Evaluation of target attainment of oral posaconazole suspension in immunocompromised children

2019 ◽  
Vol 75 (3) ◽  
pp. 726-729
Author(s):  
Tony Lai ◽  
Jan-Willem Alffenaar ◽  
Alison Kesson ◽  
Sushil Bandodkar ◽  
Jason A Roberts
Keyword(s):  
Retrospective Study ◽  
Plasma Concentration ◽  
Plasma Concentrations ◽  
Invasive Fungal Disease ◽  
Target Attainment ◽  
Breakthrough Infection ◽  
H2 Antagonist ◽  
Starting Dose ◽  
Histamine H2 Antagonist ◽  
The Mean

Abstract Background Posaconazole is a broad-spectrum antifungal that is not licensed for use in children <13 years of age. Despite this and by necessity, it is used extensively in paediatric hospitals for prophylaxis of invasive fungal disease. Objectives To determine whether initial prophylactic dosing recommendations attain a posaconazole plasma concentration of ≥700 ng/mL in immunocompromised children <13 years of age. Patients and methods We performed a retrospective study of immunocompromised children <13 years of age receiving posaconazole suspension prophylaxis at a starting dose of 5 mg/kg every 8 h for ≥7 days and who had a posaconazole concentration measured after ≥7 days. Posaconazole plasma concentrations and rate of breakthrough infection were recorded. Results A total of 70 patients were included with a median age of 5 years (range 3 months to 12 years). The mean posaconazole plasma concentration was 783.4 ng/mL (IQR 428.3–980 ng/mL) and the percentage of patients with a posaconazole plasma concentration ≥700ng/mL was 47.9%. Patients who were on a proton pump inhibitor, a histamine H2 antagonist or metoclopramide, had mucositis or were enterally fed had a lower posaconazole plasma concentration compared with patients without these co-administered drugs/mucositis/enteral feeding (542.3 versus 1069.8 ng/mL; P<0.001). The breakthrough invasive fungal infection rate was 4.3% (3/70). Conclusions The studied 5 mg/kg posaconazole suspension every 8 h resulted in target concentrations in only 47.9% of patients and further studies looking at newer posaconazole formulations are needed.

scholarly journals Influence ofABCC2andABCC4Polymorphisms on Tenofovir Plasma Concentrations in Thai HIV-Infected Patients

2015 ◽  
Vol 59 (6) ◽  
pp. 3240-3245 ◽  
Author(s):  
Kanokrat Rungtivasuwan ◽  
Anchalee Avihingsanon ◽  
Narukjaporn Thammajaruk ◽  
Siwaporn Mitruk ◽  
David M. Burger ◽  
...  
Keyword(s):  
Body Weight ◽  
Multivariate Analysis ◽  
Plasma Concentration ◽  
Protease Inhibitors ◽  
Demographic Data ◽  
Plasma Concentrations ◽  
Multidrug Resistant ◽  
Cross Sectional Study ◽  
Cross Sectional ◽  
The Mean

ABSTRACTTenofovir (TFV) is eliminated by renal excretion, which is mediated through multidrug-resistant protein 2 (MRP2) and MRP4, encoded byABCC2andABCC4, respectively. Genetic polymorphisms of these transporters may affect the plasma concentrations of tenofovir. Therefore, the aim of this study was to investigate the influence of genetic and nongenetic factors on tenofovir plasma concentrations. A cross-sectional study was performed in Thai HIV-infected patients aged ≥18 years who had been receiving tenofovir disoproxil fumarate at 300 mg once daily for at least 6 months. A middose tenofovir plasma concentration was obtained. Multivariate analysis was performed to investigate whether there was an association between tenofovir plasma concentrations and demographic data, including age, sex, body weight, estimated glomerular filtration rate (eGFR), hepatitis B virus coinfection, hepatitis C virus coinfection, duration of tenofovir treatment, concomitant use of ritonavir-boosted protease inhibitors, and polymorphisms ofABCC2andABCC4. A total of 150 Thai HIV-infected patients were included. The mean age of the patients was 43.9 ± 7.2 years. The mean tenofovir plasma concentration was 100.3 ± 52.7 ng/ml. In multivariate analysis, a low body weight, a low eGFR, the concomitant use of ritonavir-boosted protease inhibitors, and theABCC44131T → G variation (genotype TG or GG) were independently associated with higher tenofovir plasma concentrations. After adjusting for weight, eGFR, and the concomitant use of ritonavir-boosted protease inhibitors, a 30% increase in the mean tenofovir plasma concentration was observed in patients having theABCC44131 TG or GG genotype. Both genetic and nongenetic factors affect tenofovir plasma concentrations. These factors should be considered when adjusting tenofovir dosage regimens to ensure the efficacy and safety of a drug. (This study has been registered at ClinicalTrials.gov under registration no. NCT01138241.)

Diurnal changes in the plasma concentrations of LH and hypothalamic contents of LHRH-I and LHRH-II in the domestic hen

1991 ◽  
Vol 130 (3) ◽  
pp. 457-462 ◽  
Author(s):  
S. C. Wilson ◽  
R. T. Gladwell ◽  
F. J. Cunningham
Keyword(s):  
Plasma Concentration ◽  
Diurnal Rhythm ◽  
Laying Hens ◽  
Plasma Concentrations ◽  
Posterior Hypothalamus ◽  
Anterior Hypothalamus ◽  
Diurnal Changes ◽  
The Mean ◽  
The Times ◽  
Lh Secretion

ABSTRACT Diurnal changes of LH secretion in sexually immature hens of 9, 11, 13 and 15 weeks of age consisted of 25–40% increases in the mean concentrations of LH in plasma between 15.00 and 18.00 h, i.e. between 2 h before and 1 h after the onset of darkness. During this time there was a tendency for the mean contents of LHRH-I in the anterior hypothalamus and posterior hypothalamus to increase by 21–74% and 20–56% respectively. In hens of 9 and 15 weeks, diurnal changes in the plasma concentration of LH closely paralleled those of LHRH-I content in the posterior hypothalamus. In contrast, the diurnal rhythm of LH secretion in hens of 11 and 13 weeks was more marked and plasma concentrations of LH continued to rise steeply between 18.00 and 21.00 h, i.e. between 1 and 4 h after the onset of darkness. At 11 weeks, this was associated with a reduction (P<0·01) in the contents of LHRH-I and LHRH-II, particularly in the anterior hypothalamus. In laying hens, a diurnal decline (P<0·01) in the plasma concentration of LH between 1 and 4 h after the onset of darkness was preceded by a fall (P<0·05) in the content of LHRH-I in the posterior hypothalamus and in the total hypothalamic content of LHRH-II (P<0·01). In all groups of hens, irrespective of the times of day at which tissue was taken, significant (P<0·05–<0·001) correlations between the contents of LHRH-I and LHRH-II in the anterior hypothalamus were observed. It is concluded that a diurnal rhythm of release of LHRH-I may drive the diurnal rhythm of LH secretion. Thus, in sexually immature hens of 9 and 15 weeks and laying hens in which diurnal changes in plasma LH were small there were parallel changes in the content of LHRH-I in the posterior hypothalamus. However, where the plasma concentration of LH was increased substantially, as at 11 weeks, there was a decline in the hypothalamic contents of LHRH-I. A simultaneous fall in the hypothalamic content of LHRH-II raises the possibility of a causal relationship between the activities of LHRH-II, LHRH-I and the release of LH. Journal of Endocrinology (1991) 130, 457–462

Plasma Inorganic Fluoride Concentrations after Sevoflurane Anesthesia in Children

1996 ◽  
Vol 84 (2) ◽  
pp. 348-353. ◽  
Author(s):  
M. F. Levine ◽  
J. Sarner ◽  
J. Lerman ◽  
P. Davis ◽  
N. Sikich ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Elective Surgery ◽  
Plasma Concentrations ◽  
Sevoflurane Anesthesia ◽  
Inorganic Fluoride ◽  
Time Curve ◽  
Plasma Urea ◽  
The Mean ◽  
Group 2

Background Sevoflurane is degraded in vivo in adults yielding plasma concentrations of inorganic fluoride [F-] that, in some patients, approach or exceed the 50- micron theoretical threshold for nephrotoxicity. To determine whether the plasma concentration of inorganic fluoride [F-] after 1-5 MAC x h sevoflurane approaches a similar concentration in children, the following study in 120 children scheduled for elective surgery was undertaken. Methods Children were randomly assigned to one of three treatment groups before induction of anesthesia: group 1 received sevoflurane in air/oxygen 30% (n = 40), group 2 received sevoflurane in 70% N2O/30% O2 (n = 40), and group 3 received halothane in 70% N2O/30% O2 (n = 40). Mapleson D or F circuits with fresh gas flows between 3 and 61/min were used Whole blood was collected at induction and termination of anesthesia and at 1, 4, 6, 12, and 18 or 24 h postoperatively for determination of the [F-]. Plasma urea and creatinine concentrations were determined at induction of anesthesia and 18 or 24 h postoperatively. Results The mean (+/- SD) duration of sevoflurane anesthesia, 2.7 +/- 1.6 MAC x h (range 1.1-8.9 MAC x h), was similar to that of halothane, 2.5 +/- 1.1 MAC x h. The peak [F-] after sevoflurane was recorded at 1 h after termination of the anesthetic in all but three children (whose peak values were recorded between 4 and 6 h postanesthesia). The mean peak [F-] after sevoflurane was 15.8 +/- 4.6 microns. The [F-] decreased to &lt;6.2 microns b 24 h postanesthesia. Both the peak [F-] (r2 = 0.50) and the area under the plasma concentration of inorganic fluoride-time curve (r2 = 0.57) increased in parallel with the MAC x h of sevoflurane. The peak [F-] after halothane, 2.0 +/- 1.2 microns, was significantly less than that after sevoflurane (P&lt;0.00012) and did not correlate with the duration of halothane anesthesia (MAC x h; r2 = 0.007). Plasma urea concentrations decreased 24 h after surgery compared with preoperative values for both anesthetics (P&lt;0.01), whereas plasma creatinine concentrations did not change significantly with either anesthetic. Conclusions It was concluded that, during the 24 h after 2.7 +/- 1.6 MAC x h sevoflurane, the peak recorded [F-] is low (15.8 microns), F- is eliminated rapidly, and children are unlikely to be at risk of nephrotoxicity from high [F-].

Prophylactic Disopyramide: Its Clinical Effects Related to Plasma Concentration in Myocardial Infarction

1980 ◽  
Vol 8 (5) ◽  
pp. 314-320 ◽  
Author(s):  
Rowan Mary Hillson ◽  
E Boyd ◽  
J Cunningham
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Plasma Concentration ◽  
Plasma Level ◽  
Plasma Concentrations ◽  
Double Blind Study ◽  
Clinical Effects ◽  
Number Of Patients ◽  
Wide Range ◽  
The Mean

Sixty-three patients, fifty-two with acute myocardial infarction and eleven with ischaemic heart disease or non-cardiac chest pain, were given either disopyramide phosphate or placebo, orally, in a randomized double-blind study. Thirty-two patients on disopyramide (twenty-six with acute myocardial infarction) received an initial dose of 300 mg followed by 150 mg six-hourly for 3 days. There was a reduction in the number of patients with cardiac dysrhythmias on the first 3 days following infarction in subjects taking disopyramide as compared with controls. This reduction was not statistically significant. There was a significant reduction in the mean ectopic count per hour in patients taking disopyramide compared with those taking placebo on the second day only (p < 0.005). Urinary retention, dry mouth and jaundice were recorded more frequently in the test group. There were wide ranges of pre-dose plasma concentrations on all 3 days. (Day 1: 1.3 to 7.7 μg per ml. Day 2: 2.5 to 8.9 μg/ml and Day 3: 2.5 to 11.5 μg per ml). The mean plasma concentration of disopyramide was higher but not significantly so, in the treatment group without evidence of dysrhythmias than those with dysrhythmias (3.8 ± S.D. 1.5 μg/ml and 3.0 ± 0.8 μg/ml respectively). The mean plasma level in patients who required anti-emetic therapy was significantly lower than those who did not (2.8 ± 0.8 μg/ml and 3.8 ± 1.9 μg/ml respectively, p < 0.025). The wide range of plasma levels observed is probably due in part to irregular absorption with vomiting after myocardial infarction. If disopyramide is to be used prophylactically following myocardial infarction, a therapeutic plasma level will be achieved quickly in all cases only by giving an intravenous starting dose.

EFFECTS OF TEMPERATURE AND FEED INTAKE ON PLASMA CONCENTRATION OF THYROID HORMONES IN BEEF CATTLE

1979 ◽  
Vol 59 (4) ◽  
pp. 655-661 ◽  
Author(s):  
R. J. CHRISTOPHERSON ◽  
H. W. GONYOU ◽  
J. R. THOMPSON
Keyword(s):  
Plasma Concentration ◽  
Thyroid Hormone ◽  
Feed Intake ◽  
Plasma Concentrations ◽  
Beef Steers ◽  
Outdoor Temperature ◽  
Cold Environments ◽  
Hormone Responses ◽  
The Mean ◽  
Effects Of Temperature

In each of two experiments, plasma concentrations of thyroxine (T4) and triiodothyronine (T3) and the Free Thyopac Index (FTI) were determined, at intervals during winter, in beef steers housed either indoors in a heated barn or in outdoor pens. During experiment 2, a comparison was also made of the effects of four feed intake levels ranging from one to two times maintenance. In both experiments, plasma concentrations of T4 and FTI values were higher in steers kept outdoors than those kept indoors. The highest plasma T4 concentrations and FTI values were recorded in outdoor steers on a maintenance level of feed intake during February when the mean outdoor temperature was −15 °C. Under these circumstances, increasing the level of feed intake to twice maintenance reduced plasma T4 concentrations and FTI values. Level of feed intake had no effect on either plasma T4 or FTI values in steers kept in a heated barn. Plasma T3 concentrations were higher in the outdoor than the indoor steers during experiment 2. Reducing feed intake from twice maintenance to maintenance levels resulted in a decrease in plasma T3 concentrations in steers kept outdoors, but not in those kept indoors in a heated barn. These results indicate that thyroid hormone responses of cattle to cold environments are influenced by the level of feed intake.

168 INFLUENCE OF SEVERAL INSULIN PLASMA CONCENTRATIONS ON PROGESTERONE PRODUCTION AND HISTOLOGY OF CORPORA LUTEA IN SUPEROVULATED EWES

2010 ◽  
Vol 22 (1) ◽  
pp. 242
Author(s):  
H. M. Brandão ◽  
E. H. Madureira ◽  
R. V. Sousa ◽  
F. Wouters ◽  
E. L. Vargas ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Plasma Concentrations ◽  
Cell Activity ◽  
Corpora Lutea ◽  
Mean Values ◽  
Embryo Recovery ◽  
Progesterone Production ◽  
Eosinophilic Cytoplasm ◽  
The Mean ◽  
Alloxan Monohydrate

Nutritional status is essential for the determination of mammalian reproductive performance, and insulin is one of the main indicators for such condition. This hormone is able to interfere, directly or indirectly, with CL function, leading to alterations in steroidogenic capacity and cell development and, consequently, early embryonic development. The aim of this work was to identify CL histological alterations caused by different insulin plasma concentrations in superovulated ewes, as well as their interference in CL progesterone production. Santa Inês ewes (n = 24, 4 years old) were divided into 3 treatments: control (T1, n = 9); hypoinsulinemic (T2, n = 6), and hyperinsulinemic (T3, n = 9). In order to become hypoinsulinemic, ewes were treated with a single dose of alloxan monohydrate (50 mg kg-1 i.v; Sigma-Aldich, St. Louis, MO, USA) 48 h before the beginning of the superovulation protocol, whereas the hyperinsulinemic group was treated with administrations of 20 IU of NPH human insulin at every 12 h (Biolin-N; BIOBRAS, Montes Claros, Brazil). All animals were fed corn silage and minerals ad libitum. Animals had their estrus synchronized with vaginal pessaries containing medroxyprogesterone acetate (60 mg) and were superovulated with porcine FSH (250 IU, PLUSET®, Calier, Spain) and eCG (250 IU, Novormon®, Schering-Plough, Kenilworth, NJ, USA), in a 13-day protocol. After removal of vaginal pessaries, blood samples used for quantification of progesterone and plasmatic insulin by radioimmunoassay were collected daily at 0700 h until the day before embryo recovery. Hysterectomy was performed in all groups after embryo recovery (T1: n = 3, T2: n = 6, and T3: n = 4), and ovaries were placed in buffered formalin saline. CL histological sections were evaluated by hematoxylin/eosin staining. Results were assessed by SAS statistical analysis software, using the MIXED procedure (SAS Institute Inc., Cary, NC, USA). Mean values were compared by Tukey’s test. The mean CL number was lower in T2 (5.0 ± 2.7; P < 0.05) compared with T1 (10.2 ± 5.1) and T3 (11.3 ± 3.0) animals. No histological differences were observed between treatments T1 and T3. However, CL within the T2 group had a higher number of cells with picnotic nuclei and strongly contracted eosinophilic cytoplasm. Such alterations are suggestive of cellular apoptosis. The T2 group also differed for P4 production (P < 0.01) from the second (T2: 2.23 ± 0.71 ηg mL-1; T1: 5.42 ± 4.01 ηg mL-1; T3: 6.44 ± 2.76 ηg mL-1) to the sixth day post-estrus (T2: 7.58 ± 7.00; T1: 24.79 ± 8.40; T3: 32.07 ± 0.85 ηg mL-1). The mean insulin plasma concentration differed between treatments (P < 0.01); higher concentrations were obtained in the T3 group (20.05 ± 7.50 μIU mL-1), whereas the T2 group had lower concentrations (10.18 ± 3.57 μIU mL-1) compared to controls (T1: 14.52 ± 3.80 μIU mL-1). In conclusion, low plasma concentration of insulin may restrict the response to superovulatory treatment and cause CL histological changes, suggesting a reduction in cell activity due to premature cellular senescence.

scholarly journals Methadone for Opioid Use Treatment during Pregnancy: Trends in Postpartum Dose Adjustments

2020 ◽  
Vol 10 (03) ◽  
pp. e202-e209
Author(s):  
Clara Ward ◽  
Carl W. Christensen
Keyword(s):  
Retrospective Study ◽  
Dose Adjustment ◽  
Temporal Data ◽  
Opioid Use ◽  
Methadone Dose ◽  
Minimal Dose ◽  
Starting Dose ◽  
Data Points ◽  
The Mean

Abstract Objective This study examines methadone dose adjustment postpartum. Methods A retrospective study of women with methadone for opioid use treatment (OUT) during pregnancy was performed. Patient charts were reviewed and data were extracted. Methadone doses from five temporal data points for each patient were used: starting dose, day of delivery, and 1, 2, and 6 months postpartum. Results Over 26 months, 49 pregnancies to women using methadone for OUT were evaluated and 20 (41%) were included. The mean methadone starting dose was 47 mg, compared with 86 mg at the time of delivery. The mean dose postpartum remained unchanged from delivery and 75% of pregnancies required the same dose or higher 1 month postpartum. By 2 months postpartum, only 33% were able to decrease their methadone dose. Twelve pregnancies completed follow-up until 6 months postpartum; only 17% of patients were able to decrease their dose, with an overall mean dose decrease was 12%. There was no difference between the mean dose at delivery and the 6-month postpartum dose. Conclusion Patients using methadone for OUT during pregnancy achieved minimal dose decreases postpartum. Patients should be counseled that postpartum dose tapers may be challenging and about alternatives to methadone for OUT.

scholarly journals Bioavailability and pharmacokinetics of cefotaxime in Muscovy ducks

2016 ◽  
Vol 4 (1) ◽  
pp. 93 ◽  
Author(s):  
Mohamed Aboubakr
Keyword(s):  
Plasma Concentration ◽  
Plasma Concentrations ◽  
Pharmacokinetic Profile ◽  
Maximum Plasma ◽  
Mean Values ◽  
Elimination Half ◽  
Maximal Plasma ◽  
The Mean ◽  
Muscovy Ducks

The pharmacokinetic profile of cefotaxime following a single intravenous (IV) and intramuscular (IM) injection was studied in Muscovy ducks. Cefotaxime was given at a dose rate of 25 mg/kg b.wt. for both routes. After IV injection, the plasma levels of cefotaxime estimated at 0.08 h was 70.87 μg/ml, which declined gradually and cefotaxime was detected up to 10 h (0.59 μg/ml). The mean values of CL, Vdss and t1/2β of cefotaxime in muscovy ducks were 0.22 l/kg/h, 0.51 l/kg and 1.81 h, respectively. After IM injection, maximum plasma concentration (Cmax) was (14.72 μg/ml), time of maximal plasma concentration (tmax) was (2.3 h) and elimination half-life (t1/2el)was (1.77 h). Bioavailability following IM injection was 79.61%, and in vitro protein binding percent was 31.48%. A recommended IM dosage for cefotaxime in muscovy ducks would be 30 mg/kg b.wt., repeated at 12 h intervals will provide a therapeutic plasma concentrations exceeding the MIC≤0.5 µg/ml for most susceptible pathogens in ducks.

Pancreatic α cell function in the fetal and newborn pig

1986 ◽  
Vol 108 (1) ◽  
pp. 137-142 ◽  
Author(s):  
M. Silver ◽  
A. L. Fowden ◽  
R. S. Comline ◽  
S. R. Bloom
Keyword(s):  
Plasma Concentration ◽  
Gestational Age ◽  
Cell Function ◽  
Plasma Concentrations ◽  
In Utero ◽  
Plasma Glucagon ◽  
Arginine Infusion ◽  
Newborn Piglets ◽  
Ph Values ◽  
The Mean

ABSTRACT Plasma glucagon concentrations were measured in chronically catheterized fetal pigs during the last third of gestation and compared with the values observed in anaesthetized fetuses of similar gestational age. The mean plasma concentration of glucagon in the chronically catheterized fetuses was 10·0 ± 1·4 (s.e.m.) pmol/l (n = 11; term = 114 ± 2 days). Concentrations were increased after catheterization and fell to baseline values within 48 h of surgery. Arginine infusion evoked a rapid release of glucagon in chronically catheterized fetuses between 105 and 108 days of gestation; the mean maximum increment in plasma glucagon was 15·4 ± 4·5 pmol/l (n = 5). Plasma glucagon concentrations increased with increasing gestational age in both anaesthetized and chronically catheterized fetuses. Between 95 and 110 days of gestation, glucagon levels were significantly higher in anaesthetized fetuses than in chronically catheterized animals with similar normal pH values. Catheterization and prematurity had no apparent effect on plasma glucagon levels at birth. The plasma concentrations at birth were similar to those observed in the chronically catheterized fetuses in utero provided the piglets did not become acidotic during delivery. Significantly higher plasma levels of glucagon were found in newborn piglets with acidaemia (pH < 7·3) than in piglets with normal pH values at birth (pH > 7·3). When all the data from the newborn piglets were combined, there was a significant negative correlation (r= − 0·79, n = 39, P < 0·01) between blood pH and the plasma concentration of glucagon at birth. These observations demonstrate that the fetal α cells are functional and responsive in utero and at birth. J. Endocr. (1986) 108, 137–142

scholarly journals Effects of the Antifungals Voriconazole and Fluconazole on the Pharmacokinetics of S-(+)- and R-(−)-Ibuprofen

2006 ◽  
Vol 50 (6) ◽  
pp. 1967-1972 ◽  
Author(s):  
Ville-Veikko Hynninen ◽  
Klaus T. Olkkola ◽  
Kari Leino ◽  
Stefan Lundgren ◽  
Pertti J. Neuvonen ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Time Curve ◽  
Respective Control ◽  
Control Value ◽  
Racemic Ibuprofen ◽  
The Mean

ABSTRACT Our objective was to study the effects of the antifungals voriconazole and fluconazole on the pharmacokinetics of S-(+)- and R-(−)-ibuprofen. Twelve healthy male volunteers took a single oral dose of 400 mg racemic ibuprofen in a randomized order either alone, after ingestion of voriconazole at 400 mg twice daily on the first day and 200 mg twice daily on the second day, or after ingestion of fluconazole at 400 mg on the first day and 200 mg on the second day. Ibuprofen was ingested 1 h after administration of the last dose of voriconazole or fluconazole. Plasma concentrations of S-(+)- and R-(−)-ibuprofen were measured for up to 24 h. In the voriconazole phase, the mean area under the plasma concentration-time curve (AUC) of S-(+)-ibuprofen was 205% (P < 0.001) of the respective control value and the mean peak plasma concentration (C max) was 122% (P < 0.01) of the respective control value. The mean elimination half-life (t 1/2) was prolonged from 2.4 to 3.2 h (P < 0.01) by voriconazole. In the fluconazole phase, the mean AUC of S-(+)-ibuprofen was 183% of the control value (P < 0.001) and its mean C max was 116% of the control value (P < 0.05). The mean t 1/2 of S-(+)-ibuprofen was prolonged from 2.4 to 3.1 h (P < 0.05) by fluconazole. The geometric mean S-(+)-ibuprofen AUC ratios in the voriconazole and fluconazole phases were 2.01 (90% confidence interval [CI], 1.80 to 2.22) and 1.82 (90% CI, 1.72 to 1.91), respectively, i.e., above the bioequivalence acceptance upper limit of 1.25. Voriconazole and fluconazole had only weak effects on the pharmacokinetics of R-(−)-ibuprofen. In conclusion, voriconazole and fluconazole increased the levels of exposure to S-(+)-ibuprofen 2- and 1.8-fold, respectively. This was likely caused by inhibition of the cytochrome P450 2C9-mediated metabolism of S-(+)-ibuprofen. A reduction of the ibuprofen dosage should be considered when ibuprofen is coadministered with voriconazole or fluconazole, especially when the initial ibuprofen dose is high.

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