Plasma Concentrations Of Dexamethasone Research Articles

Getting the dose right using physiologically-based pharmacokinetic modeling: dexamethasone to prevent post-extubation stridor in children as proof of concept.

Critically ill patients show large variability in drug disposition due to e.g., age, size, disease and treatment modalities. Physiologically-based pharmacokinetic (PBPK) models can be used to design individualized dosing regimens taking this into account. Dexamethasone, prescribed for the prevention post-extubation stridor (PES), is metabolized by the drug metabolizing enzyme CYP3A. As CYP3A4 undergoes major changes during childhood, we aimed to develop age-appropriate dosing recommendations for children of dexamethasone for PES, as proof of concept for PBPK modeling to individualize dosing for critically ill patients. All simulations were conducted in Simcyp™ v21 (a population-based PBPK modeling platform), using an available dexamethasone compound model and pediatric population model in which CYP3A4 ontogeny is incorporated. Published pharmacokinetic (PK) data was used for model verification. Evidence for the dose to prevent post-extubation stridor was strongest for 2-6 year old children, hence simulated drug concentrations resulting from this dose from this age group were targeted when simulating age-appropriate doses for the whole pediatric age range. Dexamethasone plasma concentrations upon single and multiple intravenous administration were predicted adequately across the pediatric age range. Exposure-matched predictions of dexamethasone PK indicated that doses (in mg/kg) for the 2-6 years olds can be applied in 3 month-2 year old children, whereas lower doses are needed in children of other age groups (60% lower for 0-2 weeks, 40% lower for 2-4 weeks, 20% lower for 1-3 months, 20% lower for 6-12 year olds, 40% lower for 12-18 years olds). We show that PBPK modeling is a valuable tool that can be used to develop model-informed recommendations using dexamethasone to prevent PES in children. Based on exposure matching, the dose of dexamethasone should be reduced compared to commonly used doses, in infants <3 months and children ≥6 years, reflecting age-related variation in drug disposition. PBPK modeling is an promising tool to optimize dosing of critically ill patients.

Overestimation of the effect of (fos)aprepitant on intravenous dexamethasone pharmacokinetics requires adaptation of the guidelines for children with chemotherapy-induced nausea and vomiting

PurposeChemotherapy-induced nausea and vomiting (CINV) are common side effects in pediatric oncology treatment. Besides 5-HT3-antagonists, both dexamethasone and aprepitant are cornerstone drugs in controlling these side effects. Based on results of adult studies, the dexamethasone dose is reduced by 50% when combined with aprepitant, because of a drug-drug interaction, even though data on the interaction in children is lacking. The current study was developed to investigate the effect of aprepitant on dexamethasone clearance (CL) in children, in order to assess if dexamethasone dose reduction for concomitant use of aprepitant is appropriate in the current antiemetic regimen.MethodsIn total, 65 children (0.6–17.9 years), receiving intravenous or oral antiemetic therapy (dexamethasone ± aprepitant) as standard of care, were included. 305 dexamethasone plasma concentrations were determined using LC–MS/MS. An integrated dexamethasone and aprepitant pharmacokinetic model was developed using non-linear mixed effects modelling in order to investigate the effect of aprepitant administration on dexamethasone CL.ResultsIn this population, dexamethasone CL in patients with concomitant administration of aprepitant was reduced by approximately 30% of the uninhibited CL (23.3 L/h (95% confidence interval 20.4–26.0)). This result is not consistent with the results of adult studies (50% reduction). This difference was not age dependent, but might be related to the route of administration of dexamethasone. Future studies are needed to assess the difference in oral/intravenous dexamethasone.ConclusionWhen dexamethasone is given intravenously as a component of triple therapy to prevent CINV in children, we advise to reduce the dexamethasone dose by 30% instead of 50%.

Pharmacokinetic/Pharmacodynamic Modeling of the Anti-Cancer Effect of Dexamethasone in Pancreatic Cancer Xenografts and Anticipation of Human Efficacious Doses

Dexamethasone (DEX), a synthetic glucocorticoid, exhibited anti-cancer efficacy in pancreatic xenografts derived from patient tumor tissue or cancer cell lines. The aim of this study was to establish pharmacokinetic/pharmacodynamic (PK/PD) models to quantitatively characterize the inhibitory effect of DEX on tumor growth as well as its discrepancy among 3 xenograft models. Data of tumor growth profiles were collected from a patient-derived xenograft (PDX) model in NOD/SCID mice and 2 cell line–derived (PANC-1 and SW1990) xenograft models in BALB/c nude mice. Empirical PK/PD models were developed to establish mathematical relationships between plasma concentration of DEX and tumor growth dynamics after integrating PK parameters extracted from literature. Drug effect in each model was well described by a linear inhibitory function with a potency factor of 4.67, 3.14, and 2.35 L/mg for PDX, PANC-1, and SW1990 xenograft, respectively. Human efficacious doses of DEX were preliminarily predicted through model-based simulation, and 60% tumor growth inhibition at clinical exposure corresponded to a daily dose range of 26-52 mg intravenously. This modeling work quantified the preclinical anti-cancer effect of DEX and demonstrated the feasibility of its medication in pancreatic cancer, which would be conductive to future translational research.

A preliminary study on plasma concentration achieved following intrapterygomandibular space injection of dexamethasone as a route of drug delivery with lignocaine inferior alveolar nerve block-correlation of clinical effects.

To determine the quantity of dexamethasone plasma concentration achieved following intrapterygomandibular space injection of dexamethasone when co-administered with inferior alveolar nerve block correlating with the clinical effects in the postoperative phase. A preliminary prospective study to evaluate the dexamethasone plasma concentration achieved following intrapterygomandibular space injection of dexamethasone with 2% lignocaine inferior alveolar nerve block to achieve hemi-mandibular anesthesia for minor oral surgical procedures and derive clinical correlations. Dexamethasone is a glucocorticoid, chiefly used for the management of postsurgical sequelae like trismus and swelling in maxillofacial surgical practice. Conventionally, parenteral dexamethasone is administered via intravenous or intramuscular route. Intrapterygomandibular space injection is a novel route of steroid delivery described in literature. For minor oral surgical procedures in maxillofacial surgical practice requiring inferior alveolar nerve block, dexamethasone can be administered along with local anesthetic through a single injection as a mixture (twin mix). Prospective double-blind randomized clinical trial was designed to evaluative plasma concentration of dexamethasone achieved following injection of a freshly prepared mixture of 1.8ml of 2% lignocaine with adrenaline (1:200000) and 1ml (4mg) dexamethasone [2.8ml solution of twin mix] in the pterygomandibular space. The 30 candidates included for the trial were randomly split into three study groups (ten each)-(1) control group (C); (2) intramuscular group (IM); (3) intraspace group (IS). The mean plasma dexamethasone concentration at 30min postinjection in group IM was 226.41 ± 48.67ng/ml and for IS group it was 209.67 ± 88.13ng/ml. Post hoc (Bonferroni-Holm test) intergroup comparison for plasma dexamethasone concentration (IM and IS) was found statistically insignificant (P = 0.605). Intraspace route of drug administration can be utilized to deliver dexamethasonized local anesthetics safely with predictable clinical effects in the patients requiring mandibular minor oral surgery under local anesthesia.

Release pattern of dexamethasone after administration through an implant-mediated drug delivery device with an active plunger of super absorbent polymer.

The implant-mediated drug delivery system (IMDDS) is a novel, innovative device that allows drug delivery through bone marrow. The purpose of this study was to investigate the effect of an active plunger component made of super absorbent polymer (SAP) on the plasma concentration of dexamethasone released from the IMDDS. The IMDDSs were installed in a total of 18 rabbits. After complete healing, dexamethasone was loaded with the SAP active plunger and with water to cause expansion in the test group (n = 9), while only the drug was loaded in the control group, as per the original protocol (n = 9). The release patterns of each group were monitored for 2weeks by measuring the plasma concentration of the drug. Both groups showed sustained release of drug. However, the test groups showed more rapid increase in plasma concentration and higher area under the curve (AUC) throughout the observation period. The incorporation of a SAP active plunger component in the IMDDS resulted in an increase in initial release of drug and higher bioavailability within the observation period of 2weeks after dexamethasone administration.

Time-dependent pharmacokinetics of dexamethasone and its efficacy in human breast cancer xenograft mice: a semi-mechanism-based pharmacokinetic/pharmacodynamic model.

Dexamethasone (DEX) is the substrate of CYP3A. However, the activity of CYP3A could be induced by DEX when DEX was persistently administered, resulting in auto-induction and time-dependent pharmacokinetics (pharmacokinetics with time-dependent clearance) of DEX. In this study we investigated the pharmacokinetic profiles of DEX after single or multiple doses in human breast cancer xenograft nude mice and established a semi-mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model for characterizing the time-dependent PK of DEX as well as its anti-cancer effect. The mice were orally given a single or multiple doses (8 mg/kg) of DEX, and the plasma concentrations of DEX were assessed using LC-MS/MS. Tumor volumes were recorded daily. Based on the experimental data, a two-compartment model with first order absorption and time-dependent clearance was established, and the time-dependence of clearance was modeled by a sigmoid Emax equation. Moreover, a semi-mechanism-based PK/PD model was developed, in which the auto-induction effect of DEX on its metabolizing enzyme CYP3A was integrated and drug potency was described using an Emax equation. The PK/PD model was further used to predict the drug efficacy when the auto-induction effect was or was not considered, which further revealed the necessity of adding the auto-induction effect into the final PK/PD model. This study established a semi-mechanism-based PK/PD model for characterizing the time-dependent pharmacokinetics of DEX and its anti-cancer effect in breast cancer xenograft mice. The model may serve as a reference for DEX dose adjustments or optimization in future preclinical or clinical studies.

P-Glycoprotein in skin contributes to transdermal absorption of topical corticosteroids

ATP binding cassette transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), are expressed in skin, but their involvement in transdermal absorption of clinically used drugs remains unknown. Here, we examined their role in transdermal absorption of corticosteroids. Skin and plasma concentrations of dexamethasone after dermal application were reduced in P-gp and BCRP triple-knockout (Mdr1a/1b/Bcrp−/−) mice. The skin concentration in Mdr1a/1b/Bcrp−/− mice was reduced in the dermis, but not in the epidermis, indicating that functional expression of these transporters in skin is compartmentalized. Involvement of these transporters in dermal transport of dexamethasone was also supported by the observation of a higher epidermal concentration in Mdr1a/1b/Bcrp−/− than wild-type mice during intravenous infusion. Transdermal absorption after dermal application of prednisolone, but not methylprednisolone or ethinyl estradiol, was also lower in Mdr1a/1b/Bcrp−/− than in wild-type mice. Transport studies in epithelial cell lines transfected with P-gp or BCRP showed that dexamethasone and prednisolone are substrates of P-gp, but are minimally transported by BCRP. Thus, our findings suggest that P-gp is involved in transdermal absorption of at least some corticosteroids in vivo. P-gp might be available as a target for inhibition in order to deliver topically applied drugs and cosmetics in a manner that minimizes systemic exposure.

Time-dependent effects of dexamethasone plasma concentrations on glucocorticoid receptor challenge tests

Glucocorticoid challenge tests such as the dexamethasone suppression test (DST) and the combined dexamethasone/corticotropin-releasing hormone (dex-CRH) test are considered to be able to sensitively measure hypothalamic-pituitary-adrenal (HPA) axis activity in stress-related psychiatric and endocrine disorders. We used mass-spectrometry to assess the relationship of plasma dexamethasone concentrations and the outcome of these tests in two independent cohorts.Dexamethasone concentrations were measured after oral ingestion of 1.5mg dexamethasone in two cohorts that underwent a standard (dexamethasone at 23:00h) as well as modified (18:00h) DST and dex-CRH test. The first study population was a case/control cohort of 105 depressed patients and 133 controls in which peripheral blood mRNA expression was also measured. The second was a cohort of 261 depressed patients that underwent a standard dex-CRH test at baseline and after 12 weeks’ treatment with cognitive-behavioral therapy or antidepressants.Dexamethasone concentrations explained significant proportions of the variance in the DST in both the first (24.6%) and the second (5.2%) cohort. Dexamethasone concentrations explained a higher proportion of the variance in the dex-CRH test readouts, with 41.9% of the cortisol area under the curve (AUC) in the first sample and 24.7% in the second sample. In contrast to these strong effects at later time points, dexamethasone concentrations did not impact cortisol or ACTH concentrations or mRNA expression 3hours after ingestion. In the second sample, dexamethasone concentrations at baseline and week 12 were highly correlated, independent of treatment type and response status. Importantly, a case/control effect in the Dex-CRH test was only apparent when controlling for dexamethasone concentrations.Our results suggest that the incorporation of plasma dexamethasone concentration or measures of earlier endocrine read-outs may help to improve the assessment of endocrine dysfunction in depression.

Antileukemic Efficacy of Continuous Vs Discontinuous Dexamethasone in Murine Xenografts of Acute Lymphoblastic Leukemia

As cure rates for acute lymphoblastic leukemia (ALL) have increased, toxic complications of chemotherapy have also increased. The incidence of osteonecrosis is high – 54% of children had asymptomatic osteonecrosis, and 18% experienced symptomatic osteonecrosis in one prospective study; osteonecrosis was positively associated with plasma dexamethasone exposure (Kawedia et al. Blood 2011 PMID: 21148812). Osteonecrosis is also more common after continuous than discontinuous dosing of dexamethasone in children (Mattano et al. JCO 2012 PMID: 22901620, Seibel et al. Blood 2008 PMID: 18039957). Many ALL clinical trials now include a discontinuous glucocorticoid schedule, in which patients receive dexamethasone daily for one week, none the second week, then daily for the third week, in an attempt to reduce the rate of osteonecrosis.Using a murine model of osteonecrosis, our group previously found that mice treated with a discontinuous regimen of dexamethasone developed less osteonecrosis than those treated with a continuous regimen (Yang 2008 PMID: 18683891), consistent with clinical data. However, it is not known whether the discontinuous schedule may also compromise the cure rate. Our goal was to use murine models of ALL to determine if there was a difference in antileukemic efficacy of the continuous versus discontinuous dexamethasone regimens.Each of six patient samples of various ALL subtypes was engrafted into immunocompromised NSG mice, by intravenous injection of 1-5 million cells. In vitro sensitivity to dexamethasone was assessed at the time of diagnosis, and all samples were sensitive to nanomolar concentrations. The samples were passaged serially: they were transduced with a lentiviral vector containing YFP and luciferase prior to the second passage, sorted for YFP+ cells prior to the third passage, and tested for in vivo efficacy of continuous (cont) and discontinuous (disc) dexamethasone on the fourth and/or fifth passage. Dexamethasone was given in the drinking water, either half the week at 8 mg/L (Disc dex) or continuously at 4 mg/L (Cont dex) starting 7-28 days from ALL injection. All mice received antibiotic prophylaxis in the drinking water. Plasma concentrations of dexamethasone in mice on treatment were similar to plasma levels (20 – 200 nM) achieved in patients with ALL (Yang et al JCO PMID: 18421047).For all ALL samples engrafted, there was improved leukemia-free survival (LFS) with dexamethasone treatment compared to no dexamethasone treatment (median LFS +4 to +129 days relative to no dexamethasone, log-rank p=0.02 to p=0.001). For five of the six samples, there were no differences in LFS between the continuous and discontinuous regimens (median LFS differed by 1 – 15 days, log-rank p=0.14 to 0.9). For one of the six samples, the continuous dexamethasone was more effective (median LFS of 111 vs 77 days, log-rank p=0.002) than the discontinuous schedule. In a second experiment with the same sample, when all the mice were sacrificed on the same day from start of therapy, ALL burden as assessed by ventral luminescence (Kruskal-Wallis p=0.004) and by spleen size (Kruskal-Wallis p=0.006) was lower in the continuous dexamethasone group vs the discontinuous dexamethasone group.Thus far, these data indicate that for most pediatric ALL, discontinuous dexamethasone is likely to be as effective as continuous dexamethasone; however, it is possible that for some ALL cases, there may be differences in ALL efficacy between the continuous and discontinuous dexamethasone regimens. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Plasma concentration-dependent suppression of endogenous hydrocortisone in the horse after intramuscular administration of dexamethasone-21-isonicotinate.

Detection times and screening limits (SL) are methods used to ensure that the performance of horses in equestrian sports is not altered by drugs. Drug concentration-response relationship and knowledge of concentration-time profiles in both plasma and urine are required. In this study, dexamethasone plasma and urine concentration-time profiles were investigated. Endogenous hydrocortisone plasma concentrations and their relationship to dexamethasone plasma concentrations were also explored. A single dose of dexamethasone-21-isonicotinate suspension (0.03 mg/kg) was administered intramuscularly to six horses. Plasma was analysed for dexamethasone and hydrocortisone and urine for dexamethasone, using UPLC-MS/MS. Dexamethasone was quantifiable in plasma for 8.3 ± 2.9 days (LLOQ: 0.025 μg/L) and in urine for 9.8 ± 3.1 days (LLOQ: 0.15 μg/L). Maximum observed dexamethasone concentration in plasma was 0.61 ± 0.12 μg/L and in urine 4.2 ± 0.9 μg/L. Terminal plasma half-life was 38.7 ± 19 h. Hydrocortisone was significantly suppressed for 140 h. The plasma half-life of hydrocortisone was 2.7 ± 1.3 h. Dexamethasone potency, efficacy and sigmoidicity factor for hydrocortisone suppression were 0.06 ± 0.04 μg/L, 0.95 ± 0.04 and 6.2 ± 4.6, respectively. Hydrocortisone suppression relates to the plasma concentration of dexamethasone. Thus, determination of irrelevant plasma concentrations and SL is possible. Future research will determine whether hydrocortisone suppression can be used as a biomarker of the clinical effect of dexamethasone.

Aprepitant does not alter prednisolone pharmacokinetics in patients treated with R-CHOP

Aprepitant, a neurokinin 1 receptor antagonist, is an effective antiemetic drug in the prevention of chemotherapy-induced nausea and vomiting. Aprepitant co-administration increases plasma concentrations of dexamethasone and methylprednisolone by inhibiting cytochrome P450 (CYP) 3A4 [1], whereas pharmacokinetics of cyclophosphamide, which is also metabolized by CYP enzymes including CYP3A4, is not significantly changed by aprepitant [2]. Thus, aprepitant co-administration provides different effects on pharmacokinetics of CYP substrates; however, it is unknown whether aprepitant affects pharmacokinetics of prednisolone, another CYP3A4 substrate.

Pharmacokinetics of dexamethasone after intravenous and intramuscular administration in pigs

The pharmacokinetics of dexamethasone (DEX) were investigated after an intravenous (IV) or intramuscular (IM) bolus injection of 0.3mg/kg bodyweight DEX sodium phosphate in pigs. The plasma concentrations of DEX were determined using a validated high-performance liquid chromatography–tandem mass spectrometry (LC–MS/MS) method and the pharmacokinetics were determined by one-compartmental analysis.The mean area under the plasma concentration–time curve and the mean elimination half-life were 133.07±39.59ng.h/mL and 0.77h, and 173.24±53.59ngh/mL and 1.06h following IV and IM administration, respectively. The volume of distribution and clearance recorded after IV administration were 2.78±0.88L/kg and 2.39±0.57L/hkg, respectively.An IM bolus injection of DEX sodium phosphate in pigs resulted in a fast and complete absorption, with a mean maximal plasma concentration of 80.94±21.29ng/mL at 0.35±0.21h and a high absolute bioavailability of 131.06±26.05%.

A mechanism-based pharmacokinetic/pharmacodynamic model for CYP3A1/2 induction by dexamethasone in rats

To develop a pharmacokinetic/pharmacodynamic (PK/PD) model describing the receptor/gene-mediated induction of CYP3A1/2 by dexamethasone (DEX) in rats. A group of male Sprague-Dawley rats receiving DEX (100 mg/kg, ip) were sacrificed at various time points up to 60 h post-treatment. Their blood sample and liver were collected. The plasma concentration of DEX was determined with a reverse phase HPLC method. CYP3A1/2 mRNA, protein levels and enzyme activity were measured using RT-PCR, ELISA and the testosterone substrate assay, respectively. Data analyses were performed using a first-order conditional estimate (FOCE) with INTERACTION method in NONMEM version 7.1.2. A two-compartment model with zero-order absorption was applied to describe the pharmacokinetic characteristics of DEX. Systemic clearance, the apparent volume of distribution and the duration of zero-order absorption were calculated to be 172.7 mL·kg(-1)·h(-1), 657.4 mL/kg and 10.47 h, respectively. An indirect response model with a series of transit compartments was developed to describe the induction of CYP3A1/2 via PXR transactivation by DEX. The maximum induction of CYP3A1 and CYP3A2 mRNA levels was achieved, showing nearly 21.29- and 8.67-fold increases relative to the basal levels, respectively. The CYP3A1 and CYP3A2 protein levels were increased by 8.02-fold and 2.49-fold, respectively. The total enzyme activities of CYP3A1/2 were shown to increase by up to 2.79-fold, with a lag time of 40 h from the Tmax of the DEX plasma concentration. The final PK/PD model was able to recapitulate the delayed induction of CYP3A1/2 mRNA, protein and enzyme activity by DEX. A mechanism-based PK/PD model was developed to characterize the complex concentration-induction response relationship between DEX and CYP3A1/2 and to resolve the drug- and system-specific PK/PD parameters for the course of induction.

Comparative Bioavailability of Two Dexamethasone Tablet Formulations in Indonesian Healthy Volunteers

To compare the bioavailability of two dexamethasone (CAS 50-02-2) tablet formulations -- 4 mg Dexmethsone tablets as test formulation and 4 mg tablets of the originator product as reference formulation. The study was conducted according to an open-label, randomized two-way crossover design with a one-week washout period. Twenty-four volunteers received a single dose of two tablets of the two different dexamethasone formulations. Blood samples for pharmacokinetic profiling were taken up to 24 h after drug administration in fasting condition. Plasma concentrations of dexamethasone were determined with a validated HPLC method using an ultraviolet detector. Pharmacokinetic parameters were calculated from observed plasma concentration-time profiles. The mean AUC0-t, AUC0-infinity, and Cmax were 501.61 ng x h/ml, 518.88 ng x h/ ml and 98.02 ng/ml, respectively for the test formulation and 507.10 ng x h/ml, 525.20 ng x h/ml and 97.82 ng/ml, respectively, for the reference formulation. The median Tmax, for both formulations was 0.75 h. Plasma elimination half-lives (t1/2) were 3.44 h (test) and 3.38 h (reference). The point estimates and 90% confidence intervals (CI) for AUC0-t, AUC0-infinity and Cmax were 98.92% (94.62-103.41%), 98.80% (94.51-103.28%) and 100.20% (91.43-109.81%), respectively, satisfying the bioequivalence criteria of the European Committee for Proprietary Medicinal Products and the US Food and Drug Administration guidelines. These results indicate that the two formulations of dexamethasone are bioequivalent and thus may be prescribed interchangeably.

Intratympanic Versus Intravenous Delivery of Dexamethasone and Dexamethasone Sodium Phosphate to Cochlear Perilymph

To measure dexamethasone concentrations in the plasma and perilymph of the human ear after intravenous (IV) and intratympanic (IT) administration and to compare these with previous studies with methylprednisolone. Patients were administered dexamethasone by the IT or IV routes approximately 0.5 to 2 hours before cochlear implantation. The IT dose of 1.6 to 7.2 mg (0.4-1.8 ml of a 4 mg/ml solution) of dexamethasone sodium phosphate was administered by injection into the middle ear cavity through the external auditory canal via a 27-gauge needle passed through a small anterosuperior myringotomy. The IV dose of dexamethasone sodium phosphate was 0.17 mg/kg given as a single injection for 30 seconds. A sample of perilymph (approximately 20 μl) was collected using a needle passed through the round window, and blood was sampled simultaneously. Concentrations of free dexamethasone and dexamethasone sodium phosphate were measured using a validated liquid chromatography-tandem mass spectrometry method. In the 22 patients studied, 22 perilymph samples and 19 plasma samples were available and suitable for measurement. The median perilymph concentration of dexamethasone after IV injection of 0.17 mg/kg was 0.016 mg/L (n = 9; range, 0.008-0.17), and 1.4 mg/L (n = 13; range, 0.1-16.3) after IT administration of approximately 4 mg. Perilymph concentrations were approximately 88-fold higher after IT compared with IV administration (p = 0.0004) or approximately 260 fold after correction for dosage. The median plasma concentration of dexamethasone after IV injection was 0.12 mg/L (n = 7; range, 0.07-0.14) and 0.003 mg/L (n = 12; range, <0.0005-0.005) after IT injection. Plasma concentrations were approximately 40-fold lower (p = 0.0005) or approximately 13-fold lower after dose correction. Concentrations of dexamethasone sodium phosphate were more variable and were even higher in perilymph and lower in plasma. Administration of dexamethasone IT results in much higher perilymph concentrations and much lower plasma concentrations compared with IV administration.

Asparaginase May Influence Dexamethasone Pharmacokinetics in Acute Lymphoblastic Leukemia

Dexamethasone is used widely in oncology, but pharmacokinetic studies are lacking. We evaluated dexamethasone pharmacokinetics in children with acute lymphoblastic leukemia. We assessed 214 children with acute lymphoblastic leukemia who received 418 courses of oral dexamethasone (8 mg/m(2)/d) on days 1 and 8 of reinduction. Extensive asparaginase use preceded reinduction in the 101 children in the standard/high-risk treatment arm but not in the 113 children in the low-risk treatment arm. A one-compartment model with first-order absorption and disposition was fit to dexamethasone plasma concentrations by using maximum a posteriori probability estimation; we evaluated covariates by using linear mixed models. Interpatient and intrapatient variabilities in apparent clearance were substantial; they were 46% and 53%, respectively. Variability was explained by the serum albumin concentration (P < .0001), concomitant use of fentanyl (P = .008) and ketoconazole (P = .03), and age (P = .006). Apparent clearance was higher in the low-risk arm (P < .001) and was related to a greater serum albumin concentration (P < .001) and to a lower exposure to asparaginase than in the standard/high-risk arm. Hypoalbuminemia, a biomarker of asparaginase activity, was associated with a lower dexamethasone apparent clearance (P = .04) in patients in the standard/high-risk arm that was more pronounced in those not allergic to asparaginase. Ethnicity or gender did not explain apparent clearance variability. Dexamethasone pharmacokinetics are highly variable and are related to the concurrent use of particular drugs, age, and treatment intensity. Patients allergic to asparaginase may be doubly disadvantaged: they not only suffer from diminished exposure to asparaginase but also, by maintaining high clearance of dexamethasone, may experience fewer antileukemic effects of dexamethasone.

Pharmacokinetics of dexamethasone with pharmacokinetic/pharmacodynamic model of the effect of dexamethasone on endogenous hydrocortisone and cortisone in the horse

A compartmental model was used to describe the pharmacokinetics of dexamethasone (DXM) and changes in the plasma concentration of endogenous cortisone (COR) and hydrocortisone (HYD) following intravenous (i.v.) administration of DXM (0.05 mg/kg) in horses. Quantification of DXM, COR and HYD in equine plasma was achieved using liquid chromatography interfaced with triple spray quadrupole quantum tandem mass spectrometry (LC/TSQ-MS/MS). The median alpha (t(1/2alpha)), beta (t(1/2beta)), and gamma (t(1/2gamma)) half-lives were 0.33, 2.2, and 10.7 h respectively. The area under the DXM plasma concentration curve (AUC) was 113.5 ng.h/mL. At 72 h post-DXM administration, the plasma concentration of DXM in all horses was below the level of quantification (100 pg/mL). The baseline plasma concentration of COR was 3.5 +/- 0.69 ng/mL and declined significantly (P < 0.02) to 2.9 +/- 0.86 ng/mL at 1 h. The nadir in COR plasma concentration was 0.65 +/- 0.12 ng/mL at 28.8 +/- 9.0 h, and the DXM plasma concentration was 0.19 +/- 0.13 ng/mL. COR concentration returned to baseline at 96 h. Baseline plasma concentration of HYD was 58.8 +/- 11.7 ng/mL and declined significantly (P < 0.001) to 41.1 +/- 14.9 ng/mL at 1 h following DXM administration but recovered to baseline at 96 h. The sensitivity of LC/TSQ-MS/MS allowed complete description of the pharmacokinetics of DXM and its effect on plasma concentrations of both COR and HYD.

Comparison of dexamethasone pharmacokinetics in female rats after intravenous and intramuscular administration

This study seeks a route of drug administration that would produce a pharmacokinetic profile for dexamethasone not significantly different from the intravenous route in female rats and would offer reproducible drug input with minimal stress to the animals. The intramuscular (i.m.) route of drug administration vs intravenous (i.v.) injection were compared in three female Wistar rats administered 1 mg/kg dexamethasone phosphate. Dexamethasone plasma concentrations were measured by a normal phase HPLC assay for 12 h after drug administration. Dexamethasone exhibited monoexponential behavior after intravenous dosing and was absorbed rapidly after intramuscular dosing (absorption half-life of 14 min) with 86% bioavailability. Dexamethasone had a terminal half-life of 2.3 h after drug administration by either route. The volume of distribution of 0.78 l/kg and the clearance of 0.23 l/h/kg are in good agreement with reported pharmacokinetic parameters in male rats. Intravenous dosing can be replaced by intramuscular dosing without causing any marked difference in dexamethasone pharmacokinetics.

A LIQUID CHROMATOGRAPHIC-TANDEM MASS SPECTROMETRIC METHOD FOR THE QUANTITATIVE ANALYSIS OF DEXAMETHASONE IN HUMAN PLASMA

ABSTRACT A simple and specific assay for the rapid quantification of the plasma concentration of dexamethasone from 0.250 to 250 ng/mL has been developed and validated using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The method used methyl-t-butyl ether (MTBE) to extract dexamethasone and the internal standard (IS) beclomethasone from alkalinized human plasma sample. The chromatographic separation was on a C18 column (50 × 3 mm, 5-µm) using acetonitrile-water-formic acid (35 : 65 : 0.1, v/v) mobile phase at a flow rate of 0.500 mL/min. The retention times were approximately 1.8 min for dexamethasone and 2.0 min for the internal standard. The tandem mass spectrometric detection was by monitoring singly charged precursor→production transitions 393→373 (m/z) for dexamethasone and 409→391 (m/z) for the internal standard. The validated method used 0.5-mL plasma. The linear correlation coefficients of the calibration curves were greater than, or equal to, 0.9972. The run time for each sample injection was 3.0 min. The recoveries of the extraction were found to be 88–91% for dexamethasone at three concentration levels and 84.5% for the IS, respectively. The intra-day precision and accuracy of the control samples were of <4.8% relative standard deviation (RSD) (n=6) and −7.6 to 5.6% relative errors (RE). The inter-day precision and accuracy were <5.1% RSD (n=18) and −6.9 to −0.3% RE. The partial volume experiments showed excellent dilution integrity for high concentration level control samples. The stability data illustrated that this compound was stable in plasma at least for three freeze/thaw cycles, or keeping plasma samples at ambient temperature for 24 hours, or storing extracted samples at room temperature for 48 hours, and or storing frozen samples at approximately −20°C for up to three months.

Interstitial delivery of dexamethasone in the brain for the reduction of peritumoral edema

Controlled-release polymers have facilitated the interstitial delivery of drugs within the central nervous system. In the present study, dexamethasone was incorporated into ethylene-vinyl acetate polymers, which were then implanted adjacent to a 9L gliosarcoma in the brain of Fischer 344 rats. The effect of interstitial delivery of dexamethasone on peritumoral edema was assessed and compared to the effect of dexamethasone delivered systemically. Eighty-five rats underwent intracranial implantation of the 9L gliosarcoma. Five days later, the animals were randomly assigned to one of four treatment groups: Group 1 received intracranial implantation of controlled-release polymers containing dexamethasone; Group 2 received intraperitoneal implantation of controlled-release polymers containing dexamethasone; Group 3 received serial intraperitoneal injections of dexamethasone; and Group 4 received sham treatment. The animals were sacrificed 3 days after initiation of therapy and their brains were removed for measurement of the water content (edema) in the tumor-bearing and contralateral hemispheres. Brain and plasma samples were analyzed by reverse-phase high-performance liquid chromatography to determine the tissue and plasma concentrations of dexamethasone. Measurement of the release kinetics of dexamethasone from the ethylene-vinyl acetate polymers in an in vitro system showed that the drug was released in a controlled, tapering fashion. During the first 3 days of controlled release in vitro, 330 micrograms of a total content of 7.5 mg of dexamethasone was released into the medium. Analysis of tissue for drug levels demonstrated, however, that the interstitial delivery of this fractional amount of dexamethasone within the brain resulted in levels 19 times higher than those achieved by administering the full dose of 7.5 mg systemically over a 3-day period. Conversely, the systemic administration of dexamethasone resulted in plasma levels 16 times higher than those measured in the interstitial delivery of dexamethasone in the brain. Brain-water content determinations showed that the interstitial controlled release of the fractional amount of dexamethasone within the brain was as effective in controlling peritumoral edema as systemic administration of the full dose by serial intraperitoneal injections. The study demonstrates the following: 1) controlled-release polymeric carriers deliver biologically active dexamethasone in a sustained fashion; 2) very high concentrations of dexamethasone in brain tissue can be achieved using interstitial polymer-mediated drug delivery while minimizing plasma concentrations of this drug which are sometimes associated with serious systemic side effects; and 3) peritumoral brain edema can be effectively treated by the interstitial delivery of dexamethasone directly within the tumor bed.