Antifungal Dosage Adjustment in Kidney and Liver Dysfunction

Like many other medications, dosages of antifungal agents may be adjusted in patients with compromised kidney or liver function to minimize potential toxicities associated with drug accumulation. Drug interactions can also require a change in antifungal dosing. Fortunately, the effects of impaired kidney and liver function on antifungal concentrations in the body can be anticipated based on the pharmacokinetic properties of the specific antifungal agent; i.e. its absorption, distribution, and pathway for elimination from the body. In certain situations, measuring the serum drug concentration of an antifungal agent can provide some guidance for dosage adjustment or in the assessment of potential for toxic effects.

Although renal function can be assessed by a number of tests and procedures, creatinine clearance (an indicator of the glomerular filtration rate or GFR) is typically considered to be the guiding factor for dosage adjustment. Typically, fixed adjustments in the dose or duration are made for antifungals predominantly cleared through the kidney (i.e. fluconazole, flucytosine) as the GFR rate declines. However, these ranges encompass up to a tenfold range in renal function and may not be optimal for all patients. Therefore, antifungal dosing should always be individualized on the basis of kidney and liver function, medical status of the patient, and severity of the infection.

In patients with chronic renal failure who are receiving intermittent dialysis, the degree of drug removal is dependent upon the type of dialysis (peritoneal versus hemodialysis), the dialysis prescription (e.g., dialysis membrane composition, filter surface area, dialysate composition and flow rate) and the physiochemical characteristics of the drug (e.g., molecular weight, membrane permeability or water solubility, etc.). A more detailed description of factors that effect the dialysis of drugs can be found here. Critically-ill patients with renal failure generally require continuous dialysis or continuous renal replacement therapy (CRRT), which can be provided by a number of methods (e.g., continuous atriovenous hemofiltration, CAVH; continuous venovenous hemofiltration, CVVH; continuous atriovenous hemodialysis, CAVD; continuous venovenous hemodialysis, CVVD; continuous atriovenous hemofiltration, CAVHDF; slow continuous ultrafiltration, SCUF; continuous venovenous high-flux hemodialysis, CVVHFD). Because of the multiple techniques employed in CRRT and variability in individual patient circumstances, clinicians should always refer to the primary literature for assistance with the dosing of specific antifungals. General guidance for adjustment of antifungal dosages in the setting of renal dysfunction is summarized below.

Drug	Dose normal renal function	GFR > 50	GFR 10-50	GFR < 10	Hemodialysis	CAPD	CRRT
Amphotericin B	0.25-1.5 mg/kg q24h	q24h	q24h	q24-q36h	None	Dose for GFR < 10	Dose for GFR 10-50
ABLC	5 mg/kg q24h	q24h	q24h	q24-q36h	None	Dose for GFR < 10	Dose for GFR 10-50
ABCD	3-5 mg/kg/day	q24h	q24h	q24-q36h	None	Dose for GFR < 10	Dose for GFR 10-50
L-AMB	3-5 mg/kg q24h	q24h	q24h	q24-q36h	None	Dose for GFR < 10	Dose for GFR 10-50
Flucytosine	37.5 mg/kg q6h	q6h	q12h-24h	q24-q48h	Dose after dialysis	0.5-1 g/d	Dose for GFR 10-50
Ketoconazole	200-400 mg q24h	100% dose or interval	100% dose or interval	100% dose or interval	Full dose or interval	100% dose or interval	Dose for GFR < 10
Fluconazole	100-800 mg q24h	100% dose or interval	50% dose or interval	50% dose or interval	100% after dialysis	Dose for GFR < 10	Dose for GFR < 10
Itraconazole	200-400 mg q12h	100% dose or interval	100% dose or interval	IV not recommended*	100% dose or interval IV not recommended*	100% dose/interval	Dose for GFR 10-50
Voriconazole	6 mg/kg IV x 2 doses then 4 mg/kg q12h or 200 mg PO q12h	100% dose or interval	100% dose or interval IV not recommended*	IV not recommended*	100% dose or interval	100% dose or interval	Dose for GFR 10-50
Posaconazole	600-800 mg day in divided doses	q24h	q24h	q24h	q24h	Dose for GFR < 10	100% dose or interval
Caspofungin	70 mg initial dose, then 50 mg daily	q24h	q24h	q24h	q24h	Dose for GFR < 10	100% dose or interval
Micafungin	50-150 m daily	q24h	q24h	q24h	q24h	Dose for GFR < 10	100% dose or interval
Anidulafungin	100-200 mg initial dose, then 50-100 mg daily	q24h	q24h	q24h	q24h	Dose for GFR < 10	100% dose or interval

* Due to accumulation of the cyclodextran vehicle, which is minimally dialyzable Source: 2004 Dialysis of Drugs and The Renal Drug Book.

A number of antifungals require biotransformation into more water-soluble metabolites by the liver before excretion from the body. Antifungals are also known to have, like many other drugs, potentially toxic effects in the liver that may be enhanced with pre-existing liver disease. Therefore, antifungal therapy must be used in caution in patients with hepatic insufficiency. In terms of drug dosing, patients with moderate to severe hepatic dysfunction often exhibit a decreased capacity to metabolize certain antifungal agents, leading to decreased overall drug clearance, an increase in the plasma/serum area under the concentration curve (AUC), and prolongation of the half-life (t1/2) of the drug. Hepatic dysfunction can affect the pharmacokinetics and pharmacodynamics of antifungal agents by 1) Reducing the activity of drug metabolizing enzymes such as the cytochrome P450 system, 2) reducing the synthesis of plasma proteins to which the antifungals bind in the bloodstream, and 3) decreasing hepatic blood flow, which results in a decreased efficiency of the liver to clear drugs [1941].

Unfortunately, the severity of hepatic dysfunction and its consequent effects on drug therapy are much more difficult to quantify than renal dysfunction and no single test or calculation has been shown to satisfactorily measure hepatic function and its impairment. This is probably due to the wide spectrum of causes and clinical sequalae of liver dysfunction (e.g., cirrhosis, acute vs. chronic hepatitis, drug-induced liver disease). The most common severity index of hepatic dysfunction reported in the medical literature is the Child-Pugh Score, which is determined from well described clinical indicators of hepatic function such as protein and coagulation status, and the presence and severity of ascites and/or encephalopathy. Based on the fundamental understanding of drug pharmacokinetics, general recommendations for dosage adjustment of antifungals in patients with hepatic dysfunction can be summarized below:

Drug	Effect of hepatic impairment	Adjustment	Dosing Recommendations
Amphotericin B	Not characterized	No dosage adjustment currently recommended	Prescribing information
ABLC	Not characterized	No dosage adjustment currently recommended	Prescribing information
ABCD	Not characterized	No dosage adjustment currently recommended	Prescribing information
L-AMB	Increased deposition of L-AMB in the lung [1018]	No dosage adjustment currently recommended	Prescribing information
Flucytosine	No change in serum concentrations in cirrhotic patients[261]	No dosage adjustment required	Prescribing information
Ketoconazole	Poorly described, possible changes in drug distribution[317]	Consider 50% reduction in dosage in severe hepatic impairment	Prescribing information
Fluconazole	Decreased clearance, increased AUC and t1/2[1986]	Consider 50% reduction in dosage in mild to moderate hepatic impairment. Use only if benefits outweighs risk in patients with severe hepatic impairment	Prescribing information
Itraconazole	Decreased clearance, increased AUC and t1/2	Consider 50% reduction in dosage in mild to moderate hepatic impairment. Use only if benefits outweighs risk in patients with severe hepatic impairment	Prescribing information
Voriconazole	Decreased clearance, increased AUC and t1/2	Mild to moderate hepatic dysfunction- following standard loading dose, reduce maintenance dosage by 50%. Use only if benefits outweighs risk in patients with severe hepatic impairment.	Prescribing information
Posaconazole	Decreased clearance, increased AUC and t1/2	Use only if benefits outweighs risk in patients with severe hepatic impairment.	Prescribing information
Caspofungin	Decreased clearance, increased AUC	Mild hepatic insufficiency: No dosage adjustment needed. Moderate hepatic dysfunction-reduce maintenance dose to 35 mg/day. Not studied in severe hepatic dysfunction.	Prescribing information
Micafungin	No significant change in pharmacokinetics	No dosage adjustment recommended	Prescribing information
Anidulafungin	No significant change in pharmacokinetics	No dosage adjustment recommended	Prescribing information

* Mild hepatic insufficiency- Child-Pugh Class A; Moderate hepatic insufficiency- Child Pugh Class B.

References

261. Block, E. R. 1973. Effect of hepatic insufficiency on 5-fluorocytosine concentrations in serum. Antimicrob. Agents Chemother. 3:141-2.

317. Brass, C., J. N. Galgiani, T. F. Blaschke, R. Defelice, R. A. O'Reilly, and D. A. Stevens. 1982. Disposition of ketoconazole, an oral antifungal, in humans. Antimicrob. Agents Chemother. 21:151-8.

1018. Heinemann, V., D. Bosse, U. Jehn, A. Debus, K. Wachholz, H. Forst, and W. Wilmanns. 1997. Enhanced pulmonary accumulation of liposomal amphotericin B (AmBisome) in acute liver transplant failure. J. Antimicrob. Chemother. 40:295-297.

1941. Rodighiero, V. 1999. Effects of liver disease on pharmacokinetics. An update. Clin Pharmacokinet. 37:399-431.

1986. Ruhnke, M., R. A. Yeates, G. Pfaff, E. Sarnow, A. Hartmann, and M. Trautmann. 1995. Single-dose pharmacokinetics of fluconazole in patients with liver cirrhosis. J Antimicrob Chemother. 35:641-7.