BMJ  2005;331:293-294 (30 July), doi:10.1136/bmj.331.7511.293-a

Letter

Dose adjustment in renal impairment

Response from Drug Prescribing in Renal Failure

EDITOR—Vidal et al should be congratulated on the first scholarly, systematic review of secondary sources of prescribing information for patients with impaired renal function (p 263).¹ That they found inconsistent and conflicting recommendations across multiple sources is not surprising. Their work underscores several problems with which we have struggled to compile our dosing recommendations in Drug Prescribing in Renal Failure.²

Primary sources

Early regulatory requirements did not include formal efficacy, safety, or pharmacokinetic studies for drugs in special populations, including patients with impaired kidney or liver function. Consequently, dosing recommendations for many older drugs are based on flimsy data, including sparse case reports, common usage, and pharmacokinetic extrapolations from studies in subjects with normal renal function. in patients with impaired renal function, but the reports are often absent from the critically reviewed, scientific literature. The results are buried in regulatory reports or found only in other secondary sources. When multiple studies have been published, they are also frequently conflicting in their recommendations because of varied study design and analysis.

One particularly worrisome aspect is that nearly all pharmacokinetic studies are designed and funded by the drugs' manufacturers. Independent evaluations of drug dosing are rare.

Evidence for recommendations

I strongly support the contention that the process by which dosing recommendations are made should be transparent to practitioners. In the next edition of our dosing recommendations we intend to include a brief summary of the sources of information based on levels of evidence and the process by which information was obtained. For example, we will list after each drug recommendation one or more of the following or similar comments illustrating the basis for our recommendations:

• Level A: good and consistent scientific evidence
  
• Level B: limited or inconsistent scientific evidence
  
• Level C: consensus and expert opinion.
  

In addition to the issues found by Vidal et al, other problems related to drug prescribing recommendations continue to plague the effort to provide accurate and timely information.

New drugs and technology

Most printed compendiums of drug dosing recommendations are out of date by the time they are published. The release of new and complex molecular entities and the use of new technologies for renal replacement have made the electronic repository of drug dosing information a necessity.

We constructed an electronic data base for the revision of our drug prescribing suggestions for the authors of our book and for the use of anyone with access to the internet. Updated dosing recommendations for individual drugs can be found at www.kdp-baptist.louisville.edu/renalbook/

Individualised treatment

Even with the best evidence base, dosing recommendations for patients with decreased kidney function are extrapolated to the general population from the study of a very few patients. True individualisation of dosing cannot come from a table of dosing recommendations, but awaits new technologies for predicting drug behaviour in individual patients.³

Despite numerous secondary sources of drug dosing information, drug prescribing in renal failure remains imprecise and relies on interpolation, extrapolation, and estimation. The result in individual patients, at best, is guided trial and error. The work by Vidal et al illustrates Hans Christian Andersen's story The Emperor's New Suit: "Never the emperor's clothes were more admired. `But he has nothing on at all,' said a little child at last."⁴

University of Louisville Kidney Disease Program, 615 South Preston Street, Louisville, KY 40202, USA George.Aronoff{at}kdp.louisville.edu

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Competing interests: None declared.

See Papers p 263

References

1. Vidal L, Shavit M, Fraser A, Paul M, Leibovici L. Systematic comparison of four sources of drug information regarding adjustment of dose for renal function. BMJ 2005;331: 263-6 (30 July.)[Abstract/Free Full Text]
2. Aronoff GR, Berns JS, Brier ME, Golper TA, Morrison G, Singer I, et al, eds. Drug prescribing in renal failure: dosing guidelines for adults. Philadelphia: American College of Physicians, 1999.
3. Gaweda AE, Jacobs AA, Brier ME, Zurada JM. Pharmacodynamic population analysis in chronic renal failure using artificial neural networks—a comparative study. Neural Networks 2003;16: 841-5.[Medline]
4. Andersen HC. The Emperor's new suit (1837). English translation HP Paull (1872) Available at http://hca.gilead.org.il/emperor.html (accessed 20 Jul 2005).

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Relevant Article

Systematic comparison of four sources of drug information regarding adjustment of dose for renal function

Liat Vidal, Maya Shavit, Abigail Fraser, Mical Paul, and Leonard Leibovici
BMJ 2005 331: 263. [Abstract] [Full Text] [PDF]