-
1.
Serum 4β-hydroxycholesterol increases during fluconazole treatment.
Lütjohann, D, Stellaard, F, Kerksiek, A, Lötsch, J, Oertel, BG
European journal of clinical pharmacology. 2021;(5):659-669
-
-
Free full text
-
Abstract
PURPOSE The antifungal drugs ketoconazole and itraconazole reduce serum concentrations of 4β-hydroxycholesterol, which is a validated marker for hepatic cytochrome P450 (CYP) 3A4 activity. We tested the effect of another antifungal triazole agent, fluconazole, on serum concentrations of different sterols and oxysterols within the cholesterol metabolism to see if this inhibitory reaction is a general side effect of azole antifungal agents. METHODS In a prospective, double-blind, placebo-controlled, two-way crossover design, we studied 17 healthy subjects (nine men, eight women) who received 400 mg fluconazole or placebo daily for 8 days. On day 1 before treatment and on day 8 after the last dose, fasting blood samples were collected. Serum cholesterol precursors and oxysterols were measured by gas chromatography-mass spectrometry-selected ion monitoring and expressed as the ratio to cholesterol (R_sterol). RESULTS Under fluconazole treatment, serum R_lanosterol and R_24,25-dihydrolanosterol increased significantly without affecting serum cholesterol or metabolic downstream markers of hepatic cholesterol synthesis. Serum R_4β-, R_24S-, and R_27-hydroxycholesterol increased significantly. CONCLUSION Fluconazole inhibits the 14α-demethylation of lanosterol and 24,25-dihydrolanosterol, regulated by CYP51A1, without reduction of total cholesterol synthesis. The increased serum level of R_4β-hydroxycholesterol under fluconazole treatment is in contrast to the reductions observed under ketoconazole and itraconazole treatments. The question, whether this increase is caused by induction of CYP3A4 or by inhibition of the catabolism of 4β-hydroxycholesterol, must be answered by mechanistic in vitro and in vivo studies comparing effects of various azole antifungal agents on hepatic CYP3A4 activity.
-
2.
Efficacy of a paclitaxel-eluting biliary metal stent with sodium caprate in malignant biliary obstruction: a prospective randomized comparative study.
Jang, SI, Lee, KT, Choi, JS, Jeong, S, Lee, DH, Kim, YT, Lee, SH, Yu, JS, Lee, DK
Endoscopy. 2019;(9):843-851
Abstract
BACKGROUNDS The placement of a self-expandable metal stent (SEMS) is widely used in patients with unresectable malignant biliary obstructions, but SEMSs are susceptible to occlusion by tumor ingrowth or overgrowth. The efficacy and safety of a novel paclitaxel-eluting biliary metal stent incorporating sodium caprate (MSCPM-III) were compared prospectively with those of a covered metal stent (CMS) in patients with malignant biliary obstructions. METHODS Patients with unresectable distal malignant biliary obstructions (n = 106) were prospectively enrolled in this study at multiple treatment centers. Stents were placed endoscopically: MSCPM-III in 54 patients and CMS in 51 patients. The patients received systemic chemotherapy regimens according to their disease characteristics. RESULTS The two groups did not differ significantly in basic characteristics or mean follow-up period. Stent occlusion occurred in 14 patients who received MSCPM-III and in 11 patients who received CMS. Time to recurrent biliary obstruction (RBO) and survival time did not differ significantly between the two groups (P = 0.84 and P = 0.29, respectively). However, tumor size at 2 months after stent insertion was significantly decreased in patients in the MSCPM-III group with bile duct cancers or those who experienced stent migration compared with the CMS group. Complications, including cholangitis and pancreatitis, were found to be acceptable in both groups. CONCLUSIONS Although compared with a CMS the MSCPM-III did not significantly influence time to RBO or survival duration in patients with malignant biliary obstructions, MSCPM-III reduced tumor volume and was used safely in humans.
-
3.
QT prolongation in patients with acute leukemia or high-risk myelodysplastic syndrome prescribed antifungal prophylaxis during chemotherapy-induced neutropenia.
Barreto, JN, Cullen, MW, Mara, KC, Grove, ME, Sierzchulski, AG, Dahl, NJ, Tosh, PK, Dierkhising, RA, Patnaik, MM, Ackerman, MJ
Leukemia & lymphoma. 2019;(14):3512-3520
Abstract
Benefits of serial electrocardiographic (ECG) monitoring to detect QT prolongation in patients with hematological malignancies remain unclear. This retrospective, single-center, study evaluated 316 adult acute leukemia and high-risk MDS patients who received 11,775 patient-days of voriconazole prophylaxis during induction chemotherapy. Of these, 37 patients (16.2%) experienced QTc prolongation. Medications associated with QTc prolongation included furosemide, haloperidol, metronidazole, mirtazapine, prochlorperazine, and venlafaxine. Hypokalemia and hypomagnesemia were also significantly associated with QTc prolongation (HR 3.15; p = .003 and HR 6.47, p = .007, respectively). Management modifications due to QTc prolongation included discontinuation of QT prolonging medications (n = 25), more aggressive electrolyte repletion (n = 5), and enhanced ECG monitoring (n = 3). One patient with multiple QT prolonging factors experienced possible Torsades de Pointes. Overall mortality was 15% with no cardiac-related deaths. Serial ECG monitoring during induction chemotherapy can be tailored proportionally to QT-prolonging risk factors. Management should include aggressive electrolyte repletion and avoidance of concurrent QT prolonging medications.
-
4.
Correlation of In Vitro Susceptibility Based on MICs and Squalene Epoxidase Mutations with Clinical Response to Terbinafine in Patients with Tinea Corporis/Cruris.
Khurana, A, Masih, A, Chowdhary, A, Sardana, K, Borker, S, Gupta, A, Gautam, RK, Sharma, PK, Jain, D
Antimicrobial agents and chemotherapy. 2018;(12)
-
-
Free full text
-
Abstract
Recalcitrant dermatophytoses are on the rise in India. High MICs of terbinafine (TRB) and squalene epoxidase (SQLE) gene mutations conferring resistance in Trichophyton spp. have been recently documented. However, studies correlating laboratory data with clinical response to TRB in tinea corporis/cruris are lacking. For this study, we investigated the clinicomycological profile of 85 tinea corporis/cruris patients and performed antifungal susceptibility testing by CLSI microbroth dilution and SQLE mutation analysis of the isolates obtained and correlated these with the responses to TRB. Patients confirmed by potassium hydroxide (KOH) mounting of skin scrapings were started on TRB at 250 mg once a day (OD). If >50% clinical clearance was achieved by 3 weeks, the same dose was continued (group 1). If response was <50%, the dose was increased to 250 mg twice a day (BD) (group 2). If the response still remained below 50% after 3 weeks of BD, the patients were treated with itraconazole (ITR; group 3). Overall, skin scrapings from 64 (75.3%) patients yielded growth on culture. Strikingly, all isolates were confirmed to be Trichophyton interdigitale isolates by internal transcribed spacer (ITS) sequencing. Thirty-nine (61%) of the isolates had TRB MICs of ≥1 µg/ml. Complete follow-up data were available for 30 culture-positive patients. A highly significant difference in modal MICs to TRB among the three treatment response groups was noted (P = 0.009). Interestingly, 8 of the 9 patients in group 3 harbored isolates exhibiting elevated TRB MICs (8 to 32 µg/ml) and SQLE mutations. The odds of achieving cure with TRB MIC < 1 µg/ml strains were 2.5 times the odds of achieving cure with the strain exhibiting MIC ≥1 µg/ml.
-
5.
Serum 1,3-beta-d-glucan for antifungal treatment stratification at the intensive care unit and the influence of surgery.
Prattes, J, Hoenigl, M, Rabensteiner, J, Raggam, RB, Prueller, F, Zollner-Schwetz, I, Valentin, T, Hönigl, K, Fruhwald, S, Krause, R
Mycoses. 2014;(11):679-86
Abstract
The purpose of this study was to evaluate a preemptive approach with serum 1,3-beta-d-glucan (BDG) as a marker for treatment stratification of systemic antifungal (AF) therapy in patients with clinical suspected invasive fungal infections (IFI) at intensive care units (ICU), and the impact of surgical procedures. A total of 66 ICU patients with clinical suspected IFI were included in this retrospective analysis. Serum BDG testing was performed prior to initiation of AF treatment and in addition to routine diagnostic measures. Based on the BDG results the initial clinical decision whether or not to start systemic AF therapy was re-evaluated. Impact of surgical procedures on clinical utility of serum BDG was evaluated in a sub-group of 25 patients who had undergone surgical procedures prior to BDG evaluation. BDG test results led to discontinuation of AF therapy in 13 patients, and initiation of AF therapy in seven patients. In 46 patients the clinical decision was confirmed by BDG. The majority of suspected, probable and proven IFI cases (10/13, 77%) was predicted by the test. BDG testing turned out positive in 9/25 (36%) of patients that had undergone recent surgery and levels correlated with clinical findings. Serum BDG evaluation seems to be a promising tool to guide AF therapy in ICU patients even after recent surgical procedures.
-
6.
Evaluation of the effect of food and ketoconazole on the pharmacokinetics of the smoothened inhibitor PF-04449913 in healthy volunteers.
Shaik, MN, LaBadie, RR, Rudin, D, Levin, WJ
Cancer chemotherapy and pharmacology. 2014;(2):411-8
Abstract
PURPOSE To evaluate the effect of a potent cytochrome P450 3A4 (CYP3A4) inhibitor, ketoconazole, and separately the effect of food on PF-04449913 pharmacokinetics in healthy volunteers. METHODS This was an open-label, two-sequence, three-period, three-treatment, single-dose, crossover study. Subjects were randomized to receive single doses of 200 mg PF-04449913 after an overnight fast or after consuming a high-fat meal during Period 1 or 2, with a washout period of at least 8 days. In Period 3, all subjects received ketoconazole (400 mg/day) (days 1-7) and a co-administered single 200-mg PF-04449913 dose (day 4). RESULTS Geometric mean ratio of PF-04449913 in the presence of ketoconazole versus PF-04449913 alone was 2.40 [90% confidence interval (CI) 2.15, 2.68] for area under the plasma concentration-time curve from time zero to infinity (AUC(0-inf)) and 1.40 (90% CI 1.24, 1.58) for peak plasma concentration (C max). The geometric mean ratio for fed state compared with fasted state for AUC(0-inf) was 0.87 (90% CI 0.78, 0.97) and for C max was 0.66 (90% CI 0.56, 0.78). PF-04449913 was well tolerated, and all adverse events were mild to moderate. CONCLUSIONS PF-04449913 plasma exposures and peak concentrations were increased following concurrent administration of ketoconazole in healthy volunteers. These findings provide the upper limit for expected PF-04449913 exposures after co-administration of a strong CYP3A4 inhibitor in patients with cancer who routinely receive antifungal azoles. While a high-fat meal decreased PF-04449913 exposure, the differences in plasma exposure under the two conditions were not considered clinically meaningful.
-
7.
Eribulin mesylate pharmacokinetics in patients with solid tumors receiving repeated oral ketoconazole.
Devriese, LA, Mergui-Roelvink, M, Wanders, J, Jenner, A, Edwards, G, Reyderman, L, Copalu, W, Peng, F, Marchetti, S, Beijnen, JH, et al
Investigational new drugs. 2013;(2):381-9
Abstract
Purpose To study the influence of repeated oral administration of ketoconazole, a potent CYP3A4 inhibitor, on the plasma pharmacokinetics of eribulin mesylate administered by single-dose intravenous infusion. Eribulin mesylate is a non-taxane microtubule dynamics inhibitor that is currently under development in phase I-III trials for the treatment of solid tumors. Experimental design A randomized, open-label, two treatments, two sequences, crossover phase I study was performed in patients with advanced solid tumors. Treatments were given on day 1 and day 15 and consisted of 1.4 mg/m(2) eribulin mesylate alone or 0.7 mg/m(2) eribulin mesylate plus 200 mg ketoconazole on the day of eribulin mesylate administration and the following day. Pharmacokinetic sampling for determination of eribulin plasma concentration was performed up to 144 h following administration of eribulin mesylate. Also safety and anti-tumor activity were determined. Results Pharmacokinetic sampling and analysis was completed in ten patients. Statistical analysis of dose-normalized log-transformed AUC0-∞ and Cmax indicated that single-dose exposure of eribulin was not statistically different when co-administered with ketoconazole (ratio of geometric least square means: 0.95 (90%CI: 0.80-1.12) and 0.97 (90%CI: 0.83-1.12), respectively) in patients with solid tumors. Ketoconazole had no effect on eribulin clearance and elimination half-life. The most frequently reported treatment related adverse events were fatigue and nausea, each reported in 8/12 patients. Seven patients (58.3 %) achieved stable disease as best overall response. Conclusions The results indicate that eribulin mesylate can be safely co-administered with ketoconazole. Drug-drug interactions are not expected with other CYP3A4 inhibitors.
-
8.
Effect of clarithromycin and fluconazole on the pharmacokinetics of montelukast in human volunteers.
Hegazy, SK, Mabrouk, MM, Elsisi, AE, Mansour, NO
European journal of clinical pharmacology. 2012;(9):1275-80
Abstract
OBJECTIVE Montelukast, a leukotriene receptor antagonist, is used in the treatment of asthma. The objective of the study reported here was to determine whether multiple doses of clarithromycin or fluconazole affect the pharmacokinetics of montelukast. METHODS This was a four-phase cross-over study with a washout period of 2 weeks between phases. In phase 1, 12 volunteers received a single oral dose of 10 mg montelukast. In phase 2, the volunteers received a single, oral dose of 1,000 mg clarithromycin once daily for 2 days, followed by, on day 3, a single oral dose of 10 mg montelukast co-administered with clarithromycin. In phase 3, a single oral dose of 50 mg fluconazole was given once daily for 6 days, followed by, on day 7, a single oral dose of 10 mg montelukast co-administered with 50 mg fluconazole. In the last phase (phase 4), a single oral dose of 150 mg fluconazole was given once daily for 6 days, followed by, on day 7, a single oral dose of 10 mg montelukast co-administered with 150 mg fluconazole. The plasma concentration of montelukast was measured by high performance liquid chromatography for 24 h. RESULTS Following clarithromycin co-administration, the area under the concentration-time curve from zero to infinity ( AUC(0-∞)) of montelukast increased by 144% [90% confidence interval (CI) 2.03-2.86]. The co-administration of a single oral dose of 150 and 50 mg fluconazole decreased the montelukast AUC(0-∞) by 30.7 (90% CI 0.53-0.81) and 38.8% (90% CI 0.57-0.69), respectively. CONCLUSIONS Clarithromycin increased the plasma concentrations of montelukast whereas fluconazole reduced the plasma concentrations of montelukast. The mechanism of the interaction is probably due to interference of the interacting drugs with transporters mediating the uptake of montelukast.
-
9.
CYP3A5*1/*3 genotype influences the blood concentration of tacrolimus in response to metabolic inhibition by ketoconazole.
Chandel, N, Aggarwal, PK, Minz, M, Sakhuja, V, Kohli, KK, Jha, V
Pharmacogenetics and genomics. 2009;(6):458-63
Abstract
OBJECTIVES Ketoconazole retards metabolic degradation of tacrolimus through its effect on the cytochrome P-450 enzyme system and allows reduction in treatment costs. Enzyme activity is determined by a single nucleotide polymorphism (*1/*3) in the CYP3A5 gene. METHODS We prospectively investigated the impact of this polymorphism on tacrolimus concentration in a cohort of 79 renal transplant recipients on ketoconazole. Genotyping was carried out by using polymerase chain reaction-restriction fragment length polymorphism technique. Dose-adjusted trough level (C0) was calculated at baseline and at 3, 7, 15, 30, and 60 days. RESULTS The baseline C0 was significantly lower in those with at least one *1 allele [44.95+/-14.12 vs. 63.43+/-14.72 (ng/ml)/(mg/kg/day), P<0.0001]. After starting ketoconazole in all genotypes, dose-normalized C0 increased and the cost of therapy decreased. Compared with baseline, the magnitude of increase was 112% and 79% in those without and with *1 allele, respectively (P<0.001). The cost savings were 32% and 39% in mycophenolate mofetil-treated and 47% and 61% in azathioprine-treated patients who were with and without one *1 allele, respectively. CONCLUSION We show that the CYP3A5*1/*3 polymorphism is an important determinant of the response to inhibition of tacrolimus metabolism by ketoconazole, with a 30% greater inhibition in those lacking *1 allele. This finding will allow better dose adjustment and minimize exposure to subtherapeutic or toxic concentrations.
-
10.
Effects of oral posaconazole on the pharmacokinetic properties of oral and intravenous midazolam: a phase I, randomized, open-label, crossover study in healthy volunteers.
Krishna, G, Moton, A, Ma, L, Savant, I, Martinho, M, Seiberling, M, McLeod, J
Clinical therapeutics. 2009;(2):286-98
Abstract
BACKGROUND Like itraconazole and ketoconazole, posaconazole, a broad-spectrum oral triazole antifungal, inhibits the activity of the cytochrome P450 (CYP) isozyme 3A4. Midazolam, a short-acting benzodiazepine, is metabolized by CYP3A4. Potential drug interactions can be expected in patients who are concurrently receiving inhibitors and substrates of CYP3A4 (eg, ketoconazole, posaconazole) and benzodiazepines (eg, midazolam). Because of the potential for drug interactions, it is important to determine the effects of posaconazole on the pharmacokinetic properties of midazolam. OBJECTIVE The aim of this study was to compare the effects of oral administration of posaconazole versus ketoconazole on the pharmacokinetic properties of orally and intravenously administered midazolam. METHODS This Phase I, randomized, open-label, crossover study was conducted at Swiss Pharma Contract Ltd., Allschwil, Switzerland. Healthy volunteers were randomly assigned to 1 of 2 treatment arms. Arm 1 received posaconazole 200 mg BID for 7 days, posaconazole 400 mg BID for 7 days, no drugs during a 28-day washout, and ketoconazole 400 mg once daily for 7 days. Arm 2 received posaconazole and ketoconazole in the reverse order, with a 28-day washout between treatments. An oral/IV midazolam sequence (oral midazolam 2 mg and IV midazolam 0.4 mg) was administered on days -2/-1, 6/7, 13/14 (arm 1), 36/17 (arm 2), 43/44, and 50/51 in both treatment arms. Blood samples were collected up to 24 hours after midazolam administration. Pharmacokinetic parameters, including C(max), C(min) (before azole administration), terminal-phase t(1/2) (t(1/2z)), and AUC to final measurable sampling time (AUC(tf)), were calculated using noncompartmental methods, and drug interactions were evaluated using analysis of variance. Adverse events were collected using physical examination, including vital sign measurements; clinical laboratory analysis; electrocardiography; and direct questioning at predefined time points throughout the study to assess tolerability. RESULTS A total of 12 subjects were enrolled (11 men, 1 woman; all white; mean age, 42.8 years [range, 28-53 years]; mean weight, 80.6 kg; and mean body mass index, 25.6 kg/m(2)). All of the subjects completed the study. Based on point estimates of logarithm-transformed data, posaconazole 200 and 400 mg BID were associated with significant increases in midazolam C(max) (up to 1.3- and 2.4-fold) and AUC(tf) values (up to 4.6- and 6.2-fold), respectively. Ketoconazole 400 mg once daily was associated with significantly increased midazolam C(max) and AUC(tf) (up to 2.8- and 8.2-fold, respectively). When midazolam was concurrently administered with either azole, t(1/2z) was prolonged. Seven of 12 (58%) subjects reported > or =1 adverse event during the study (5 with posaconazole alone and 4 with posaconazole + midazolam). The most common adverse events were diarrhea (3 subjects [25%] with posaconazole alone, 2 [17%] with ketoconazole alone, and 1 [8%] with posaconazole + midazolam) and flatulence (1 [8%] with posaconazole alone and 1 [8%] with midazolam alone). CONCLUSIONS The results from this study in a small, all-white population of healthy volunteers suggest that posaconazole was a potent inhibitor of CYP3A4, but to a lesser extent than was ketoconazole. Monitoring patients for adverse events, the need for dose adjustments, or both during coadministration with posaconazole may be warranted in patients being treated with benzodiazepines that are predominantly metabolized through CYP3A4 (eg, midazolam).