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Comparison of Clinical Pharmacology of Voriconazole and Posaconazole 367

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Comparison of Clinical Pharmacology of Voriconazole and Posaconazole 367 Review Despite greater knowledge and pos- sibilities in pharmacotherapy, fungal infections remain a challenge for cli- nicians. As the population of immu- Comparison of clinical nocompromised patients and those treated for their hematologic ailments pharmacology of voriconazole increases, the number of fungal infec- tions grows too. This is why there is and posaconazole still a quest for new antifungal drugs as well as for optimization of phar- macotherapy with already registered pharmaceutics. Voriconazole and posaconazole are broad-spectrum, new generation, tri- Beata M. Sienkiewicz, Łukasz Łapiński, Anna Wiela-Hojeńska azole antifungal agents. The drugs are used in the pharmacotherapy of Wroclaw Medical University, Wroclaw, Poland invasive aspergillosis, Candida and Fusarium infections. Voriconazole is also used in infections caused by Sce- dosporium. Posaconazole is used in Introduction the treatment of coccidioidomycosis Fungal infections are one of the most severe problems in clinical practice, and chromoblastomycosis. Besides some similarities, the two mentioned especially in hematology and oncology units. They make up from 9 to 10% drugs also show differences in thera- of all infections developing among hospitalized patients. Fungemia can be peutic indications, pharmacokinetics either a complication connected with the malignancy itself or an adverse (mainly absorption and metabolism), effect of the oncological treatment (chemo-, radio- and corticotherapy). Fur- frequency and severity of adverse thermore, it can influence the final result of treatment. In the group of pa- drug reactions, drug–drug interactions tients with oncological diseases, allogenic bone marrow transplantations, and dosage. As both of the drugs are relapse of leukemia, pancytopenia lasting longer than ten days, undergoing used in the treatment of invasive fun- gal infections in adults and children, corticotherapy and broad-spectrum antibiotic therapy, immunosuppressive detailed knowledge of the clinical treatment and graft versus host disease (GVHD) are the main factors predis- pharmacology of antifungal agents is posing to fungal infections. Pathogens mainly responsible for invasive fungal the main factor in pharmacotherapy infections (IFI) are Candida spp. and Aspergillus spp. The first kind often de- optimization in treatment of fungal velops as a concurrent illness during acute mucosa inflammation, infections infections. connected with central venous catheters and the use of broad-spectrum The goal of the article is to present and compare the clinical pharmacol- antibiotics, and pre-existing colonization with the pathogen in at least one ogy of voriconazole and posaconazole body area. The second kind leads to infection resulting from inhalation of as well as to point out the indications spores from the air. This is why pulmonary aspergillosis is one of the most and contraindications of using the frequent infections caused by Aspergillus spp. (87% of patients), followed by drugs, determine factors influencing sinusitis and rhinitis (16%), and less frequently encephalitis (8%). The risk their pharmacotherapy, and provide factors of aspergillosis are neutropenia lasting for longer than two weeks, information that might be helpful in staying in an endemic region, tuberculosis and cytomegalic virus infection. the treatment of fungal infections. The risk factors promoting fungal infections are presented in Table 1 [1–8]. Key words: voriconazole, posacon- The frequency of fungal infections is still growing, and the prophylactic azole, clinical pharmacology, cyto- and empiric antifungal treatment using extended spectrum drugs leads to chrome P-450 enzyme system, drug development of resistance. Unfortunately, such infections are not easy to monitoring. diagnose, especially in their early stages. This is mainly connected with their nonspecific nature – similar to virus and bacterial infections, affecting im- Contemp Oncol (Pozn) 2016; 20 (5): 365–373 munocompromised patients, few symptoms usually limited to pyrexia, de- DOI: 10.5114/wo.2016.64594 creased options of diagnostic testing in patients in a serious condition, and false negative results of performed diagnostic tests. It has been determined that the median mortality rate among patients, after chemotherapy, caused by invasive yeast infections is 39% and it varies among different types of fungi. As an example, the mortality rate in Aspergillus spp. infections is 49.3% and it can rise to 86.7% in patients after hematopoietic cell trans- plantation. For patients with candidiasis the mortality rate is about 14–36%, for invasive fusariosis it is much higher, and varies from 66 to 75%, and for scedosporiosis the estimated mortality rate is between 65 and 100% [9–11]. Every patient with neutropenia and long lasting pyrexia who is not getting better after antibiotic therapy should be suspected of fungal infection, and there is an urgent need to perform laboratory tests. Diagnostic procedures covering microscopic, microbiologic, serologic and genetic testing help to de- cide which pharmacological treatment would be the best [2, 3, 12]. For over 40 years, the treatment of fungal infections was based on ampho- tericin B. The numerous adverse effects, especially nephrotoxicity, forced sci- 366 contemporary oncology Table 1. Risk factors promoting fungal infections Factors connected with: the patient ailments hospitalization and chemo-, radio- and corticotherapy medical invasive procedures Born SGA (small for Disorders of the humoral and Long-term use of central venous Damage of skin and mucous membrane gestational age) cell-mediated immunity catheters integrity due to chemo- and radiotherapy Colonization with Deterioration of phagocytosis and Central lines Long-term use of immunosuppressive Candida fungus intracellular bacterial lysis drugs Damage of natural Disorders in function of B and T Abdominal cavity surgery Long-term use of monoclonal antibodies barriers lymphocytes (especially repeatedly performed, and complicated) Protein and energetic Reduction of immunoglobulin Organ transplantation (especially Long-term cortico- and antibiotic therapy insufficiency production liver transplantation) Complement system disorders Dialysis Long-term neutropenia (> 9 days) Parenteral nutrition lymphopenia, monocytopenia Alkalization of body fluids Colonization of skin and mucosa with hospital bacterial flora Gastrointestinal tract passage Long-term hospitalization disorders Bacterial infections Necrotizing pancreatitis Running malignant disease entists to search for other drugs. In the 1980s, a new gen- The main indications for treatment with voriconazole eration – azole antifungal drugs – entered therapeutic use. are invasive aspergillosis (first line treatment [15, 20]), can- Depending on the amount of nitrogen atoms in the azole didiasis in non-neutropenic patients, fluconazole-resistant ring, the new pharmacotherapeutic group has been divided severe invasive Candida infections (including C. krusei) and into imidazoles (with 2 nitrogen atoms) represented by ke- also invasive Scedosporium spp. and Fusarium spp. infec- toconazole, miconazole, clotrimazole, tioconazole, econazole, tions (first line treatment [20]). The drug can be used in isoconazole, and triazoles (3 nitrogen atoms) – the first gen- children older than two years, and in adults. It is classified eration with fluconazole and itraconazole, the second gener- as C in the FDA Pregnancy Categorization, which means ation with voriconazole and posaconazole [13, 14]. that the drug can be used in pregnant women only when The goal of this article is to present and compare the the benefits for the mother outweigh the risk for the fetus. clinical pharmacology of the new generation triazole drugs It is contraindicated during lactation [16]. voriconazole (approved for therapy in 2002) and posacon- In the prevention of fungal infections, no greater ef- azole (approved for therapy in 2006) [13]. fectiveness of voriconazole over fluconazole has been es- tablished. A decrease in the mortality rate compared with Mode of action and therapeutic indications amphotericin B treatment in the group of patients with The mode of action of voriconazole and posaconazole invasive aspergillosis has been observed [18]. Voriconazole is the inhibition of fungal cytochrome P450 mediated is available on the market in the form of film-coated tab- 14-alpha lanosterol demethylation, which causes damage lets, oral suspension, and as an infusion [20]. It should be in the structure and the loss of cell membrane function. administered a minimum of 1 h before meals. A contraindi- Voriconazole is a broad spectrum antifungal agent indicat- cation for the use of voriconazole is hypersensitivity to the ed for the treatment of candidiasis also caused by fluco- drug itself or other azoles. During the treatment, liver and nazole-resistant C. glabrata and C. krusei. Moreover, it can kidney biochemical parameters should be monitored. The be used in Aspergillus (A. flavus, A. fumigatus, A. terreus, patients should avoid long exposure to the sun. Photosen- A. niger, A. nidulans), Cryptococcus neoformans, Fusari- sitivity usually develops after 12 weeks of treatment [15]. um, Scedosporium, Penicillium, Alternaria, Blastomyces According to numerous adverse drug reactions (ADR), dermatidis, Blastoschizomyces capitatus, Cladosporium, the duration of antifungal therapy should be as short as Coccidioides immitis, Conidiobolus coronatus, Madurella possible. In cases of treatment longer than 6 months, the mycetomatis,
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