Concomitant Fluconazole Research Articles

Tacrolimus pharmacokinetics are influenced by CYP3A5, age, and concomitant fluconazole in pediatric kidney transplant patients.

Tacrolimus, the most common immunosuppressant for organ transplant, has a narrow therapeutic range and is metabolized by CYP3A4/5. Trough concentration monitoring and dosing adjustments are used to reach a therapeutic range. CYP3A5 intermediate and normal metabolizers (*1 allele carriers; IM/NM) demonstrate faster tacrolimus metabolism than poor metabolizers (PM). We analyzed the electronic health records of 93 patients aged <21 years for the first 8 weeks after a kidney transplant between January 2010 and December 2021. The target tacrolimus trough was 10-15 ng/mL in the first 4 weeks and 7-10 ng/mL in the next 4 weeks. Banked DNA was collected and genotyped for CYP3A5*3, *6, *7, and *8 alleles. We found that CYP3A5 IM/NM (n = 21) took longer than PM (n = 72) to reach the therapeutic range (7 vs. 4 days, p = 0.048). IM/NM had more dose adjustments (8 vs. 6, p = 0.025) and needed >150% of the required daily dose compared with PM. The concentration/dose ratio was influenced by age and concomitant fluconazole (p = 0.0003, p = 0.034, respectively) and the average daily dose decreases with age in CYP3A5 PM (p = 0.001). Tremors were more common in patients who ever had a trough concentration >15 ng/mL compared with those who never had a trough concentration >15 ng/mL (OR 3.31, 95% CI 1.03-8.98, p = 0.038). Using standard dosing, CYP3A5 IM/NM took longer to reach the goal range and require more dose adjustments and higher doses than PM. Preemptive genotyping could decrease the number of dose changes necessary to reach a therapeutic dose. We have implemented pre-transplant CYP3A5 testing at our institution.

Ulcerative colitis successfully treated with vedolizumab in the presence of comorbid opportunistic infections: a case report

BackgroundOpportunistic infections associated with immunosuppressive treatments for inflammatory bowel disease pose an important safety concern. Here we report the case of a patient with active ulcerative colitis and cryptococcal pneumonia who was treated with vedolizumab combined with fluconazole.Case presentationA 56-year-old Japanese man with ulcerative colitis and a history of Sweet’s syndrome who was taking prednisolone and azathioprine presented with a moderate exacerbation of ulcerative colitis, abdominal pain, diarrhea, and bloody stools along with cytomegalovirus infection. Increasing the prednisolone dose without using antiviral drugs improved cytomegalovirus infection; however, ulcerative colitis did not improve, and cryptococcal pneumonia occurred. Thus, treatment with fluconazole followed by vedolizumab was initiated for ulcerative colitis. The patient gradually recovered and achieved clinical remission without the exacerbation of pneumonia.ConclusionsWe reported the first case of a patient with ulcerative colitis who was treated with vedolizumab and concomitant fluconazole for active cryptococcal pneumonia. Vedolizumab constitutes a high-potential treatment regimen owing to its safety in inflammatory bowel disease associated with opportunistic infections.

Vincristine Side Effects With Concomitant Fluconazole Use During Induction Chemotherapy in Pediatric Acute Lymphoblastic Leukemia.

As a mainstay of treatment for acute lymphoblastic leukemia (ALL), vincristine's side effect profile is well known. Parallel administration of the antifungal fluconazole has been shown to interfere with the metabolism of vincristine, potentially resulting in increased side effects. We conducted a retrospective chart review to determine whether concomitant administration of vincristine and fluconazole during pediatric ALL induction therapy impacted the frequency of vincristine side effects, namely, hyponatremia and peripheral neuropathy. We also evaluated whether the incidence of opportunistic fungal infections was impacted by fluconazole prophylaxis. Medical charts of all pediatric ALL patients treated with induction chemotherapy at Children's Hospital and Medical Center in Omaha, NE, from 2013 to 2021 were retrospectively reviewed. Fluconazole prophylaxis did not significantly impact the rate of fungal infections. We found no correlation between fluconazole use and increased incidence of hyponatremia or peripheral neuropathy, which supports the safety of fungal prophylaxis with fluconazole during pediatric ALL induction therapy.

Emergence of resistant Candida glabrata in Germany.

Background Candida glabrata is the second leading fungal pathogen causing candidaemia and invasive candidiasis in Europe. This yeast is recognized for its rapid ability to acquire antifungal drug resistance.ObjectivesWe systematically evaluated 176 C. glabrata isolates submitted to the German National Reference Center for Invasive Fungal Infections (NRZMyk) between 2015 and 2019 with regard to echinocandin and fluconazole susceptibility.MethodsSusceptibility testing was performed using a reference protocol (EUCAST) and a range of commercial assays. Hot spot regions of the echinocandin target FKS genes were sequenced using Sanger sequencing.ResultsIn total, 84 of 176 isolates were initially classified as anidulafungin-resistant based on EUCAST testing. Of those, 71 harboured mutations in the glucan synthase encoding FKS genes (13% in FKS1, 87% in FKS2). Significant differences in anidulafungin MICs were found between distinct mutation sites. 11 FKS wild-type (WT) isolates initially classified as resistant exhibited anidulafungin MICs fluctuating around the interpretation breakpoint upon re-testing with multiple assays. Two FKS WT isolates consistently showed high anidulafungin MICs and thus must be considered resistant despite the absence of target gene mutations. Over one-third of echinocandin-resistant strains displayed concomitant fluconazole resistance. Of those, isolates linked to bloodstream infection carrying a change at Ser-663 were associated with adverse clinical outcome.ConclusionsResistant C. glabrata strains are emerging in Germany. Phenotypic echinocandin testing can result in misclassification of susceptible strains. FKS genotyping aids in detecting these strains, however, echinocandin resistance may occur despite a wild-type FKS genotype.

Sirolimus Pharmacokinetics in Early Postmyeloablative Pediatric Blood and Marrow Transplantation

This study examined the pharmacokinetics of sirolimus in pediatric allogeneic blood and marrow transplantation (BMT) recipients in the presence and absence of concomitant fluconazole. Forty pediatric BMT recipients received a daily oral dose of sirolimus and a continuous i.v. infusion of tacrolimus for graft-versus-host disease prophylaxis. Fluconazole was administered i.v. to 19 patients and orally to 6 patients. Full pharmacokinetic profiles of sirolimus within a single dosing interval were collected. Whole-blood sirolimus concentrations were measured by HPLC/mass spectrometry. Noncompartmental analysis was performed using WinNonlin. Nonlinear mixed-effects pharmacokinetic models were developed using NONMEM following standard procedures. The mean ± SD sirolimus trough level before the dose (C0) was 8.0 ± 4.6 ng/mL (range, 1.8-21.6 ng/mL). The peak concentration was 19.9 ± 11.8 ng/mL (range, 3.9-46.1 ng/mL), and the trough level 24 hours later (C24) was 9.1 ± 5.3 ng/mL (range, 1.0-19.1 ng/mL). The terminal disposition half-life (T1/2) was 24.5 ± 11.2 hours (range, 5.8-53.2 hours), and the area under the concentration-versus-time curve (AUC0-24) was 401.1 ± 316.3 ng·h/mL (range, 20.7-1332.3 ng·h/mL). In patients at steady state, C0 and C24 were closely correlated (R2 = 0.77) with a slope of 0.99, indicating the achievement of steady state. C24 was 1.7-fold greater (P = .036) and AUC0-24 was 2-fold greater (P = .012) in Caucasian patients (n = 22) compared with Hispanic patients (n = 9). The average apparent oral clearance was 3-fold greater (P = .001) and the apparent oral volume of distribution was 2-fold greater (P = .018) in patients age ≤12 years compared with those age >12 years. C24 was significantly lower in patients (n = 10) who developed grade III-IV aGVHD (n = 10) than in those with grade 0-II aGVHD (n = 22) (6.1 ± 2.9 ng/mL versus 9.4 ± 5.5 ng/mL; P = .044). Dose-normalized sirolimus trough concentrations were significantly higher in patients receiving concomitant fluconazole therapy compared with those not receiving fluconazole (C0: 3.9 ± 2.5 versus 2.4 ± 1.5 ng/mL/mg, P = .030; C24: 4.8 ± 3.3 versus 2.5 ± 1.7 ng/mL/mg, P = .018). This pharmacokinetic study of sirolimus in pediatric patients documents a large interindividual variability in the exposure of sirolimus. Steady-state trough blood concentrations were correlated with drug exposure. Trough concentrations were higher with a concomitant use of fluconazole and were higher in Caucasian patients than in Hispanic patients. Oral clearance was greater in children age ≤12 years than in older children and adolescents. With therapeutic drug monitoring, the majority (79%) of sirolimus trough levels could be maintained within the target range (3-12 ng/mL). This study provides a rationale and support for dose adjustments of sirolimus based on steady-state blood concentrations aimed at achieving a target concentration to minimize toxicity and maximize therapeutic benefits in pediatric BMT recipients.

Multicenter Phase I Dose-Escalation Study of Lenalidomide in Patients with Relapsed Adult T-Cell Leukemia-Lymphoma (ATL) or Peripheral T-Cell Lymphoma (PTCL).

Abstract 2737 Introduction: ATL is prevalent in Japan and has the worst prognosis among T-cell malignancies. PTCL also has a poor prognosis with currently available chemotherapeutic regimens, and both would benefit from better treatment modality. Lenalidomide is an immunomodulatory agent with direct tumoricidal and antiproliferative activity, and is approved for multiple myeloma (MM) in combination with dexamethasone after at least 1 prior therapy and for transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with 5q deletion. We conducted a phase 1 study of lenalidomide in patients with relapsed ATL or PTCL to establish the recommended dose and schedule for a subsequent phase 2 study. Patients and Methods: This multicenter, phase 1, dose-escalation study assessed the safety, maximum tolerated dose (MTD), pharmacokinetics, and efficacy in patients with relapsed advanced ATL or PTCL. Dose-escalation was conducted according to the standard 3+3 design. Up to one PTCL patient was allowed to be included in each cohort of 3 patients. Patients in Cohort 1 received oral lenalidomide 25 mg daily on Days 1–21 of a 28-day cycle. Patients in Cohorts 2 and 3 received 25 and 35 mg/day, respectively, on each day of the 28-day cycle. Dose-limiting toxicity (DLT) was defined as febrile neutropenia lasting 5 or more days; thrombocytopenia (platelets Results: From July 2010–June 2012, 13 Japanese patients (9 ATL and 4 PTCL; age 32–74 years [median, 64]; 1–11 prior therapies [median, 1]) were enrolled: 3 in Cohort 1, 6 in Cohort 2, and 4 in Cohort 3. The 3 patients in Cohort 1 received lenalidomide for 21, 103, and 637 days, respectively, until PD with no instances of DLT. In Cohort 2, 1 patient experienced DLT (thrombocytopenia, platelets 75% reduction in lymph nodes, which lasted for 282 days. PK profiles of patients in the study were generally consistent with that observed in Japanese MM patients. Plasma exposure of lenalidomide increased with increasing dose with a mean Cmax on Day 1 for 25 mg and 35 mg of 493 ng/mL and 628 ng/mL, respectively, and a mean AUC24 of 2774 ng/mL and 3062 ng/mL, respectively. There was no evidence of accumulation following multiple dosing for 8 days. Conclusions: This phase 1 study identified lenalidomide 25 mg daily per 28-day cycle as the dose and schedule for a subsequent phase 2 study in patients with ATL or PTCL. Based on the preliminary evidence of antitumor activity in ATL and PTCL patients, a phase 2 study in patients with relapsed ATL in Japan is planned. Disclosures: Off Label Use: Lenalidomide (CC-5013) is an investigational agent in Japan; this abstract assesses its use in adult ATL patients. Tobinai:Merck: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Zenyaku: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Genzyme: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Eisai: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Symbio: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Eli Lilly: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Kyowa-Kirin: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Biomedics: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Solasia Pharma: Clinical trials, Clinical trials Other, Research Funding; Novartis: Research Funding; Johnson & Johnson: Research Funding; Pfizer: Research Funding; GSK: Research Funding; Chugai/Roche: Research Funding; Takeda: Clinical trials, Clinical trials Other, Research Funding.

Potentiation of Vincristine Toxicity with Concomitant Fluconazole Prophylaxis in Children with Acute Lymphoblastic Leukemia

Use of azole antifungals as prophylaxis is becoming an increasingly common practice in acute lymphoblastic leukemia (ALL). Limited literature in adults heightened the awareness of possible increased vincristine (VCR) toxicity in patients receiving concomitant azole therapy. This is due to inhibition of cytochrome P450 3A4, which may increase overall exposure to VCR, resulting in dose reductions or omissions. The primary objective of this study was to determine whether the use of fluconazole prophylaxis increases vincristine toxicity in children with ALL. The authors retrospectively evaluated children with ALL between January 2004 and December 2009. Patients were subdivided into 2 groups based on whether or not they received fluconazole prophylaxis during induction therapy. Data were collected for up to 3 months following the completion of induction therapy. Thirty-one patients were included for analysis. There was no significant difference in gender, race, steroid use, gastrointestinal (GI) toxicity, VCR dose modification, and the rate of fungal or bacterial infections between these 2 groups. Only advanced age is an independent predictor of neuropathy. Patients receiving fluconazole were 4.5 times more likely to experience neuropathy than those not receiving azole; however, this was not statistically significant. The authors report an increased incidence of VCR toxicity in patients with ALL receiving concomitant fluconazole prophylaxis. Judicious use of azole anitfungals is warranted in children with ALL.

Pharmacokinetics of Voriconazole Administered Concomitantly with Fluconazole and Population-Based Simulation for Sequential Use

In clinical practice, antifungal therapy may be switched from fluconazole to voriconazole; such sequential use poses the potential for drug interaction due to cytochrome P450 2C19 (CYP2C19)-mediated inhibition of voriconazole metabolism. This open-label, randomized, two-way crossover study investigated the effect of concomitant fluconazole on voriconazole pharmacokinetics in 10 subjects: 8 extensive metabolizers and 2 poor metabolizers of CYP2C19. The study consisted of 4-day voriconazole-only and 5-day voriconazole-plus-fluconazole treatments, separated by a 14-day washout. Voriconazole pharmacokinetics were determined by noncompartmental analyses. A physiologically based pharmacokinetic model was developed in Simcyp (Simcyp Ltd., Sheffield, United Kingdom) to predict the magnitude of drug interaction should antifungal therapy be switched from fluconazole to voriconazole, following various simulated lag times for the switch. In CYP2C19 extensive metabolizers, fluconazole increased the maximum plasma concentration and the area under the plasma concentration-time curve (AUC) of voriconazole by 57% and 178%, respectively. In poor metabolizers, however, voriconazole pharmacokinetics were unaffected by fluconazole. The simulations based on pharmacokinetic modeling predicted that if voriconazole was started 6, 12, 24, or 36 h after the last dose of fluconazole, the voriconazole AUC ratios (sequential therapy versus voriconazole only) after the first dose would be 1.51, 1.41, 1.28, and 1.14, respectively. This suggests that the remaining systemic fluconazole would result in a marked drug interaction with voriconazole for ≥ 24 h. Although no safety issues were observed during coadministration, concomitant use of fluconazole and voriconazole is not recommended. Frequent monitoring for voriconazole-related adverse events is advisable if voriconazole is used sequentially after fluconazole.

Sildenafil exposure in neonates with pulmonary hypertension after administration via a nasogastric tube

ObjectiveTo describe the pharmacokinetics and exposure of oral sildenafil (SIL) in neonates (2–5 kg) with pulmonary hypertension (PH).DesignWe included 11 neonates (body weight 2–5 kg, postnatal age 2–121 days) who...

Fluconazole-Carbamazepine Interaction

The patient we describe had elevated carbamazepine serum concentrations during concomitant fluconazole administration (400 mg/day), including serial concentrations both before and after antifungal therapy. Since fluconazole is a known inhibitor of the cytochrome P450 enzyme system, this suggests an inhibition of carbamazepine metabolism.

Evaluation of interaction between fluconazole and an oral contraceptive in healthy women

OBJECTIVE: To evaluate the potential pharmacokinetic interaction between 2 × 150 mg fluconazole administered once weekly and an oral contraceptive (OC) containing ethinyl estradiol and norethindrone. METHODS: A placebo-controlled, double-masked, randomized, two-way crossover study was used to investigate the pharmacokinetic interaction between 300 mg fluconazole once weekly and the OC Ortho Novum 7/7/7 (Ortho-McNeil Pharmaceutical, Inc., Raritan, NJ) in 26 healthy women, 18–36 years old. In the first cycle (28 days), subjects received OC only. In the second cycle, subjects were assigned randomly to receive OC-fluconazole or OC-placebo. In the third cycle, subjects were crossed over to the opposite treatment. RESULTS: Data for 21 subjects who completed the study were included in the pharmacokinetic analysis; data for all 26 subjects were included in the safety analysis (26 OC only; 24 OC-fluconazole; 23 OC-placebo). Treatment with OC-fluconazole resulted in small but statistically significant increases in 0–24 hour area under the plasma concentration-time curve (AUC 0–24) for both ethinyl estradiol (mean 24%, 95% confidence interval [CI] 18%, 31%) and norethindrone (mean 13%, 95% CI 8%, 18%) as compared with treatment with OC-placebo. Ethinyl estradiol maximum plasma concentration (C max) was slightly (mean 8%, 95% CI 2%, 15%) though statistically significantly higher for OC-fluconazole treatment as compared with OC-placebo treatment. Norethindrone C max was not different (95% CI −6%, 11%) between the two treatment groups. No adverse events related to treatment were seen in the fluconazole treatment group. CONCLUSION: The concomitant administration of 300 mg fluconazole once weekly, twice the recommended dose for vaginal candidiasis, to women using OCs results in a slight increase in OC concentrations. Therefore, it appears that there is no threat of contraceptive failure because of concomitant fluconazole administration.

Population pharmacokinetics of rifabutin in human immunodeficiency virus-infected patients.

Rifabutin pharmacokinetics were studied by the population approach (NONMEM) with 40 human immunodeficiency virus-infected patients receiving rifabutin at different doses for prophylaxis or therapy of mycobacterial infections. A two-compartment open model with first-order absorption was used as the structural pharmacokinetic model. Parameter estimates were the absorption rate constant (0. 201/h), clearance/bioavailability (CL/F; 60.9 liters/h), volume of the central compartment/bioavailability (231 liters), intercompartmental clearance (60.3 liters/h), and volume of the peripheral compartment/bioavailability (Vp/F; 1,050 liters). The distribution and elimination half-lives were 1.24 and 25.4 h, respectively. The covariates tested for influence on CL/F and Vp/F were sex, age, weight, height, body surface area, tobacco smoking, drug addiction, alanine aminotransferase levels, creatinine clearance, total protein, bilirubin, numbers of CD4(+) cells, presence of diarrhea, cachexia index, rifabutin use (prophylaxis versus therapy), rifabutin dose, study site, and the concomitant administration of clarithromycin, fluconazole, phenobarbital, ciprofloxacin, azithromycin, or benzodiazepines. The only statistically significant effects on rifabutin pharmacokinetic parameters were a 27% decrease in Vp/F due to the concomitant administration of azithromycin and a 39% increase in Vp/F due to tobacco smoking. Such effects may be considered clinically unimportant. Our results confirm the lack of a correlation of rifabutin pharmacokinetic parameters with parameters of disease progression and gastrointestinal function. Also, the lack of a correlation with covariates which were previously found to be significant, such as concomitant fluconazole and clarithromycin use, may suggest that the effect of such covariates may be less important in the real clinical setting, in which several concomitant factors may influence pharmacokinetic parameters, with an overall effect of no apparent correlation.

Glucuronidation of 3'-azido-3'-deoxythymidine (zidovudine) by human liver microsomes: relevance to clinical pharmacokinetic interactions with atovaquone, fluconazole, methadone, and valproic acid.

Zidovudine (3'-azido-3'-deoxythymidine [AZT]), an antiviral nucleoside analog effective in the treatment of human immunodeficiency virus infection, is primarily metabolized to an inactive glucuronide form, GAZT, via uridine-5'-diphospho-glucuronosyltransferase (UGT) enzymes. UGT enzymes exist as different isoforms, each exhibiting substrate specificity. Published clinical studies have shown that atovaquone, fluconazole, methadone, and valproic acid decreased GAZT formation, presumably due to UGT inhibition. The effect of these drugs on AZT glucuronidation was assessed in vitro by using human hepatic microsomes to begin understanding in vitro-in vivo correlations for UGT metabolism. The concentrations of each drug studied were equal to those reported with the usual clinical doses and at concentrations at least 10 times higher than would be expected with these doses. High-performance liquid chromatography was used to assess the respective metabolism and formation of AZT and GAZT. All four drugs exhibited concentration-dependent inhibition of AZT glucuronidation. The respective concentrations of atovaquone and methadone which caused 50% inhibition of GAZT were > 100 and 8 micrograms/ml, well above their usual clinical concentrations. Fluconazole and valproic acid exhibited 50% inhibition of GAZT at 50 and 100 micrograms/ml, which are within the clinical ranges of 10 to 100 and 50 to 100 micrograms/ml, respectively. These data suggest that inhibition of AZT glucuronidation may be more clinically significant with concomitant fluconazole and valproic acid. Factors such as inter- and intraindividual pharmacokinetic variability and changes in AZT intracellular concentrations should be considered as other mechanisms responsible for changes in AZT pharmacokinetics with concomitant therapies.

The effect of fluconazole on circulating ethinyl estradiol levels in women taking oral contraceptives

This open-label, two-period, crossover study was conducted to evaluate the effect of a single 150 mg dose of fluconazole on the pharmacokinetics of ethinyl estradiol in healthy female subjects. Ten subjects regularly taking Ortho-Novum 7/7/7 (Ortho Pharmaceutical, Raritan, N.J.) and 10 subjects regularly taking Triphasil (Wyeth-Ayerst Laboratories, Philadelphia), which contain ethinyl estradiol 35 microg and 30 microg during days 1 to 6, respectively, were randomly assigned to receive a single 150 mg dose of fluconazole 2 hours before the oral contraceptive, on pill day 6 of one of two menstrual cycles. Ethinyl estradiol serum concentrations were measured at baseline and up to 24 hours after oral contraceptive intake. No fluconazole was administered during the other menstrual cycle, which served as the control. Mean serum concentrations of ethinyl estradiol were increased after fluconazole administration in both oral contraceptive groups. Maximum observed serum concentration and area under the concentration-time curve values were significantly (p < 0.05) greater during the fluconazole regimens (vs regimens without fluconazole) for both oral contraceptive groups and for combined values of the two oral contraceptive groups. The mean time to reach the maximum concentration was not altered by concomitant fluconazole administration. These findings suggest that there is a potential for a clinically significant interaction between coadministration of fluconazole and ethinyl estradiol in oral contraceptives.

Increased Plasma Rifabutin Levels with Concomitant Fluconazole Therapy in HIV-Infected Patients

To determine the effect of fluconazole on rifabutin pharmacokinetics. An open-label, crossover, phase 1 trial. Outpatient clinical research center at a university medical center in Washington, D.C. 12 persons with human immunodeficiency virus (HIV) infection whose CD4 lymphocyte counts were between 200 and 500 cells/mm3 and who were receiving maintenance therapy with zidovudine. Fluconazole, 200 mg/d for 2 weeks; then a combination of fluconazole, 200 mg/d, and rifabutin, 300 mg/d, for 2 weeks; and then rifabutin, 300 mg/d, for the final 2 weeks of the study. Blood and urine samples were obtained at regular intervals for 24 hours at the end of each 2-week dosing period to ascertain concentrations of fluconazole and rifabutin and the 25-desacetyl metabolite of rifabutin, LM565. Fluconazole significantly increased the plasma concentrations of both rifabutin and LM565. Mean increases in the area under the plasma concentration curve compared with the time curve over a 24-hour dosing interval were 82% (5442 +/- 2404 ng.h/mL compared with 3025 +/- 1117 ng.h/mL; P less than or equal to 0.05) for rifabutin and 216% (959 +/- 529 ng.h/mL compared with 244 +/- 141 ng.h/mL; P less than or equal to 0.05) for LM565. Fluconazole significantly increases the systemic exposure of both rifabutin and LM565. This pharmacokinetic interaction offers a mechanism that may explain the changes reported in both the efficacy and toxicity of rifabutin with concomitant fluconazole therapy.

Ketoconazole and Fluconazole Drug Interactions

This article reviews potential drug interactions that exist between ketoconazole or fluconazole and other drugs. English-language data sources included human subjects' computerized databases and published indexes. Case reports and studies demonstrate decreased dosage requirements of cyclosporine sodium, methylprednisolone sodium succinate, and possibly anticoagulants and phenytoin after ketoconazole or fluconazole administration, suggesting hepatic enzyme inhibition. Increased dosage requirements of ketoconazole are necessary after rifampin administration, suggesting rifampin's induction of hepatic microsomal enzymes. Possibly a similar effect may occur with concomitant fluconazole and rifampin. The effect of ketoconazole administration on prednisolone sodium phosphate and theophylline warrants further study. Fluconazole, a more selective agent for fungal P-450, seems to be of less concern regarding the potential for drug interactions than ketoconazole.

Effect of fluconazole on the disposition of phenytoin

In a randomized, placebo-controlled, parallel study, phenytoin was given in the presence and absence of fluconazole. Twenty healthy male subjects received phenytoin, 200 mg orally, on study days 1 to 3 and 18 to 20 and 250 mg intravenously on study days 4 and 21. Ten subjects received fluconazole, 200 mg orally, and 10 received placebo daily on study days 8 to 21. Serial blood samples were collected during a 24-hour period after the intravenous phenytoin dose. Fluconazole trough concentrations were determined on days 14, 18, and 21. Serum phenytoin area under the concentration-time curve from 0 to 24 hours increased 75% and minimum plasma drug concentration increased 128% after administration of fluconazole, 200 mg/day, for 14 days. These values were significantly greater than the 5% increase in area under the concentration-time curve from 0 to 24 hours and 11.6% increase in minimum plasma drug concentration in the placebo group. Fluconazole trough concentrations remained unchanged during the coadministration of phenytoin. The increased phenytoin concentrations in the presence of fluconazole suggest that fluconazole inhibits phenytoin metabolism. Serum concentration monitoring with a reduction in phenytoin dosage is clinically warranted in patients receiving phenytoin and concomitant fluconazole therapy.