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Therapeutic Drug Monitoring of Systematic Antifungal Therapy
Therapeutic drug monitoring (TDM) involves measuring and interpreting drug concentrations in biological fluids (typically serum) and applying well-described pharmacokinetic and pharmacodynamic principles of the drug to optimize a treatment regimen for an individual patient [2197]. Typically, four criteria must be fulfilled to justify the use of serum drug concentrations to guide drug dosing: First, an assay with appropriate sensitivity, specificity and "turnaround time" from the clinical laboratory must be available for analysis of the drug in question. Second, the clinical efficacy or toxicity of the drug must be delayed or difficult to directly measure. Third, the drug must exhibit significant inter-patient variability in pharmacokinetics to an extent that drug concentrations cannot be assumed from empirical dosing strategies. The fourth requirement (and often most problematic) is that a correlation must be established between drug concentrations and clinical efficacy/toxicity.
Although antifungal therapy does not typically fulfill all four criteria for routine TDM, serum drug level monitoring may be helpful for certain agents where non-compliance, drug interactions, or unexpected toxicity is encountered. For example, measurement of a single trough concentration of an azole-antifungal can verify sub-therapeutic antifungal concentrations in the serum resulting from drug interactions involving cytochrome P450 3A4. TDM is most frequently indicated for flucytosine, itraconazole, and occasionally voriconazole and posaconazole. TDM for other antifungals is more difficult to interpret and apply to clinical dosing. An overview of antifungal TDM parameters are summarized below.
| Drug |
Assay Available? |
Significant inter-patient variability in pharmacokinetics? |
Possible correlation between serum drug concentrations and efficacy/ toxicity? |
Proposed therapeutic range |
Proposed Toxic range |
Sampling |
Reference |
| Amphotericin B |
HPLC Bioassay |
No |
No |
Not established |
Not established |
-- |
-- |
| ABLC |
HPLC Bioassay |
No |
No |
Not established |
Not established |
-- |
-- |
| ABCD |
HPLC Bioassay |
No |
No |
Not established |
Not established |
-- |
-- |
| L-AMB |
HPLC Bioassay |
No |
No |
Not established |
Not established |
-- |
-- |
| Flucytosine |
HPLC Bioassay
Fluorimetry |
Yes, in renal insufficiency |
Yes, for bone marrow suppression |
Not established |
>100-125 µg/mL |
Peak level (2h post dose) |
[1167, 2145] |
| Ketoconazole |
HPLC Bioassay |
Yes, due to poor absorption and differences in intestinal and/or hepatic metabolism |
No |
Not established |
> 6 µg/mL |
Trough level (pre-dose) after 7 days of therapy |
[1624] |
| Fluconazole |
HPLC |
Yes, in renal insufficiency |
Not established, concentrations of 10-20 µg/mL are expected with standard dosing (6 mg/kg/day) |
Not established |
Not established |
Trough level (pre-dose) after 5- 7 days of therapy |
|
| Itraconazole |
Bioassay HPLC |
Yes, due to poor absorption and differences in intestinal and/or hepatic metabolism |
Yes-efficacy |
> 0.5 µg/ml (HPLC) > 1 µg/mL (bioassay) |
Not established |
Trough level (pre-dose) after 7 days of therapy |
[849, 850] |
| Voriconazole |
HPLC |
Yes, due to significant differences in intestinal and/or hepatic metabolism |
Possible, although data are limited |
>0.25-1000 µg/mL |
> 6 µg/mL |
Trough level (pre-dose) after 7 days of therapy |
[574] |
| Posaconazole |
HPLC
LC/MS/MS |
Yes, due to significant differences in absorption |
Possible, although data are limited |
>0.25-1000 µg/mL |
Not established |
Trough level (pre-dose) after 7 days of therapy |
European Medicines Agency |
Caspofungin
Micafungin
Anidulafungin |
HPLC |
No |
Yes-efficacy |
> 1 µg/mL |
Not established |
Peak level (2h post dose) |
[2171] |
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References
574. Denning, D. W., P. Ribaud, N. Milpied, D. Caillot, R. Herbrecht, E. Thiel, A. Haas, M. Ruhnke, and H. Lode. 2002. Efficacy and safety of voriconazole in the treatment of acute invasive aspergillosis. Clin Infect Dis. 34:563-571.
849. Glasmacher, A., C. Hahn, E. Molitor, G. Marklein, T. Sauerbruch, and I. G. H. Schmidt-Wolf. 1999. Itraconazole trough concentrations in antifungal prophylaxis with six different dosing regimens using hydroxypropyl-beta- cyclodextrin oral solution or coated-pellet capsules. Mycoses. 42:591-600.
850. Glasmacher, A., C. Hahn, E. Molitor, T. Sauerbruch, G. Marklein, and I. G. H. Schmidt-Wolf. 2000. Definition of an itraconazole target concentration for antifungal prophylaxis. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Abstract No. 700.
1167. Kauffman, C. A., and P. T. Frame. 1977. Bone marrow toxicity associated with 5-fluorocytosine therapy. Antimicrob. Agents Chemother. 11:244-7.
1624. National Institute of Allergy and Infectious Diseases Mycosis Study Group. 1985. Treatment of blastomycosis and histoplasmosis with ketoconazole: results of a prospective, randomized clinical trial. Ann. Intern. Med. 103:861-872.
2145. Stamm, A. M., R. B. Diasio, W. E. Dismukes, S. Shadomy, G. A. Cloud, C. A. Bowles, G. H. Karam, and A. Espinel-Ingroff. 1987. Toxicity of amphotericin B plus flucytosine in 194 patients with cryptococcal meningitis. Am. J. Med. 83:236-242.
2171. Stone, E. A., H. B. Fung, and H. L. Kirschenbaum. 2002. Caspofungin: An echinocandin antifungal agent. Clin Ther. 24:351-377.
2197. Summers, K. K., T. C. Hardin, S. J. Gore, and J. R. Graybill. 1997. Therapeutic drug monitoring of systemic antifungal therapy. J. Antimicrob. Chemother. 40:753-764.
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