Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 49th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)

San Francisco, California / September 12-15, 2009

As presented here at ICAAC, the importance of therapeutic drug monitoring (TDM) was a recurring theme in a series of studies attempting to define optimal use of newer azole antifungal agents for the treatment of invasive mycotic infections. When the target drug level is known, TDM is a valuable potential tool for improving outcomes, according to experts here at ICAAC and several recently completed studies. Of the newer azoles, voriconazole has been particularly well studied for the potential benefits of TDM. The experimental and clinical data on this agent have been fairly consistent in identifying the optimal area-under-the-curve (AUC) plasma level to the minimum inhibitory concentration (MIC) of approximately 25.

“It should now be mandatory that we do TDM when using voriconazole. We know there is interpatient variability in the pharmacokinetics [PK], we have a well-defined target and we can easily adjust the dose,” stated Dr. Johan W. Mouton, Department of Medical Microbiology and Infectious Diseases, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands. Speaking at a symposium, where others, including Dr. David Andes, Head, Section of Infectious Diseases, University of Wisconsin School of Medicine and Public Health, Madison, made the same point, Dr. Mouton cautioned, “There are huge PK variations [among patients] with all of the azoles except for fluconazole.” He specifically singled out a need for TDM for posaconazole and itraconazole for the same reasons it is appropriate in voriconazole.

The newer azoles have proven very effective and are regarded as first-line therapy for several fungal infections, but they differ for a variety of features such as protein binding, elimination and ability to cross the blood-brain barrier. It has been shown previously with antifungals, including fluconazole, that lower drug exposure leads to increased mortality in life-threatening fungal infections, making interpatient variability likely to be a critical factor for outcome. TDM provides an opportunity to ensure that adequate drug levels are providing appropriate potency with an acceptable risk of adverse events.

Variability of Plasma Levels

The importance of TDM is based on the variability of plasma levels in clinical studies. Two recent studies with voriconazole in children and one with posaconazole in patients with hematologic malignancy all led to the conclusion that TDM is a useful and important tool. In a pediatric study discussed by Dr. Miguel Lanaspa, Pediatric Infectious Diseases and Immunodeficiencies Unit, Vall d’Hebron Hospital, Barcelona, Spain, plasma levels from consecutive children receiving voriconazole were assessed with high-pressure liquid chromatography five days after voriconazole initiation and then weekly to evaluate the antifungal concentration. Not only was the dose-concentration variability large in the 13 patients evaluated, but 84% required dosage adjustment to restore levels to the appropriate therapeutic window.

“We believe that TDM should now be considered necessary in all children receiving voriconazole,” indicated Dr. Lanaspa. He told delegates that this approach is now being initiated at his institution with weekly plasma sampling planned.

The same conclusion was drawn from a study conducted in Canada. In this study reported by Nastya Kassir, PhD, Pharm D, Department of Pharmacy, Université de Montréal, Quebec, plasma concentrations were collected from 33 children receiving oral or intravenous (IV) voriconazole at steady state. Again, the PK parameters were found to be highly variable between patients and within patients, even though Dr. Kassir noted that PK behaviour in children, unlike adults, has been previously identified to be linear. “The large interindividual and intraindividual variability on PK parameters suggests that TDM should be recommended [in a pediatric population],” Dr. Kassir remarked.

In the posaconazole study, adult patients with acute myeloid leukemia who were receiving this antifungal for prophylaxis were evaluated for drug concentrations seven days after initiating oral therapy. On TDM, almost 80% of patients failed to reach a target of 0.5 mcg/mL, according to the authors, led by Dr. M. Bryant, Department of Microbiology, West Virginia University Hospital, Morgantown. The mean concentration of posaconazole was found to be 0.35 mcg/mL.

“No single factor was able to explain the low concentration,” according to the investigators, who said that there was no relationship between drug concentrations and either weight or body surface area in linear regression analyses. They characterized therapeutic posaconazole drug concentrations as difficult to achieve outside of clinical trials and concluded that optimization of dosing in routine care probably requires TDM.

IMPROVIT Study

The incorporation of TDM into routine application of newer azole drugs is expected to be accelerated by these data as well as by expert option based on PK and pharmacodynamics (PD) data, but data are still being generated by studies that are employing fixed doses. A late-breaking study was presented here at ICAAC called IMPROVIT. It compared voriconazole and itraconazole for invasive fungal infection prophylaxis in patients undergoing allogeneic hematopoietic cell transplant; 489 patients were randomized to standard dosages of each drug for a planned regimen of 100 days or 180 days if there were persistent risk factors for fungal infection. To control for a greater risk of adverse events expected on itraconazole, drug-free periods of up to 14 days were permitted.

On the basis of a composite end point of survival without a proven or probable invasive fungal infection or without discontinuing therapy for more than 14 days, voriconazole appeared to be more effective than itraconazole at 100 days (55% vs. 41%; P=0.0007) and 180 days (49% vs. 35%; P=0.0004). Although there was no difference in survival at 180 days (85% in both groups), no patient on voriconazole developed an invasive fungal infection vs. three on itraconazole. Side effects, except visual impairment (6% vs. 0%) and abnormal liver function tests (7% vs. 2%), tended to be lower on voriconazole than itraconazole, for which the median duration of therapy was only 68 days (97 days for voriconazole).

Reported Dr. David I. Marks, University Hospital, Bristol, UK, “Voriconazole appears to be safe and effective for the long-term prophylaxis against invasive fungal infections in this population and more effective than itraconazole.” He remarked that as aspergillosis is a major threat in a neutropenic hematopoietic cell transplant population, the efficacy of voriconazole, which is highly effective as a therapy for this organism, was not unexpected.

CNS Fungal Infections

One of the areas of particular focus in the exploration of the optimal use of the newer azoles is treatment of fungal infections in the CNS. Tissue distribution is a key issue for site-specific treatment of fungal infections and although such differences as protein binding have potential relevance to relative ability to reach difficult compartments, experimental models may not reflect clinical practice. For example, Dr. Michael Henry, Caritas St. Elizabeth’s Medical Center, Boston, Massachusetts, noted that although voriconazole has better CNS penetration than other newer azoles, fungal infection of the CNS would be expected to compromise the integrity of the blood brain barrier, reducing potential differences with other agents. Although Dr. Henry presented data that suggest voriconazole, which is approved for CNS aspergillosis, quickly reaches therapeutic concentrations in the CNS, he called for better studies to determine the relationship between plasma and site-specific drug concentrations.

In remarks on the same subject, Dr. Andes agreed that the relationship between site-specific PK and outcomes might be important in protected sites, particularly the CNS, but that plasma concentrations are generally reflective of target tissue concentrations. Regarding the role of TDM specifically, he indicated that this tool would be expected to be reliable in most clinical situations for verifying that antifungal drug concentrations are within the therapeutic window.

Summary

The newer azoles have been instrumental in improving control of many challenging invasive fungal infections, but new data suggest that PK and PD variability is considerable with these agents. As a result, TDM is increasingly being identified as a clinical tool to ensure that drug concentrations are within the therapeutic window at the time that a steady state is reached, usually two to five days after initiation of therapy, and at regular intervals over the course of a prolonged therapy. More data are needed to demonstrate a direct relationship between TDM and improved outcomes with the most effective of the newer agents, but data with both voriconazole and posaconazole predict improvement in both safety and efficacy.