Pharmacogenomics of triazole antifungal agents: implications for safety, tolerability and efficacy.

INTRODUCTION: Triazole antifungal agents are prescribed to treat invasive fungal infections in neutropenic and non-neutropenic patients. These antifungal agents are substrates and inhibitors of cytochrome P450 (CYP). Genetic polymorphisms in CYP2C9, CYP2C19 and CYP3A5 can lead to large population-specific variations in drug efficacy and safety, optimal dosing, or contribute to drug interactions associated with this class. Areas covered: This manuscript reviews the pharmacogenomics (i.e. the influence of genetics on drug disposition) of triazole antifungal agents related to their CYP-mediated metabolism and summarizes their implications on triazole efficacy, safety, and tolerability. A search of English language original research, and scholarly reviews describing the pharmacogenomics of triazole antifungal agents and their impact on drug efficacy, safety, and tolerability published from 1980 to present was undertaken using PubMed. Expert opinion: Currently studies demonstrating the pharmacogenomic influences on itraconazole, posaconazole and isavuconazole are minimal and limited to their inhibitory effects on CYP3A4 in expressors of CYP3A5 variants. Conversely, there are significant pharmacogenomic considerations for voriconazole because it interacts with several polymorphic CYPs, most notably CYP2C19. Pharmacogenomics of CYP2C9 do not appear to effect fluconazole safety and efficacy. However, genetic polymorphisms may influence its drug interactions but this needs further study.

Steady-state pharmacokinetics of oral voriconazole and its primary metabolite, N-oxide voriconazole, pre- and post-autologous peripheral stem cell transplantation.

Voriconazole (VCZ) is frequently utilized for prevention and treatment of invasive fungal infections in peripheral stem cell transplant (PSCT) patients. We performed an open-label pharmacokinetic study to compare VCZ and N-oxide voriconazole (N-oxide VCZ) pharmacokinetics in patients pre- and post-PSCT. Ten patients completed both sampling periods. The pharmacokinetics of VCZ were unchanged; however, those of N-oxide VCZ were significantly different pre- and post-PSCT.

Pharmacokinetics and buccal mucosal concentrations of a 15 milligram per kilogram of body weight total dose of liposomal amphotericin B administered as a single dose (15 mg/kg), weekly dose (7.5 mg/kg), or daily dose (1 mg/kg) in peripheral stem cell transplant patients.

The pharmacokinetics and safety of extended-interval dosing of prophylactic liposomal amphotericin B (L-AMB) in peripheral stem cell transplant recipients were evaluated. The patients received L-AMB daily at 1 mg/kg of body weight or weekly at 7.5 mg/kg or received L-AMB as a single dose (15 mg/kg). The buccal mucosal tissue concentrations of L-AMB were measured. Of the 24 patients enrolled, 5 withdrew after the initial dose due to an infusion-related reaction (n = 2) or significant increases in the serum creatinine (Scr) levels (n = 3). Weekly L-AMB dosing (7.5 mg/kg) produced mean plasma concentrations of >0.300 microg/ml for the first 7 days and >0.220 microg/ml for 7 days after the second dose. A single L-AMB dose (15 mg/kg) produced mean plasma concentrations of >0.491 microg/ml for at least 7 seven days. These concentrations are within the range of the MICs reported in the literature for susceptible strains of Candida and are at the lower limits of the MICs for Aspergillus spp. Extended-interval dosing produced buccal mucosal tissue concentrations well in excess of the MICs reported in the literature for susceptible strains of Candida and Aspergillus spp. Infusion-related reactions occurred in 24% of the patients. Baseline and end-of-study Scr, electrolyte (K+, Mg2+, PO4), and serum transaminase levels were similar across the dosage groups. Five (31%) patients met the nephrotoxicity definition prior to completion of the study. Patients in the weekly or single-dose groups experienced nephrotoxicity significantly faster than the patients in the daily dosing cohort. A weekly L-AMB dose (7.5 mg/kg) or a single L-AMB dose (15 mg/kg) produced sufficient concentrations in plasma and highly vascular tissue to warrant further studies of the safety, efficacy, and practicality of the weekly prophylactic administration of L-AMB.

Successful treatment of West Nile virus infection after approximately 3 weeks into the disease course.

West Nile virus can cause a febrile illness that may progress to meningoencephalitis. The only available treatments are ribavirin (although it has had limited success in humans) and interferon alpha-2b. A small pilot study showed that starting treatment with interferon alpha-2b on days 1-4 of hospital admission may reduce disease severity and complications. We encountered an 83-year-old man with West Nile meningoencephalitis who began taking interferon alpha-2b 3 weeks after disease presentation. Although studies and reports indicate that treatment is less likely to provide a favorable response if administered after days 1-6 of the disease course, the patient experienced substantial beneficial effects from this treatment. This is the first case report, to our knowledge, that describes successful treatment with interferon alpha-2b after several weeks of West Nile virus infection. Further studies are warranted to more fully understand the value of interferon alpha-2b in treating West Nile meningoencephalitis.

Drug-drug interactions of antifungal agents and implications for patient care.

Drug interactions in the gastrointestinal tract, liver and kidneys result from alterations in pH, ionic complexation, and interference with membrane transport proteins and enzymatic processes involved in intestinal absorption, enteric and hepatic metabolism, renal filtration and excretion. Azole antifungals can be involved in drug interactions at all the sites, by one or more of the above mechanisms. Consequently, azoles interact with a vast array of compounds. Drug-drug interactions associated with amphotericin B formulations are predictable and result from the renal toxicity and electrolyte disturbances associated with these compounds. The echinocandins are unknown cytochrome P450 substrates and to date are relatively devoid of significant drug-drug interactions. This article reviews drug interactions involving antifungal agents that affect other agents and implications for patient care are highlighted.

Effect of high-dose vitamin C on the steady-state pharmacokinetics of the protease inhibitor indinavir in healthy volunteers.

STUDY OBJECTIVE: To determine whether daily high-dose vitamin C alters the steady-state pharmacokinetics of indinavir, a protease inhibitor indicated for treatment of the human immunodeficiency virus type 1. DESIGN: Prospective, open-label, longitudinal, two-period time series. SETTING: University medical center. SUBJECTS: Seven healthy volunteers. INTERVENTION: Indinavir 800 mg every 8 hours was given to subjects for four doses on days 1 and 2. Plasma samples were then collected for indinavir pharmacokinetic determination. After a 7-day washout period, subjects were given vitamin C 1000 mg/day for 7 days. Beginning on day 6 of vitamin C administration, indinavir 800 mg every 8 hours was restarted for four doses. Plasma was then collected from subjects to determine indinavir pharmacokinetics. All subjects were given a vitamin C content-controlled diet for 1 week before the study began and throughout the study period. MEASUREMENTS AND MAIN RESULTS: Steady-state plasma samples were collected before dosing (0 hr) and 0.5, 1, 2, 3, 4, and 5 hours after dosing to determine indinavir pharmacokinetics. Parameters of interest were maximum plasma concentration (C max ), time to C max , area under the plasma concentration-time curve from 0-5 hours after the dose (AUC 0-5 ), an extrapolated 8-hour AUC (AUC 0-8 ), trough (minimum) plasma concentration (C min ), and oral clearance. Mean steady-state indinavir C max was significantly reduced (20%) after 7 days of vitamin C administration (10.3 +/- 1.5 vs 8.2 +/- 2.9 microg/ml, p=0.04). The corresponding mean AUC 0-8 was also significantly decreased (14%; 26.4 +/- 7.2 vs 22.7 +/- 8.1 microg*hr/ml, p=0.05). Although not statistically significant, the mean indinavir C min was 32% lower in the presence of vitamin C (0.27 +/- 0.17 C vs 0.18 +/- 0.08 microg/ml, p=0.09). Indinavir oral clearance and half-life were not significantly different. CONCLUSION: Concomitant administration of high doses of vitamin C can reduce steady-state indinavir plasma concentrations. Subtherapeutic concentrations of antiretroviral agents have been associated with viral resistance and regimen failure, but the clinical significance of our findings remains to be established.

Tick-borne bacterial, rickettsial, spirochetal, and protozoal infectious diseases in the United States: a comprehensive review.

Approximately 900 tick species exist worldwide, and they parasitize a variety of mammals, including humans; thus, ticks play a significant role in the transmission of infectious diseases. In the United States, tick-borne diseases are seasonally and geographically distributed; they typically occur during spring and summer but can occur throughout the year. Tick-borne diseases are endemic to a variety of geographic regions of the United States, depending on the species of tick commonly found in a specific locale. Specific tick-borne diseases are difficult to diagnose. Most patients have vague constitutional symptoms and nonspecific laboratory findings. Initially, serologic methods are of little benefit because they lack sensitivity early in the disease course. Therefore, a thorough history and physical examination are necessary for establishing a diagnosis. Antimicrobial regimens for tick-borne infections are poorly studied but well established. Tetracyclines and rifampin form the cornerstones of therapy for most tick-borne infections, but these agents may not be suitable for all patient populations. Therefore, no single agent can be chosen empirically to treat all tick-borne diseases. Because pharmacists are the most accessible health care providers, they are often asked how to treat tick-borne diseases. Thus, practitioners should be familiar with the ticks that inhabit their locale.