Dosage Regimen Adjustment in Renal Failure: Why, When and How
WSAVA 2002 Congress
H.P. Lefebvre, DMV, PhD, Dipl ECVPT
UMR 181 Experimental Physiopathology and Toxicology, National Veterinary School of Toulouse
France

Introduction

When drug therapy is initiated in a patient with renal dysfunction, the risk of adverse iatrogenic effects is increased. However, rational approaches exist that enable adjustment of the dosage regimen according to the level of renal function to minimize such risks.

1. Why is dosage regimen adjustment required for some drugs?

Dosage regimen adjustment may be required in renal-impaired conditions for several reasons. The most important one is probably the effect of kidney dysfunction on renal clearance of substances: drug or active metabolites, that are mainly cleared by this route, may accumulate and lead to overexposure. Other effects that might be observed include decrease or increase in hepatic function, decrease in plasma protein binding (this effect however is often overestimated in the literature) and changes in systemic drug availability after oral administration.

2. When should adjustment be considered?

Dosage regimen adjustment is mainly considered in the two following cases: i) the drug is mainly (at least 70% of the dose) excreted by the kidney either unchanged or as an active metabolite, and ii) the therapeutic window of the drug or the metabolite is narrow.

3. How to adjust?

Dosage adjustment is generally based on the assumption that only renal clearance is changed (other pharmacokinetic and pharmacodynamic variables being taken as unaltered). The key factor for dosage regimen adjustment is the dose fraction (Kf), defined as Kf=GFRr/GFRn, where GFRr and GFRn are the GFR values under renal-impaired and healthy conditions, respectively. Change in GFR is considered the best overall indicator of renal dysfunction and the change in drug renal clearance.

The first step of dosage regimen adjustment is to determine the GFR value in the patient. Most of the current recommended techniques for GFR assessment are not practicable. Estimation of Kf based from the observed plasma creatinine value is contraindicated because there is no single linear relationship between plasma creatinine concentration and GFR. The plasma exogenous creatinine clearance test may represent an interesting approach to assess GFR (see next presentation).

Dosage regimen adjustment options involve i) reduction of the dose level, ii) extension of the dosing interval, iii) administration of a loading dose, and/or iv) therapeutic drug monitoring.

The "constant-interval, dose reduction" method-here, the dosing interval is unchanged and the dose is multiplied by Kf. This approach should be used when the dosage interval is less than the elimination half-life, and with drugs with low therapeutic index (Fig. 1).

The "constant-dose, interval extension" method-the dose is unchanged and the dosing interval is increased by dividing it by Kf. This strategy is appropriate for fixed-dosage form, but the dosage interval may be too long and therefore the owner may be less compliant (Fig. 1).

The method may be chosen according to pharmacodynamic considerations. For antibacterial drugs like fluoroquinolones with concentration-dependent kill rate, the "constant-dose, interval extension" method is appropriate, while for those with time-dependent activity (beta-lactams, macrolides...), the "constant-interval, dose-reduction" method is recommended to maintain plasma concentrations above MIC.

Administer a loading dose at the beginning of the treatment-Because the time required to reach steady state (about 5×t1/2) is increased (due to increase in half-life), a loading dose (the same as in healthy conditions) allows therapeutic concentrations to be reached more rapidly when adjusted drug doses are administered thereafter.

Monitor concentrations of drugs with a narrow therapeutic index-This should be performed for drugs with a narrow therapeutic index at regular intervals during the treatment period if renal dysfunction progresses or adverse reactions or therapeutic failure occur. The dose may be adjusted by the following equation: D2=D1×(Ecn/Ocn), with D2, the new dose; D1, the old dose; Ecn, the effective plasma (or serum) concentration (fixed); and Ocn, the plasma (or serum) concentration (observed). Monitoring free concentrations is highly recommended as total concentration may be misleading.

Conclusion

Dosage regimen adjustment remains a difficult challenge in small animal medicine. The best strategy is probably to try to avoid the problem by selecting drugs that are not mainly eliminated by the kidney and having high therapeutic index.


 

 

Figure 1.

Simulated plasma kinetics (depicted by an open monocompartmental model) of a hypothetical drug administered twice daily by the oral route, with half-life of 12 h and totally cleared by the kidney (healthy dog: thin line, renal-impaired adjusted: thick line). The GFR was decreased by 80%. A. Dosage adjustment is performed by "constant interval-dose reduction" method. B. Dosage adjustment is performed by "constant dose-interval extension" method.

Table 1. Recommendations for dosage regimen adjustment (DRA) in renal-impaired dogs.

Comments

Antimicrobial Agents

Aminoglycosides

Contraindicated because of nephrotoxicity.

Penicillins

Accumulation, but high therapeutic index. For dicloxacillin and oxacillin, no change. For others, when GFR<0.5 ml/kg/min, divide the dose by 2 or multiply the dosage interval by 2.

Cephalosporins

Potentially nephrotoxic (especially cephaloridine)

Sulfonamides

Apparently slightly nephrotoxic in the dog. DRA recommended: for sulfisoxazole, multiply the dosage interval by 2-3 when GFR<1 mL/kg/min.

Tetracyclines

Severe accumulation, potentially nephrotoxic, exacerbation of azotemia, contraindicated except doxycycline, which has substantial nonrenal elimination.

Fluoroquinolones

DRA recommended in humans. No DRA required for marbofloxacin in dogs.

Lincosamides and macrolides

No DRA required for erythromycin and clindamycin.

Metronidazole

No DRA required

Anti-Inflammatory Drugs

NSAIDs

Nephrotoxic risk. No accumulation observed with tolfenamic acid.

Corticosteroids

Worsen azotemia

Cardiovascular Drugs

Digitalis glycosides

Accumulation of digoxin, but not digitoxin. TDMhighly recommended.

ACE inhibitors

Enalaprilat and captopril are extensively cleared by the kidney in dogs. No risk of overexposure with benazeprilat.

Antiarrhythmic drugs

Hepatic elimination, but active metabolites are most often cleared by the kidney and the therapeutic index is low.

Diuretics

Decreased elimination and diuretic response for furosemide.

Anesthetics

Barbiturates

Adverse renal hemodynamic effects and potential increase in sensitivity of the central nervous system.

Ketamine

Reduced risk of adverse effects in renal-impaired dogs

Volatile anesthetics

Isoflurane should be preferred to halothane and methoxyflurane.

References

1.  Boothe DM. Therapeutic drug monitoring. In Small Animal Clinical Diagnosis by Laboratory Methods, Willard MD, Tvedten H, Turnwald GH, WB Saunders Company, Philadelphia, 1999, 348-355.

2.  Lefebvre HP, Braun JP, Toutain PL. Drug prescription in renal-impaired dogs. Rev Med Vet, 1996, 147:757-782.

3.  Riviere JE, Vaden SL. Drug therapy during renal disease and renal failure. In Canine and Feline Nephrology and Urology, Osborne CA, Finco DR, Williams and Wilkins, Baltimore, 1995, 555-572.

4.  Riviere JE. Dosage adjustments in renal disease. In Comparative Pharmacokinetics: Principles, Techniques, and Applications, Riviere JE, 1999, Iowa State University Press, Ames, 283-295.

Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)

Hervé P. Lefebvre, DMV, PhD, Dipl. ECVPT
UMR 181 Experimental Physiopathology and Toxicology
National Veterinary School of Toulouse
France


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