- Open Access
Pharmacology and metabolism of voriconazole and posaconazole in the treatment of invasive aspergillosis-review of the literature
© I. Holzapfel Publishers 2011
- Received: 7 February 2011
- Accepted: 22 February 2011
- Published: 28 April 2011
Invasive fungal infections, predominantly aspergillosis and candidiasis, are among the most important causes of morbidity and mortality in immunocompromised patients. Primarily, patients with acute leukemia undergoing myelosuppressive chemotherapy and allogeneic stem cell transplant recipients are affected. Up to 60% of patients with invasive aspergillosis, the most common invasive mycosis among patients with hematologic malignancies, may still die of their infection, once it has become clinically overt. The spectrum of antifungal agents for clinical use now has expanded over the past ten years and includes the novel class of the echinocandins and two newer generation triazoles with an extended spectrum of activity against a wide range of fungal pathogens. This review will address pharmacological characteristics of the two broad-spectrum antifungal azoles, voriconazole and Posaconazole, which are important for their proper use in clinical practice.
- Invasive Aspergillosis
The incidence of invasive fungal infections has increased over the past decades. This is due to an increased number of at-risk immunocompromised individuals, such as patients with acute leukemia undergoing myelosuppressive chemotherapy or allogeneic stem cell transplantation. Advances in treatment options for hematologic malignancies, severe graft-versus-host disease and serious bacterial infections as well as less myelosuppressive conditioning regimens for allogeneic stem cell transplantation have improved clinical outcome for patients, resulting in an increasing number of patients living with a profoundly compromised immune system. One of the sequelae is the rise of invasive fungal diseases (IFD), which for instance have doubled in the past twenty years among allogeneic stem cell transplant recipients . Besides relapse of leukemia and severe bacterial infection, IFD remains the main risk factor for poor outcome of leukemia treatment . Up to 60% of patients with invasive aspergillosis, representing the most common invasive mycosis among patients with hematologic malignancies may still die of their infection, once it has become clinically overt . This has remained a challenge over the past decades, while the spectrum of antifungal agents available for clinical use now has expanded markedly. Therapeutic options now include the novel class of the echinocandins and two newer generation triazoles with an extended spectrum of activity against a wide range of fungal pathogens .
However, many of the new antifungal agents have a pronounced variability in drug levels based on either inconsistent absorption or elimination, resulting in a wide interpatient variability of serum concentrations. Therefore, treatment with the most potent and safe antifungal agent in the most appropriate dosage is one of the main challenges for the clinical management of invasive fungal diseases.
Azole antifungal drugs are frequently used for prophylaxis and treatment of IFD . They exhibit a large number of drug-drug interactions. To date, fluconazole, itraconazole, voriconazole and posaconazole are used for prophylaxis and treatment of IFD in patients with hematologic malignancies. They are substrates for and inhibitors of cytochrome P450 (CYP450) isoenzymes, as well as inhibitors of membrane transporters such as p-glycoprotein (P-gP). The antifungal triazoles target ergosterol biosynthesis by inhibiting the fungal cytochrome P450-dependent enzyme lanosterol 14-alpha-demethylase, causing cell membrane defects and cell death or inhibition of cell growth and replication. The triazoles also inhibit cytochrome P450-dependent enzymes of the functional respiration chain. Itraconazole, voriconazole and posaconazole are active in vitro and in vivo against all common species of Aspergillus. So far, clinically relevant resistance has only rarely been reported, but may become increasingly important in the future .
Pharmacokinetic properties of voriconazole and posaconazole.
(depending on dosage regimen and food)
hepatic: CYP2C19, 2C9, 3 A4
< 1% excreted unchanged in urine 66% excreted unchanged in faeces
hepatic; < 2% excreted unchanged in urine
Voriconazole is a second-generation triazole with broad spectrum of antifungal activity. The most important therapeutic impact is related to its activity against all common Aspergillus spp. It is considered the first-line drug for the treatment of invasive aspergillosis . Voriconazole is also approved for treatment of candidemia in non-neutropenic patients, esophageal candidiasis and disseminated candidiasis and as first-line therapy for mycoses caused by Scedosporium and Fusarium species. It is not active against mucormycoses, primarily caused by Rhizopos, Mucor and Absidia species.
Pharmacokinetics describes and predicts the time course of drug concentrations in body fluids. Voriconazole has non-linear pharmacokinetics and its dose-response relationship exhibits wide interpatient variability. The therapeutic index is narrow, and serum concentrations are significantly influenced by a broad range of drug-drug interactions.
Voriconazole can be given orally or as an intravenous infusion. After oral administration, it is absorbed rapidly within 2 hours with an oral bioavailability of > 90% . Absorption is not affected by gastric pH, but food delays absorption and reduces bioavailability by 22%. Therefore, voriconazole should be taken on an empty stomach . Oral voriconazole reaches steady-state concentrations after 5-7 days of multiple oral administrations depending on the dosage regimen. The time to steady-state can be reduced to 1-2 days by starting with a loading dose. Studies showed non-linear pharmacokinetics with Cmax and area under the plasma concentration time curve (AUC) increasing disproportionately with dose for both intravenous and oral application of the drug . This indicates saturation of its metabolism with respect to dose. The variability in plasma concentration and systemic dosing depends on genetic polymorphisms of the cytochrome P450 (CYP) isoenzymes, which are involved in the metabolism of voriconazole.
It is a major substrate for the CYP2C19 isoenzyme . Depending on genetic polymorphisms, resulting in poor metabolizers and extensive (or rapid) metabolizers, significantly different plasma concentrations are observed despite identical dosing schedules, and low trough concentrations have been reported to be associated with poor clinical results. This has been documented in healthy volunteers, in patients with IFD and those undergoing hematopoietic stem cell transplantation [12–14]. In patients receiving voriconazole for antifungal prophylaxis, 15% had undetectable concentrations and 27% had trough levels below 0.5 mg/l. Only 62% of stem cell transplant recipients had therapeutic concentrations between 0.5 and 2 mg/l . In one study examining the pharmacokinetics of voriconazole in patients after stem cell transplantation, a wide range of serum concentrations even in intraindividual measurements was observed .
Plasma protein binding of voriconazole is 58% and is independent of plasma concentration. Cerebrospinal fluid concentrations of voriconazole are 50% of plasma concentrations with even higher concentrations obtained in brain tissue. According to the "free-drug hypothesis" of anti-infective agents, the free-drug concentration must be considered when exploring the relationship between pharmacokinetic parameters and in vivo activity . The mean elimination half-life (t1/2) of voriconazole is about 6 hours . The mean t1/2 values were greater after multiple oral or intravenous administrations. Voriconazole is distributed widely into tissues with a volume of distribution of approximately 4.6 L/kg.
Since voriconazole is eliminated predominantly by metabolism, it is likely that its non-linear pharmacokinetic profile is probably due to saturation of its metabolism with respect to dose. The variability in plasma concentrations and systemic exposure varies between patients, depending on the genotype of the hepatic cytochrome P450 (CYP) enzymes. The CYP2C19 isoenzyme, for which voriconazole is an important substrate, displays frequent genetic polymorphisms . Homozygous extensive metabolizers have a significantly lower exposure to voriconazole than heterozygous extensive or poor metabolizers. Poor metabolizers can have up to 4 times higher serum voriconazole concentrations than extensive metabolizers . However, to date, no dosage adjustments are recommended with regard to these observations.
Overall, the CYP2C19 genotype accounts (in addition to gender and age) for a large variability in clearance and AUC of voriconazole.
Drug interactions with voriconazole.-
Decreases voriconazole interactions
Increases in concentration by voriconazole
reduce dose by half
Likely increases in concentration by voriconazole
HMG-CoA reductase inhibitors
Calcium channel blockers
HIV protease inhibitors, not indinavir
Voriconazole drug-drug interactions are highly clinically relevant, especially in the treatment of patients with leukemia and after stem cell transplantation, since voriconazole may interact with immunosuppressive drugs and chemotherapeutic agents.
Pharmacodynamic parameters of voriconazole.
Time course of activity
Candida: time-dependent fungistatic
Aspergillus: time-dependent slowly
PAFE in vitro
Candida: no PAFE
Aspergillus: short PAFE
Voriconazole is recommended for first-line treatment of invasive aspergillosis in patients with hematologic malignancies and post allogeneic stem cell transplantation , since it has been associated with superior response and survival rates in a prospective randomized clinical trial comparing the drug with the former gold standard of amphotericin B deoxycholate . In a post-hoc analysis, it could be demonstrated, that response and survival rates in voriconazole-treated patients were approximately 20% higher if the antifungal was started on the basis of a typical radiological sign of invasive pulmonary aspergillosis, as compared to a deferred treatment based upon criteria for proven or probable aspergillosis, as defined by a consensus panel of the European Organization for Research and Treatment of Cancer and the Mycoses Study Group of the National Cancer Institute. The place of voriconazole in the treatment algorithm of empiric therapy for antibiotic-refractory neutropenic fever is less well defined. A prospective study of voriconazole versus liposomal amphotericin B has shown a very low rateof breakthrough fungal infections in voriconazole recipients in this setting, but failed non-inferiority in the primary composite endpoint and thereby the approval of voriconazole for empirical antifungal therapy in febrile neutropenic patients. Further studies of voriconazole in this clinical scenario are ongoing. Voriconazole has demonstrated non-inferiority to fluconazole in prophylaxis of invasive fungal disease in patients after allogeneic stem cell transplantation in a recently published phase III trial. When compared to fluconazole 400 mg daily, it reduced the incidence of invasive aspergillosis, but was non-superior with respect to disease-free survival or overall survival in this patient population at the pre-defined primary endpoint, i.e. 180 days posttransplant .
The efficacy of voriconazole may be related to its serum concentration. While this has never been demonstrated in a prospective phase III trial, retrospective data suggest that it might be reasonable to maintain serum voriconazole trough concentrations of 1-2 mg/l to ensure efficacy. The value of a regular and routine therapeutic drug monitoring, however, is still debated .
Posaconazole is a lipophilic triazole antifungal agent with broad-spectrum antifungal activity in vitro and in vivo against most Candida spp., Cryptococcus neoformans, Aspergillus spp. and several zygomycetes . It has been developed for prophylaxis and treatment of fungal infections in immunocompromised individuals with special consideration of patients with hematologic malignancies and allogeneic stem cell transplant recipients. Posaconazole is the first antifungal drug that has demonstrated superior overall survival when used for antifungal prophylaxis in patients with acute myeloid leukemia or myelodysplastic syndrome undergoing intensive remission induction chemotherapy.
Posaconazole is available as an oral formulation. Its pharmacokinetic profile is characterized by a strong impact of nutrients on its absorption, a long elimination half-life and, in contrast to voriconazole, an only minor metabolism via cytochrome P450 isoenzymes . The oral absorption of posaconazole is dose-limited and strongly dependent on the intake of fat-containing food. The time to reach the maximum plasma concentration is 5-8 hours after administration of a single dose . The relative bioavailability is significantly increased by administration in divided doses. Compared with a single dose, the relative bioavailability of posaconazole 800 mg is increased by 98% when administered in two divided doses every 12 hours, and by 220% when divided in 4 doses administered at 6-hours intervals . Studies on plasma concentrations with doses between 50 mg and 800 mg showed a saturation of absorption occurring above 800 mg. In febrile neutropenic patients or those with refractory invasive fungal disease, there was no further increase in exposure when the dose was increased from 400 mg to 600 mg twice daily .
Posaconazole is highly protein bound (> 98%) and the binding is concentration-independent. This lipophilic drug has a large volume of distribution at steady-state from approximately 5 L/kg to 25 L/kg. This suggests extensive extravascular distribution and penetration into intracellular spaces. Steady-state concentrations are achieved after 7-10 days resulting in a mean terminal half-life of around 35 hours . Peak serum concentration differs significantly between individuals although differences in renal or hepatic function, gender, or body mass or surface area differences do not account for this variation. The reasons for this interindividual variability remain poorly defined.
Posaconazole is not metabolized to a significant extent through the CYP enzyme system . The metabolism of posaconazole is mediated predominantly through phase-2 biotransformation via uridine diphosphate (UDP)-glucuronyltransferase (UGT) enzyme pathways . Posaconazole is also both a substrate and an inhibitor of p-glycoprotein. The role of polymorphisms in genes encoding drug-metabolizing enzymes and transporters in the pharmacokinetics of posaconazole remains to be explored in detail.
Oral food intake increases the bioavailability of posaconazole . Systemic exposure increases by 4-and 2.6-fold when it is consumed with a high-fat or non-fat meal, respectively, when compared to fasting individuals. Administering posaconazole with non-fat food increases its exposure by 164% while inclusion of fat in a meal further increases posaconazole exposure by 48%. Therefore, posaconazole should be administered with a full meal whenever possible, in order to optimize absorption. In patients who are unable to eat, e.g. those with severe mucositis after stem cell transplantation, the addition of a liquid nutritional supplement to the administration of posaconazole has shown efficacy in maintaining sufficient absorption of the drug .
For prophylaxis of IFD in patients with acute leukaemia or with GvHD after allogeneic stem cell transplantation, posaconazole is administered at a dosage of 600 mg daily divided in 3 doses, and for systemic treatment in patients with invasive fungal disease, 800 mg daily divided in 2 doses with a full meal or 4 doses without meal.
Drug interactions with Posaconazole.
Concentration increased by posaconazole
Concentration is increased by posaconazole/decreases posaconazole concentration
Decreases posaconazole concentration
Concentration may be increased by posaconazole
Calcium channel blockers
Drugs for erectile dysfunction (e.g. sildenafil)
HMG-CoA reductase inhibitors
May decrease posaconazole concentrations
Pharmacodynamics refers to the time course and intensity of drug effects on an organism. In these analyses, both the Cmax and the AUC are important factors in determining the efficacy of posaconazole in experimental settings. Posaconazole has shown activity against fungal infections including invasive candidiasis, aspergillosis, cryptococcosis, histoplasmosis, coccidioidomycosis, fusariosis and mucormycosis in numerous preclinical animal and human models .
Posaconazole has considerable in vivo antifungal activity, which has been demonstrated in clinical trials. In clinical practice, it is the drug of first choice for antifungal prophylaxis in patients with acute myeloid leukemia or myelodysplastic syndrome undergoing intensive remission induction chemotherapy as well as in patients with graft-versus-host disease requiring immunosuppressive treatment .
Ullmann et al. randomized over 500 patients with graft-versus-host disease undergoing intensive immunosuppressive therapy to antifungal prophylaxis with either posaconazole or fluconazole . The incidence of proven or probable invasive fungal infection was 5.3% versus 9%, thus not reaching statistically significant difference. A significant reduction in the number of cases of invasive aspergillosis in posaconazole recipients was recorded. While all-cause mortality was not reduced, a significant difference was observed with respect to mortality due to invasive fungal infection (1% versus 4%). The number needed to treat (NNT) in order to prevent one invasive fungal infection with the use of posaconazole versus fluconazole was 27, whereas the NNT to prevent 1 case of invasive aspergillosis was 22.
Cornely et al. studied the role of posaconazole for prophylaxis of IFD in patients with acute leukemia or myelodysplastic syndrome undergoing intensive chemotherapy in a phase III trial comparing posaconazole with standard azole prophylaxis in 602 patients . Patients were randomized to receive either posaconazole or fluconazole or itraconazole, with the latter selected by local investigators. The mean duration of prophylaxis was 29 days in the posaconazole patients and 25 days in the comparator group. Posaconazole significantly reduced the incidence of IFD from 8% to 2%, providing effective prevention of invasive aspergillosis. For the first time, posaconazole improved overall survival in this patient population. The NNT to prevent 1 invasive fungal infection or 1 case of aspergillosis was 17 for each. The NNT to prevent one death was 33. Prophylaxis failures were not explained by the variability in bioavailability of posaconazole. Plasma concentrations of the drug in patients with breakthrough fungal infection were not significantly different from those in the overall patient population.
These two large randomized trials have established the role of posaconazole as antifungal of choice for prophylaxis in these specific patient populations . Although there is no head-to-head randomized trial to date, posaconazole appears superior to voriconazole for prophylaxis of IFD in patients with acute leukemia or myelodysplastic syndrome. Current evidence-based guidelines recommend its prophylactic use in this high-risk patient population undergoing intensive myelosuppressive chemotherapy.
Posaconazole has been evaluated as salvage therapy in patients with refractory IFD . The partial or complete response rate was 60% among patients who had treatment failure with or were intolerant of other antifungal drugs. One-fifth of these patients had developed breakthrough infections with a zygomycete while receiving voriconazole. In this patient cohort, 62% survived and around 40% of deaths were attributed to fungal infection. In another study in patients with refractory invasive aspergillosis in 107 patients, success was obtained in 42% of patients treated with posaconazole . Successful outcome was associated with higher serum concentrations of posaconazole. In a quartile analysis of steady-state maximum or average plasma concentration and response, the response rate in those 25% patients with lowest concentrations was 24% in opposite to the quartile of patients with highest concentrations, in whom a 75% success rate could be demonstrated .
The therapeutic value of serum level monitoring of posaconazole remains unclear to date. In a subsequent analysis of the two above-mentioned posaconazole prophylaxis trials, posaconazole concentrations were found to significantly correlate with a composite efficacy end point including parameters such as absence of premature discontinuation of the prophylactic drug, no IFD and no death. However, the major driving factor for clinical failure was the administration of empiric antifungal therapy and not breakthrough fungal infections or death. Based upon these data, posaconazole drug monitoring cannot be recommended by now.
- Marr KA, Carter RA, Crippa F, et al.: Epidemiology and outcome of mould infections in haematopoietic stem cell recipients. Clin Infect Dis 2002, 34: 909–17. 10.1086/339202PubMedView ArticleGoogle Scholar
- Pagano L, Caira M, Candoni A, et al.: The epidemiology of fungal infections in patients with hematological malignancies: the SEIFEM-2004 study. Haematologica 2006, 91: 1068–75.PubMedGoogle Scholar
- Cuenca-Estrella M, Bernal-Martinez I, Buitrago MJ, et al.: Update on the epidemiology and diagnosis of invasive fungal infections. Int J Antimicrob Agents 2008,32(suppl2):S143–7.PubMedView ArticleGoogle Scholar
- Patterson TF: Advances and challenges in management of invasive mycosis. Lancet 2005, 366: 1013–25. 10.1016/S0140-6736(05)67381-3PubMedView ArticleGoogle Scholar
- Steinbach WJ, Stevens DA: Review of newer antifungal and immunomodulatory strategies for invasive aspergillosis. Clin Infect Dis 2003,37(suppl3):S157–87.PubMedView ArticleGoogle Scholar
- Verweij PE, Mellado E, Melchers WJ: Multiple-triazole-resistant aspergillosis. N Engl J Med 2007, 356: 1481–3.PubMedView ArticleGoogle Scholar
- Boucher HW, Groll AH, Chiou CC, et al.: Newer systemic antifungal agents: pharmacokinetics, safety and efficacy. Drugs 2004, 64: 1997–20. 10.2165/00003495-200464180-00001PubMedView ArticleGoogle Scholar
- Purkins L, Wood N, Greenhalgh K, et al.: Voriconazole, a novel wide-spectrum triazole: oral pharmacokinetics and safety. Br J Clin Pharmacol 2003, 56: Suppl 1:10–6.Google Scholar
- Purkins L, Wood N, Kleinermans D, Greenhalgh K, et al.: Effect of food on the pharmacokinetics of multiple-dose oral Voriconazole. Br J Clin Pharmacol 2003, 56: 17–23.PubMed CentralPubMedView ArticleGoogle Scholar
- Purkins L, Wood N, Ghahramani P, et al.: Pharmacokinetics and safety of Voriconazole following intravenous- to oral-dose escalation regimens. Antimicrob Agents Chemother 2002, 46: 2546–53. 10.1128/AAC.46.8.2546-2553.2002PubMed CentralPubMedView ArticleGoogle Scholar
- Hyland R, Jones BC, Smith DA: Identification of the cytochrome P450 enzymes involved in the N-oxidation of Voriconazole. Drug Metab Dispos 2003, 31: 540–7. 10.1124/dmd.31.5.540PubMedView ArticleGoogle Scholar
- Miyakis S, van Hal SJ, Ray J, et al.: Voriconazole concentrations and outcome of invasive fungal infections. Clin Infect Dis 2010, 16: 927–33.View ArticleGoogle Scholar
- Bruggemann RJ, Blijlevens NM, Burger DM, et al.: Pharmacokinetics and safety of 14 days intravenous voriconazole in allogeneic haematopoietic stem cell transplant recipients. J Antimicrob Chemother 2010, 65: 107–13. 10.1093/jac/dkp416PubMedView ArticleGoogle Scholar
- Denning DW, Ribaud P, Milpied N, et al.: Efficacy and safety of voriconazol in the treatment of acute invasive aspergillosis. Clin Infect Dis 2002, 34: 563–71. 10.1086/324620PubMedView ArticleGoogle Scholar
- Trifilio S, Pennick G, Pi J, et al.: Monitoring plasma voriconazole levels may be necessary to avoid subtherapeutic levels in haematopoietic stem cell recipients. Cancer 2007, 109: 1532–5. 10.1002/cncr.22568PubMedView ArticleGoogle Scholar
- Craig WA, Suh B: Protein binding and the antimicrobial effects: methods for determination of protein binding. In Antibiotics in laboratory medicine. Edited by: Lorian V. Philadelphia (PA): Lippincott Williams & Wilkins; 1991:367–402.Google Scholar
- Jeu L, Piacenti FJ, Lyakhovetskiy AG, et al.: Voriconazole. Clin Ther 2003, 25: 1321–81. 10.1016/S0149-2918(03)80126-1PubMedView ArticleGoogle Scholar
- Ikeda Y, Umemura K, Kondo K, et al.: Pharmacokinetics of Voriconazole and cytochrome P450 2C19 genetic status. Clin Pharmacol Ther 2004, 75: 587–8. 10.1016/j.clpt.2004.02.002PubMedView ArticleGoogle Scholar
- Pfizer Inc: Label: Voriconazole for injections, tablets, oral suspension: LAB -0271–12. 2005.Google Scholar
- Drago M, Scaltrito MM, Morace G: In vitro activity of voriconazole and other antifungal agents against clinical isolates of Candida glabrata and Candida krusei. Eur J Clin Microbiol Infect Dis 2004, 23: 619–24.PubMedView ArticleGoogle Scholar
- Gil-Lamaignere C, Hess R, Salvenmoser S: Effect of media composition and in vitro activity of Posaconazole, Caspofungin and Voriconazole against zygomycetes. J Antimi-crob Chemother 2005, 55: 1016–9. 10.1093/jac/dki140View ArticleGoogle Scholar
- Walsh TJ, Anaissie EL, Denning DW, et al.: Treatment of Aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis 2008, 46: 327–60. 10.1086/525258PubMedView ArticleGoogle Scholar
- Herbrecht R, Denning DW, Patterson TF, et al.: Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002, 347: 408–15. 10.1056/NEJMoa020191PubMedView ArticleGoogle Scholar
- Wingard JL, Carter SL, Walsh TJ, et al.: Randomized, double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infection after allogeneic haematopoietic cell transplantation. Blood 2010, 116: 5111–18. 10.1182/blood-2010-02-268151PubMed CentralPubMedView ArticleGoogle Scholar
- Smith JA: What is the role of therapeutic drug monitoring in antifungal therapy? Curr Infect Dis Rep 2009, 11: 439–46. 10.1007/s11908-009-0064-9PubMedView ArticleGoogle Scholar
- Nagappan V, Deresinski S: Posaconazole: a broad-spectrum triazole antifungal agent. Clin Infect Dis 2007, 45: 1610–7. 10.1086/523576PubMedView ArticleGoogle Scholar
- Li Y, Theuretzbacher U, Clancy CJ, et al.: Pharmacokinetic/Pharmacodynamic profile of Posaconazole. Clin Pharmacokinet 2010, 49: 379–96. 10.2165/11319340-000000000-00000PubMedView ArticleGoogle Scholar
- Courtney R, Pai S, Laughlin M, et al.: Pharmacokinetics, safety, and tolerability of oral Posaconazole administered in single and multiple doses in healthy adults. Antimicrob Agents Chemother 2003, 47: 2788–95. 10.1128/AAC.47.9.2788-2795.2003PubMed CentralPubMedView ArticleGoogle Scholar
- Ezzet F, Wexler D, Courtney R, et al.: Oral bioavailability of Posaconazole in fasted healthy subjects: comparison between three regimens and basis for clinical dosage recommendations. Clin Pharmacokinet 2005, 44: 211–20. 10.2165/00003088-200544020-00006PubMedView ArticleGoogle Scholar
- Schering-Plough Inc: Label: Noxafil ® (Posaconazole) oral suspension. Labeling - 31029708. Kenilworth (NJ): Schering-Plough Inc.; 2006.Google Scholar
- Wexler D, Courtney R, Richards W, et al.: Effect of Posaconazole on cytochrome P450 enzymes: a randomized, open-label, two-way crossover study. Eur J Pharm Sci 2004, 21: 645–53. 10.1016/j.ejps.2004.01.005PubMedView ArticleGoogle Scholar
- Ghosal A, Hapangama N, Yuan Y, et al.: Identification of human UDP-glucuronosyltransferase enzyme(s) responsible for the glucuronidation of posaconazole (Noxafil ® ). Drug Metab Dispos 2004, 32: 267–71. 10.1124/dmd.32.2.267PubMedView ArticleGoogle Scholar
- Courtney R, Wexler D, Radwanski E, et al.: Effect of food on the relative bioavailability of two oral formulations of Posaconazole in healthy adults. Br J Clin Pharmacol 2004, 57: 218–22.PubMed CentralPubMedView ArticleGoogle Scholar
- Courtney R, Radwanski E, Lim J, et al.: Pharmacokinetics of Posaconazole coadministered with antacid in fasting or nonfasting healthy men. Antimicrob Agents Chemother 2004, 48: 804–8. 10.1128/AAC.48.3.804-808.2004PubMed CentralPubMedView ArticleGoogle Scholar
- Ullmann A, Lipton J, Vesole D, et al.: Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med 2007, 356: 335–47. 10.1056/NEJMoa061098PubMedView ArticleGoogle Scholar
- Cornely OA, Maertens J, Winston D, et al.: Posaconazole vs fluconazole or itraconazole prophylaxis for patients with neutropenia. N Engl J Med 2007, 356: 348–359. 10.1056/NEJMoa061094PubMedView ArticleGoogle Scholar
- De Pauw BE, Donnelly JP: Prophylaxis and aspergillosis - has the principle been proven? N Engl J Med 2007, 356: 409–11. 10.1056/NEJMe068266PubMedView ArticleGoogle Scholar
- van Burik JAH, Hare RS, Solomon HF, et al.: Posaconazole is effective as salvage therapy in zygomycosis: a retrospective summary of 91 cases. Clin Infect Dis 2006, 42: e61–5. 10.1086/500212PubMedView ArticleGoogle Scholar
- Walsh TJ, Raad I, Patterson TF, et al.: Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy: an externally controlled trail. Clin Infect Dis 2007, 44: 2–12. 10.1086/508774PubMedView ArticleGoogle Scholar