Paul O. Gubbins

Expansion in academic pharmacy and other health professions has increased the demand for clinical faculty members. The requirement to provide clinical service is unique to clinical faculty and creates a competing demand with the expectation to excel in the tripartite missions of their institution. The efforts of clinical faculty are heavily focused towards the institution’s educational mission. However, often they lack formal training in educational methodology and require ongoing professional development to hone their teaching skills. Therefore, as clinical faculty develop as scholarly teachers, the scholarship of teaching and learning (SoTL) represents an ideal form of scholarship for them to pursue. This essay provides guidance on how clinical faculty members in academic pharmacy and other health professions can transform the act of teaching into scholarly teaching to develop a program of scholarship in SoTL.

Introduction: Triazole antifungal agents are often prescribed as first-line therapy for candidemia, in non-neutropenic hosts and invasive pulmonary aspergillosis, and in critically ill patients who receive many concomitant medications. As substrates and inhibitors of cytochrome P450 (CYP), the triazoles can interact with many drugs, which may lead to enhanced toxicity of the concomitant medication(s) or ineffective antifungal treatment. Therefore, clinicians must understand the drug interaction profile of this class. Areas covered: This manuscript reviews the role of human hepatic CYP in triazole–drug interactions, illustrates how recent discoveries in pharmacogenetics and triazole metabolism impact our understanding of these interactions, and summarizes the most clinically important triazole–drug interactions. A search of English language, original research and scholarly reviews describing interactions between triazole antifungal agents and human CYP published from 1980 to present was undertaken using PubMed. Expert opinion: Triazoles interact with many drugs and the primary mechanism for these interactions is hepatic CYP. Many studies published in the past 2 decades characterize these interactions using the state-of-the-art methods of the time. However, advances in genotyping, improved analytical technology and bioanalytical methods, which enable accurate molecular identification and stereochemical analysis, have substantially added to the understanding of the role hepatic CYP plays in triazole–drug interactions in humans.

Antifungal agents are often prescribed in critically ill patients who are receiving many other medications. When using systemic antifungals, clinicians may possess susceptibility data and they are typically aware of the potential toxicity of these agents. However, the myriad of potential drugs that antifungal agents can interact with is daunting and can be confusing. This article reviews the pharmacokinetic properties of antifungal agents and their clinically relevant drug interactions. The antifungal agents differ markedly in their pharmacokinetic properties and in how they interact with other medicines. The amphotericin B formulations interact with other medicines primarily by reducing their renal elimination or producing additive toxicities. The azoles interact with other medicines primarily by inhibiting biotransformation or by affecting drug distribution and elimination. The echinocandins have the lowest propensity to interact with other medicines. The clinical relevance of antifungal-drug interactions varies substantially. While certain interactions are benign and result in little or no untoward clinical outcomes, others can produce significant toxicity or compromise efficacy if not properly managed through monitoring and dosage adjustment. However, certain interactions produce significant toxicity or compromise efficacy to such an extent that they cannot be managed and the particular combination of antifungal and interacting medicine should be avoided.

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 μg/ml for the first 7 days and >0.220 μg/ml for 7 days after the second dose. A single L-AMB dose (15 mg/kg) produced mean plasma concentrations of >0.491 μg/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 ⁺ , Mg ²⁺ , PO ₄ ), 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.

To explore whether sex-related differences in intestinal itraconazole metabolism exist in healthy adults using grapefruit juice (GFJ) as a selective enteric cytochrome P450 3A4 (CYP3A4) inhibitor.

Mould-active azoles are used to treat systemic mycoses in neutropenic patients because of their broad spectrum activity, their availability as intravenous or oral formulations, and their safety. These agents exhibit complex pharmacokinetics and interact with many drugs, however, which can make their use in neutropenic patients challenging. With the addition of two mould-active azoles to the marketplace in the past several years, this paper will provide an overview of the pharmacokinetics and drug-drug interaction profiles of these azoles and will review the issues surrounding the therapeutic drug monitoring of these agents. New mould-active azoles have sparked interest in correlating their serum concentrations to efficacy and toxicity. Efforts to establish such correlations have, however, generally proved unsuccessful. All mould-active azoles interact significantly with calcineurin inhibitors. When used in combination with mould-active azoles, calcineurin inhibitor doses should be reduced by at least 50% and their blood or serum concentrations should be closely monitored.

The pharmacokinetics of posaconazole oral suspension in neutropenic patients undergoing high-dose chemotherapy and stem cell transplantation were evaluated, and the association of plasma posaconazole exposure with the presence and severity of oral mucositis was explored in this nonrandomized, open-label, parallel-group, multiple-dose pharmacokinetic study. Thirty patients were enrolled and received one of three regimens (group I, 200 mg once daily; group II, 400 mg once daily; group III, 200 mg four times daily) for the duration of neutropenia. The mean total exposure for day 1, as shown by the area under the concentration-time curve from 0 to 24 h (AUC _0-24 ), was 1.96 mg · h/liter in group I and was 51% higher in group II and in group III. Increases in AUC _0-24 and maximum plasma concentration ( C _max ) in groups II and III were dose related. The AUC _0-24 and C _max values on day 1 were similar between groups II and III. There was interpatient variability of up to 68% in the pharmacokinetic values for our study population. Steady state was attained by days 5 to 6. Average steady-state plasma posaconazole trough values were 192, 219, and 414 ng/ml in groups I, II, and III, respectively. The AUC _0-24 and apparent oral clearance increased by increasing dose and dosing frequency. Mucositis appeared to reduce exposure but did not significantly affect mean total posaconazole exposure (AUC and C _max ) at steady state ( P = 0.1483). Moreover, this reduction could be overcome by increasing the total dose and dosing frequency. Posaconazole was safe and well tolerated.

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.

Study Objective. To evaluate the effect of repeated ingestion of grapefruit juice on the systemic availability of itraconazole (ITZ) and hydroxy‐itraconazole (OHITZ) serum concentrations in subjects administered hydroxypropyl‐β‐cyclodextrin‐ITZ (HP‐β‐CD ITZ) oral solution.Design. Randomized, two‐period, crossover study.Setting. College of pharmacy research unit.Subjects. Twenty healthy, adult volunteers (10 men, 10 women).Intervention. Subjects received 240 ml of regular‐strength grapefruit juice from frozen concentrate or bottled purified water 3 times/day for 2 days. On the third day they received a single dose of HP‐β‐CD ITZ oral solution 200 mg (20 ml) with 240 ml of the beverage. Two hours after dosing they received another 240 ml of the beverage.Measurements and Main Results. Repeated blood samples were drawn for 72 hours after dosing. After a 14‐day washout period, subjects were crossed over to the beverage they had not received previously and the above procedure was repeated. There was no difference in peak ITZ concentration (C_max) or time to C_max (T_max). Coadministration of grapefruit juice reduced OHITZ C_max nearly 10%, but this difference was not statistically significant. It produced a statistically significant increase in ITZ area under the concentration‐time curves from 0–48 hours (AUC_0–48) (17%) and from time zero extrapolated to infinity (AUC_0–) (19.5%). Apparent oral clearance of ITZ was significantly reduced (14%). Significant changes in OHITZ exposure were not observed; however, grapefruit juice coadministration produced statistically significant decreased mean OHITZ:ITZ AUC_0–48 and AUC_0– ratios. Grapefruit juice also decreased the mean OHITZ:ITZ C_max ratio, but the difference was not statistically significant.Conclusion. Repeated grapefruit juice consumption moderately affects ITZ systemic availability in subjects administered HP‐β‐CD ITZ oral solution. Unlike previous findings with ITZ capsules, changes in the disposition of ITZ and OHITZ after repeated grapefruit juice consumption are consistent with grapefruit juice inhibition of intestinal cytochrome P450 3A4.