vancomycin from plasma into tissues.

This method, while being much more mathematically complex, can be simplified into the weight based dosing models with loading doses and some nomograms (modified Matzke).2 But we also encounter limitations with these models as well.  Loading doses, particularly in obese patients where following dosing recommendations lead to compromises in either adjusting the dose to 2g or less, or accepting the increased risk of nephrotoxicity.3  As a result success rates for achieving desired troughs in obese patients float around 39-42%.4,5
Troughs as a surrogate for AUC 0-24/MIC is a debate for another post, but in the real world the practice is to follow trough.6-8

Given this high rate of failure in such a prolific drug, I’m surprised that this paper has flown so far under the radar. Dr. Tina Denetclaw out of the UCSF School of Pharmacy recently published a protocol of divided loading doses in obese patients that achieved a target trough in 97% of patients at 24 hours.9
Population: This was a prospective analysis of the divided vancomycin loading protocol in consecutive patients weighing > 137% IBW (mean weight: 111 + 31 kg) and admitted to a single community hospital (Marin General Hospital). Patients were excluded if they had long-term paralysis, pregnant, receiving some other vancomycin protocol or had monitoring errors.

Comparison: No real control. Troughs were compared to historical patients who received a protocol by Reynolds et al.
Intervention: Divided load protocol was dependent on the IBW, % over IBW and CrCl. Most patients received 1g IV q6 x 4 doses unless they were a) very tall or b) low CrCl.

Outcome: Percent of patients within target trough range within 12 to 24 hours of dosing initiation.
Within 12 hours: 
  • Trough 10-20, n = 48 (89%); mean 14.5 + 3.2
  • Trough > 10, n = 51 (94%); including the above 48 patients, with the other 3 (6%) having troughs > 20 (20.5 – 22.5)
Within 24 hours: 31 patients had troughs drawn at 24 hours.  19 patients had dosing interval changes that moved the trough draw beyond 24 hours (unclear why, i.e. change in protocol, poor follow up, clinical event (AKI), etc.)
  • Trough 10-20, n = 30/32 (97%); mean 15.0 + 3.1

Authors’ conclusion:
“The biphasic, divided-load obese protocol described here achieved vancomycin trough concentrations in the range of 10-20 within the first 12 hours of treatment for 89% of patients weighing up to 245.2kg, and 97% of trough concentrations sampled during maintenance dosing for the patients were within target range.”

Of course this study has limitations:
No clinical outcomes or patient oriented outcomes.
Small sample, although met its predefined power at 12 hours.

Single center, essentially observational methods and no comparison also limit this study. It may very well be that the expertise of the clinical pharmacist is the reason this result was observed and it is unclear whether this could be externally extrapolated to hospitals with fewer or more limited clinical pharmacists.
Then there is whether it should be taken to a three compartment model.

The three compartment model makes logical sense with vancomycin given the different tissue distribution of the drug (CNS vs skin vs bone vs lung). But these models aren’t easily applied to functional nomograms or dosing protocols. However, my knowledge and understanding of the mathematics involved here left me long ago when I was on an engineering track.  A higher level discussion that is beyond my pk understanding is hopefully taking place somewhere.
We’re still between a rock and a hard place when it comes to dosing vancomycin in obese patients. This new approach seems logical and in this limited study and appears to achieve the desired outcome, but not necessarily improved patient oriented outcomes.  Clearly more evidence is needed to hash out how to dose vancomycin in obese patients, but this protocol could have a role in the future.

1.       Winter ME. Basic Clinical Pharmacokinetics.  3rd edition. Edited by Mary Anne Koda-Kimble, Applied Therapeutics Inc. Vancouver, WA. Copyright 1996
2.       Matzke GR et al.  Pharmacokinetics of vancomycin in patients with various degrees of renal function.  Antimicrob Agents Chemother 1984:25;433-7
3.       Rybak MJ, Lomaestro BM, Rotschafer JC et al. Therapeutic monitoring of vancomycin in adults summary of consensus recommendations from the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Pharmacotherapy. Nov 2009;29(11):1275–1279
4.       Wesner AR, Brackbill ML, Coyle LL, Kidd RS. Prospective trial of a novel nomogram to achieve updated vancomycin trough concentrations. Interdiscip Perspect Infect Dis. 2013;2013:839456. doi:10.1155/2013/839456
5.       Reynolds DC, Waite LH, Alexander DP, DeRyke CA. Performance of a vancomycin dosage regimen developed for obese patients. Am J Health Syst Pharm. 2012;69:944-950
6.       Brown J, Brown K, Forrest A. Vancomycin AUC24/MIC ratio in patients with complicated bacteremia and infective endocarditis due to methicillin-resistant Staphylococcus aureus and its association with attributable mortality during hospitalization. Antimicrob Agents Chemother. 2012;56:634-638. doi:10.1128/AAC.05609-11
7.       Lodise TP, Drusano GL, Butterfield JM, Scoville J, Gotfried M, Rodvold KA. Penetration of vancomycin into epithelial lining fluid in healthy volunteers. Antimicrob Agents Chemother. 2011;55:5507-5511
8.       Skhirtladze K, Hutschala D, Fleck T, et al. Impaired target site penetration of vancomycin in diabetic patients following cardiac surgery. Antimicrob Agents Chemother. 2006;50: 1372-1375
9.       Denetclaw TH, Yu MK, Moua M, Dowling TC, Steinke D. Performance of a divided-load intravenous vancomycin dosing strategy for obese patients. Ann Pharmacother 2015;49(8): 861-868

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