Voriconazole and posaconazole therapeutic drug monitoring: a retrospective study

Background

Therapeutic drug monitoring (TDM) aims to minimize the clinical impact of posaconazole and voriconazole pharmacokinetic variability. However, its benefits on clinical outcomes are still being defined. Additionally, TDM data are limited for posaconazole IV and delayed-release tablet formulations among specific patient populations, including critically ill. The aim of this study was to determine the percentage of therapeutic posaconazole and voriconazole drug levels across all formulations in a real-world clinical setting and elucidate factors affecting attainment of target concentrations.

Methods

This study was a retrospective cohort study conducted at the University of Colorado Hospital between September 2006 and June 2015 that evaluated patients who received posaconazole or voriconazole TDM as part of routine care.

Results

Voriconazole (n = 250) and posaconazole (n = 100) levels were analyzed from 151 patients. Of these, 54% of voriconazole and 69% of posaconazole levels were therapeutic. For posaconazole, 14/38 (37%), 28/29 (97%) and 27/33 (82%) levels were therapeutic for the oral suspension, IV, and delayed-release tablet, respectively. Intravenous and delayed-release tablet posaconazole were 20 fold (p < 0.01) and sevenfold (p = 0.002) more likely than the oral suspension to achieve a therapeutic level. Subsequent levels were more likely to be therapeutic after dose adjustments (OR 3.31; 95% CI 1.3–8.6; p = 0.02), regardless of timing of initial non-therapeutic level. In a multivariable logistic regression analysis, no characteristics were independently predictive of therapeutic voriconazole levels and only absence of H2RA/PPI use was independently predictive of therapeutic posaconazole levels. There was no correlation between survival and therapeutic drug levels for either voriconazole (p = 0.67) or posaconazole (p = 0.50).

Conclusions

A high percentage of drug levels did not achieve TDM targets for voriconazole and posaconazole oral suspension, supporting the need for routine TDM for those formulations. The utility of TDM for the IV and delayed-release tablet formulations of posaconazole is less apparent.

     

Applying Pharmacogenomics to Antifungal Selection and Dosing: Are We There Yet?

This review summarizes recent literature for applying pharmacogenomics to antifungal selection and dosing, providing an approach to implementing antifungal pharmacogenomics in clinical practice. The Clinical Pharmacogenetics Implementation Consortium published guidelines on CYP2C19 and voriconazole, with recommendations to use alternative antifungals or adjust voriconazole dose with close therapeutic drug monitoring (TDM). Recent studies demonstrate an association between CYP2C19 phenotype and voriconazole levels, clinical outcomes, and adverse events. Additionally, CYP2C19-guided preemptive dose adjustment demonstrated benefit in two prospective studies for prophylaxis. Pharmacokinetic–pharmacodynamic modeling studies have generated proposed voriconazole treatment doses based on CYP2C19 phenotypes, with further validation studies needed. Sufficient evidence is available for implementing CYP2C19-guided voriconazole selection and dosing among select patients at risk for invasive fungal infections. The institution needs appropriate infrastructure for pharmacogenomic testing, integration of results in the clinical decision process, with TDM confirmation of goal trough achievement, to integrate antifungal pharmacogenomics into routine clinical care.     

Antifungal Dosing in Critically Ill Patients

This article reviews appropriate dosing for antifungals and emphasizes factors specific to the critically ill patient, along with drug pharmacokinetics and pharmacodynamics. The rationale for doses of the echinocandins (caspofungin, micafungin, anidulafungin), triazoles (fluconazole, voriconazole, itraconazole, posaconazole), amphotericin B (including lipid formulations), and flucytosine are discussed.     

The role of second-generation triazole antifungal agents voriconazole and posaconazole in patients with hematologic malignancies

The second-generation triazoles, voriconazole and posaconazole, have found important roles in the management of invasive fungal infections in high-risk patients. Both agents are more active against Candida albicans and the non-albicans Candida species than the first-generation triazoles. They are active against Aspergillus species, including those species less susceptible to polyenes, and against a variety of non-Aspergillus molds. In contrast to posaconazole, voriconazole has no activity against the zygomycetes, and breakthrough infections have been observed. Both are well absorbed, but considerable intra- and interpatient pharmacokinetic variability has raised the question of therapeutic drug monitoring. Both inhibit hepatic cytochrome P450 isoenzymes, which are important in the metabolism of various drugs coadministered in the management of high-risk patients. Clinical trials have demonstrated the safety and efficacy of both agents for antifungal prophylaxis and treatment in invasive candidiasis, invasive aspergillosis, and in invasive fungal infections caused by a variety of non-Aspergillus molds. Posaconazole is the only triazole approved for use in the treatment of invasive zygomycosis. Voriconazole is the accepted standard first-line therapy for invasive aspergillosis.     

In vitro antifungal activities of anidulafungin and micafungin, licensed agents and the investigational triazole posaconazole as determined by NCCLS methods for 12,052 fungal isolates: review of the literature

The echinocandins anidulafungin and micafungin and the triazole posaconazole are currently undergoing phase III clinical trials. Caspofungin and voriconazole have recently been licensed for the treatment of aspergillosis (both agents), other less common mould (voriconazole) and candidal (caspofungin) infections. This review summarizes the published in vitro data obtained by NCCLS or NCCLS modified methods on the in vitro fungistatic and fungicidal activities of these five agents for yeasts and moulds in comparison to the established agents, amphotericin B, fluconazole, itraconazole, and flucytosine. Among the yeasts, the echinocandins have less activity for Candida parapsilosis and Candida guilliermondii, no activity for Cryptococcus neoformans and Trichosporon spp., but good fungistatic and fungicidal activity in vivo and in vitro for most of the other Candida spp.; this fungicidal activity has been reported by minimum fungicidal concentrations (MFCs) or time kill curve results. The new triazoles exhibit good fungistatic activity (but not fungicidal) for most Candida spp., C. neoformans, and Trichosporon spp. For the Aspergillus spp. evaluated, the echinocandins have similar or better fungistatic activity than those of amphotericin B and the triazoles, but fungicidal activity has been demonstrated only with amphotericin B and the triazoles, with the exception of fluconazole. Most studies showed posaconazole and voriconazole minimum inhibitory concentrations (MICs) ranging from 0.25 to 8 microg/ml for non-solani Fusarium spp., while MIC and minimum effective concentration (MEC) endpoints of the echinocandins were >8 microg/ml. The fungistatic activity of the triazoles is also superior to that of the echinocandins for most of the dimorphic fungi and the Zygomycetes. However, micafungin has activity for the mould phase of most dimorphic fungi, but not for the parasitic or yeast phase of Paracoccidioides brasiliensis. The echinocandins appear to have variable and species dependent fungistatic activity for the dematiaceous fungi, but all agents have poor or no activity against most isolates of Scedosporium prolificans. Only amphotericin B exhibit good fungistatic activity against the Zygomycetes. The combination of caspofungin with some triazoles, amphotericin B or liposomal amphotericin B has been synergistic in vitro, in animal models and in patients. Breakpoints are not available for any mould and antifungal agent combination. In vitro/in vivo correlations should aid in the interpretation of these results, but standard testing conditions are needed for the echinocandins, especially for mould testing, to obtain reliable results.     

Therapeutic Drug Monitoring of Posaconazole: an Update

Posaconazole is a second-generation triazole agent with a potent and broad antifungal activity. In addition to the oral suspension, a delayed-release tablet and intravenous formulation with improved pharmacokinetic properties have been introduced recently. Due to the large interindividual and intraindividual variation in bioavailability and drug-drug interactions, therapeutic drug monitoring (TDM) is advised to ensure adequate exposure and improve clinical response for posaconazole. Here, we highlight and discuss the most recent findings on pharmacokinetics and pharmacodynamics of posaconazole in the setting of prophylaxis and treatment of fungal infections and refer to the challenges associated with TDM of posaconazole.     

Pharmacokinetic considerations for the use of newer antifungal agents

Endogenous commensal yeast and saprophytic molds remain important causes of morbidity and mortality in immunocompromised patients. Treatment options for patients with serious fungal infections have improved over the past decade with the introduction of a novel class of antifungals that target the fungal cell wall (echinocandins) and a new generation of broader-spectrum triazoles (voriconazole, posaconazole). Although these newer therapies provide a number of important advantages in terms of spectrum and safety, their efficacy in some patients can be compromised by limited penetration into some sites of infection or by variable serum concentrations. Hence, pharmacokinetic considerations have become increasingly important for the effective use of these newer antifungals. This article provides a brief overview of the pharmacology and important pharmacokinetic considerations of systemic antifungal therapies, with special focus on newer triazoles and echinocandins.     

Update on Therapeutic Drug Monitoring of Antifungals for the Prophylaxis and Treatment of Invasive Fungal Infections

Purpose of Review

Certain antifungals used as therapy for invasive fungal disease, including the extended-spectrum triazoles, may be limited by variable pharmacokinetics and drug interactions. This is especially important when drug exposure, as measured by trough concentrations, may be linked to either efficacy or toxicity. We review the rationale, indications, and controversies in TDM of antifungals.

Recent Findings

The monitoring of voriconazole drug levels is often practiced in patients that receive this triazole based on clinical data. Posaconazole delayed-release tablets achieve higher drug exposure more consistently, necessitating reconsideration of a role for therapeutic drug monitoring. Isavuconazole has predictable population kinetics, although exposure appears to be reduced in certain groups. However, the utility of isavuconazole therapeutic drug monitoring is unknown.

Summary

Therapeutic drug monitoring is warranted for certain antifungals, while its utility is being reconsidered for others.

     

Emerging Resistance to Azoles and Echinocandins: Clinical Relevance and Laboratory Detection

Failure to respond to antifungal therapy could be due to in vitro resistance (intrinsic or developed during therapy) or clinical resistance. In vitro resistance is mostly due to genetic mutations (resistance mechanisms), and it is associated with high minimal inhibitory concentrations (MICs), minimal effective concentrations (MECs), and/or clinical failure. Clinical breakpoints (CBPs) and/or epidemiologic cutoff values (ECVs) are useful to detect the in vitro antifungal resistance when isolates are tested by standardized methods. ECVs are available from the Clinical and Laboratory Standards Institute (CLSI) for Candida spp. versus echinocandins (anidulafungin, caspofungin, and micafungin) and triazoles (fluconazole, posaconazole, and voriconazole). Lately, the CLSI has adjusted to species-specific CBPs for Candida spp. versus fluconazole, similar to those of the European Committee on Antimicrobial Susceptibility Testing (EUCAST), and versus echinocandins. However, the available voriconazole EUCAST and CLSI CBPs differ. In the absence of CBPs, EUCAST and CLSI assigned ECVs for various Aspergillus spp. and triazoles. This article reviews emerging resistance, laboratory detection, and clinical relevance as reported in the literature in the past 3 to 4 years.     

Simultaneous quantification of voriconazole and posaconazole in human plasma by high-performance liquid chromatography with ultra-violet detection

A sensitive and selective high-performance liquid chromatographic (HPLC) method with ultra-violet detection has been developed and validated for the simultaneous determination of posaconazole and voriconazole, two systemic anti-fungal agents. An internal standard diazepam was added to 100 microL of human plasma followed by 3 mL of hexane-methylene chloride (70:30, v/v). The organic layer was evaporated to dryness and the residue was reconstituted with 100 microL of mobile phase before being injected in the chromatographic system. The compounds were separated on a C8 column using sodium potassium phosphate buffer (0.04 M, pH 6.0): acetonitrile:ultrapure water (45:52.5:2.5, v/v/v) as mobile phase. All compounds were detected at a wavelength of 255 nm. The assay was linear and validated over the range 0.2-10.0 mg/L for voriconazole and 0.05-10.0 mg/L for posaconazole. The biases were comprised between -3 and 5% for voriconazole and -2 and 8% for posaconazole. The intra- and inter-day precisions of the method were lower than 8% for the routine quality control (QC). The mean recovery was 98% for voriconazole and 108% for posaconazole. This method provides a useful tool for therapeutic drug monitoring.     

Azole resistance in aspergillosis: The next threat?

During the past years, aspergilli less susceptible to antifungals have begun to emerge, and antifungal drug resistance may partially account for treatment failures. Resistance of Aspergillus fumigatus clinical isolates to itraconazole, voriconazole, and posaconazole has been reported with increasing frequency, although it is considered an uncommon phenomenon. Molecular biologists have begun to shed light on the mechanisms of A. fumigatus resistance to azoles. Several mechanisms of resistance have been described, such as point mutations of cyp51A and reduced concentrations of intracellular drug. The latter mechanism might be the result of either overexpression of efflux pumps or reduced drug penetration. The issue of cross-resistance between the newer triazoles is of concern and depends on cyp51 mutations. Fungal drug resistance is an issue because of the limited number of antifungal compounds. Patients receiving long-term azole treatment are at highest risk for developing multidrug-resistant A. fumigatus infections.     

How I Treat Blastomycosis

Blastomyces dermatitidis, a dimorphic fungus endemic to the Midwestern, South Central and Northeastern United States, causes the disease blastomycosis. Aerosolized spores from the environment are inhaled into the lungs where primary infection may be asymptomatic or subclinical. Pneumonia, the most common presentation of symptomatic blastomycosis, can be acute, subacute or chronic. Cutaneous, osteoarticular, genitourinary or central nervous system involvement may result from extra-pulmonary dissemination. The Infectious Diseases Society of America has published treatment guidelines for blastomycosis Chapman (Clin Infect Dis 46:1801-1812, 2008). Oral itraconazole has been the mainstay of therapy for mild to moderate infection, while amphotericin B, or alternatively a lipid formulation, is reserved for more severe infection. Newer triazoles, such as voriconazole and posaconazole, have shown clinical potential and expand available treatment options.     

In Vitro Antifungal Susceptibility of Oral <Emphasis Type="Italic">Candida</Emphasis> Isolates from Patients Suffering from Caries and Chronic Periodontitis

Caries and chronic periodontitis are common oral diseases where a higher Candida colonization is reported. Antifungal agents could be adjuvant drugs for the therapy of both clinical conditions. The aim of the current study has been to evaluate the in vitro activities of conventional and new antifungal drugs against oral Candida isolates from patients suffering from caries and/or chronic periodontitis. In vitro activities of amphotericin B, fluconazole, itraconazole, miconazole, nystatin, posaconazole and voriconazole against 126 oral Candida isolates (75 Candida albicans, 18 Candida parapsilosis, 11 Candida dubliniensis, six Candida guilliermondii, five Candida lipolytica, five Candida glabrata, four Candida tropicalis and two Candida krusei) from 61 patients were tested by the CLSI M27-A3 method. Most antifungal drugs were highly active, and resistance was observed in less than 5% of tested isolates. Miconazole was the most active antifungal drug, being more than 98% of isolates susceptible. Fluconazole, itraconazole, and the new triazoles, posaconazole and voriconazole, were also very active. Miconazole, fluconazole and voriconazole have excellent in vitro activities against all Candida isolates and could represent suitable treatment for a hypothetically adjunctive therapy of caries and chronic periodontitis.     

Rapid and Simple Reversed-Phase High-Performance Liquid Chromatography (RP-HPLC) Method for Simultaneous Quantifications of Triazole Antifungals in Human Serum

Purpose

To develop and validate a one-step, rapid and simple reversed-phase high-performance liquid chromatography (HPLC)-based protocol for the simultaneous measurement of voriconazole (VCZ), posaconazole (POSA), itraconazole (ITC) in serum/plasma.

Methods

Calibration standards (CS) and quality control samples were prepared in drug-free serum by spiking with the triazoles at different concentrations. HPLC was performed with C₁₈ column, isocratic mobile phase after extraction with cold acetonitrile. The standardized method was tested in 2693 patients’ serum/plasma samples.

Results

Linearity of CS for ITC, VCZ and POSA was proportional to the nominal concentration (correlation coefficient?>?0.999). Limit of detection (mg/L) for ITC, VCZ and POSA was 0.25, 0.25 and 0.125, respectively. The lower limit of quantification (mg/L) for ITC, VCZ and POSA was 0.5, 0.5 and 0.25, respectively. Precision and accuracy were in acceptable range with 100% average percentage recovery. No interferences from endogenous substances and other antimicrobial compounds were noted. In clinical samples, the therapeutic range achieved for VCZ was 39.9%. Whereas, 61.1% and 44% of samples with ITC and POSA, respectively, were in the sub-therapeutic range.

Conclusion

We developed a rapid and simple HPLC method to quantify common triazoles in a single chromatographic run allowing simultaneous measurement of different antifungals in a small volume of serum/plasma. Thus, therapeutic drug monitoring requests can be processed in one run without changing the protocol parameters, column or column conditioning thereby improving turnaround time.

     

Therapeutic drug monitoring of antifungal agents

Despite a dramatic increase in the number of commercially available agents to treat invasive fungal infections, they remain a common and devastating problem in a variety of patients. The impact of these infections has furthered interest in optimizing antifungal therapy. Therapeutic drug monitoring has emerged as a potentially important area allowing the efficacy of select antifungals to be optimized. This article reviews emerging data examining the utility and rationale for voriconazole and posaconazole therapeutic drug monitoring.     

Method for therapeutic drug monitoring of azole antifungal drugs in human serum using LC/MS/MS

Fungal infections occur in immunocompromised patients. Azole antifungal agents are used for the prophylaxis and treatment of these infections. The interest in therapeutic drug monitoring azole agents has increased over the last few years. Inter- and intra-patient variability of pharmacokinetics, drug–drug interactions, serum concentration related toxicity and success of therapy has stressed the need of frequently therapeutic drug monitoring of the drugs, belonging to the group of azoles. Therefore a simple, rapid and flexible method of analysis is required. This method is based on the precipitation of proteins in human serum with LC/MS/MS detection. Validation was performed according to the guidelines for bioanalytical method validation of the food and drug administration agency. The four most used azole drugs can be detected in human serum within the clinical relevant serum levels with good accuracy and reproducibility at the limit of quantification. Intra- and inter-day validation demonstrated good accuracy and reproducibility. A rapid, sensitive and flexible LC/MS/MS method has been developed and validated to measure voriconazole (VRZ), fluconazole (FLZ), itraconazole (ITZ) and posaconazole (PSZ) in human serum. This new method is suitable for clinical pharmacokinetic studies and routine monitoring in daily practice.     

Antifungal Susceptibility Profile of Candida Albicans Isolated from Vulvovaginal Candidiasis in Xinjiang Province of China

We investigated the antifungal susceptibility profiles of 207 independent Candida albicans strains isolated from patients with vulvovaginal candidiasis (VVC) in Xinjiang Province of China. Using CLSI M27-A3 and M27-S4 guidelines, anidulafungin and micafungin were the most active drugs against C. albicans showing an MIC₅₀/MIC₉₀ corresponding to 0.016/0.0313 µg/mL, followed by caspofungin (0.25/0.25 µg/mL), posaconazole (0.125/0.5 µg/mL), ravuconazole (0.063/1 µg/mL), itraconazole (0.125/1 µg/mL), amphotericine B (0.5/1 µg/mL), isavuconazole (0.063/2 µg/mL), 5-flucytosine (1/2 µg/mL), voriconazole (0.125/4 µg/mL), and fluconazole (0.5/4 µg/mL). 96.1% (199)–100.0% (207) isolates were sensitive to the three echinocandins tested, amphotericine B and 5-flucytosine. The in vitro activity of triazoles against all isolates tested was variable; itraconazole and voriconazole had reduced the activity to almost half of the isolates (55.1% (114) and 51.2% (106) susceptible, respectively). Fluconazole was active against 76.3% (158) isolates tested. The new triazoles ravuconazole, isavuconazole and posaconazole showed good in vitro potency against 89.9% (186)–95.2% (197) of isolates with the geometric mean MIC (µg/mL) of 0.10, 0.12 and 0.14 µg/mL, respectively. In conclusion, our study indicates that for effective management of systemic candidiasis in Xinjiang Province of China, it is important to determine the susceptibility profiles of isolated C. albicans from patients with VVC.

     

EUCAST and CLSI: Working Together Towards a Harmonized Method for Antifungal Susceptibility Testing

The U.S. Clinical and Laboratory Standards Institute (CLSI) and the European Committee of Antimicrobial Susceptibility Testing (AFST-EUCAST) have developed broth microdilution methodologies for testing yeasts and filamentous fungi (molds). The mission of these methodologies is to identify in vitro antifungal resistance, which is accomplished by the use of either clinical breakpoints (CBPs), or to a lesser degree, epidemiologic cutoff values (ECVs). The newly adjusted and species-specific CLSI CBPs for Candida spp. versus fluconazole and voriconazole have ameliorated some of the differences between the two methodologies. In the absence of CBPs for mold testing, CLSI ECVs are available for six Aspergillus species versus the triazoles, caspofungin and amphotericin B. Recently, breakpoints were developed by the EUCAST for certain Aspergillus spp. versus amphotercin B, itraconazole and posaconazole, which to some extent are comparable to ECVs. We summarize these latest accomplishments, which have made possible the harmonization of some susceptibility cutoffs, if not methodologies for some agent/species combinations.     

Antifungal Therapy for Invasive Fungal Diseases in Allogeneic Stem Cell Transplant Recipients: An Update

Invasive fungal diseases (IFDs) remain a major cause of morbidity and mortality in allogeneic stem cell transplant (SCT) recipients. While the most common pathogens are Candida spp. and Aspergillus spp., the incidence of infections caused by non-albicans Candida species as well as molds such as Zygomycetes has increased. For many years, amphotericin B deoxycholate (AMB-D) was the only available antifungal for the treatment of IFDs. Within the past decade, there has been a surge of new antifungal agents developed and added to the therapeutic armamentarium. Lipid-based formulations of amphotericin B provide an effective and less nephrotoxic alternative to AMB-D. Voriconazole has now replaced AMB-D as first choice for primary therapy of invasive aspergillosis (IA). Another extended-spectrum triazole, posaconazole, also appears to be a promising agent in the management of zygomycosis, refractory aspergillosis, and for prophylaxis. Members of the newest antifungal class, the echinocandins, are attractive agents in select infections due to their safety profile, and are a more attractive option compared to AMB-D as initial treatment for invasive candidiasis and (based on one study) challenge fluconazole for superiority in management with this mycoses. However, challenges do exist among these newer agents in very high-risk individuals like allogeneic SCT recipients, which may include adverse drug events, drug–drug interactions, variability in oral absorption, and availability of alternative formulations. The addition of newer agents has also stimulated interest in the potential application of combination therapy in serious, life-threatening infections. However, adequate studies are not available for most IFDs; thus, the clinical use of combination therapy is not evidenced based on most cases and preciseness in its use is uncertain. Finally, therapeutic drug monitoring of select antifungals (notably posaconazole and voriconazole) may play an increasing role due to significant interpatient variability in serum concentrations after standard doses.