Influence of age on frequency of vancomycin dosing

Background:

Vancomycin is commonly prescribed at the authors’ institution because of a high prevalence of invasive infections caused by methicillin-resistant Staphylococcus aureus (MRSA) in a generally younger population. The most commonly prescribed empiric dosing interval is every 12 h (q12h). However, observations have suggested that younger adult patients require more frequent dosing, such as every 8 h (q8h). Initial underdosing of vancomycin may increase the risk of antibiotic failure.

Objective:

To determine whether patients under 40 years of age are more likely than older patients to require q8h dosing of vancomycin and whether recommendations can be made to alter current prescribing practices.

Methods:

This retrospective unmatched case–control study involved patients who had received vancomycin for suspected or confirmed severe MRSA infections. The cases were patients who had been confirmed as requiring q8h dosing, and the controls were patients who had been confirmed as requiring q12h dosing (on the basis of target predose serum levels). The influence of age (the predictor variable) on outcome (the vancomycin regimen) was evaluated by logistic regression.

Results:

The odds ratio for patients under 40 years of age requiring q8h dosing was 3.1 (95% confidence interval 1.5–6.3) (p = 0.002). Sixty percent of patients under 40 ultimately required a q8h regimen to achieve target predose serum levels. Patients who required q8h dosing took longer to achieve their first therapeutic serum level than those with q12h dosing (median 6 versus 4 days; p < 0.001).

Conclusions:

In this patient population, age less than 40 years was a strong predictor for requiring more frequent dosing of vancomycin. The authors suggest that doses of 15 mg/kg IV q8h be used empirically for younger patients with severe infections and normal renal function.     

Development and validation of a novel vancomycin dosing nomogram for achieving high-target trough levels at 2 canadian teaching hospitals

Background:

Recent guidelines recommend a vancomycin trough (predose) level between 15 and 20 mg/L in the treatment of invasive gram-positive infections, but most initial dosing nomograms are designed to achieve lower targets (5–15 mg/L). Clinicians need guidance about appropriate initial dosing to achieve the higher target.

Objective:

To develop and validate a high-target vancomycin dosing nomogram to achieve trough levels of 15–20 mg/L.

Methods:

A retrospective study was conducted at 2 teaching hospitals, St Paul’s Hospital and Vancouver General Hospital in Vancouver, British Columbia. Patients who were treated with vancomycin between January 2008 and June 2010 and who had achieved a trough level of 14.5–20.5 mg/L were identified. Demographic and clinical data were collected. Multiple linear regression was used to develop a vancomycin dosing nomogram for each hospital site. An integrated nomogram was constructed by merging the data from the 2 hospitals. A unique set of patients at each institution was used for validating their respective nomograms and a pooled group of patients for validating the integrated nomogram. Predictive success was evaluated, and a nomogram was deemed significantly different from another nomogram if p < 0.05 via “χ² testing.

Results:

Data from 78 patients at one hospital and 91 patients at the other were used in developing the respective institutional nomograms. For each hospital’s data set, both age and initial serum creatinine were significantly associated with the predicted dosing interval (p < 0.001). Validation in a total of 105 test patients showed that the integrated nomogram had a predictive success rate of 56%.

Conclusions:

A novel vancomycin dosing nomogram was developed and validated at 2 Canadian teaching hospitals. This integrated nomogram is a tool that clinicians can use in selecting appropriate initial vancomycin regimens on the basis of age and serum creatinine, to achieve high-target levels of 15–20 mg/L. The nomogram should not replace clinical judgment for patients with unstable and/or reduced renal function.     

A sensitive indirect competitive enzyme-linked immunosorbent assay for the detection of sarsasapogenin in rat plasma

Aim:

To generate a polyclonal antibody against sarsasapogenin and to develop an indirect competitive enzyme-linked immunosorbent assay (IC-ELISA) method for the pharmacokinetic study of Sarsasapogenin in rats.

Methods:

The antigen of sarsasapogenin was produced using an active ester method and subsequently used for raising polyclonal antibodies in rabbits. The specificity and sensitivity of the antibody were measured by IC-ELISA. Using the ELISA method, sarsasapogenin levels were measured in the serum of rats after an oral dose of 100 mg/kg.

Results:

Polyclonal antibodies raised against sarsasapogenin-bovine serum albumin were generated and showed a high reactivity to sarsasapogenin. The antibodies exhibited minor cross-reactivity to ruscogenin (23%), diosgenin (22%), 25 (R, S) ruscogenin l-O-[β-D-glucopyranosyl (1→2)][β-D-xylopyranosyl (1→3)]-β-D-fucopyranoside (26%) and no cross-reactivity to diammonium glycyrrhizinate and notoginseng R1. The detection range of sarsasapogenin by this ELISA method was approximately 2.4−760 ng/mL. The recovery rates of 10 ng/mL, 100 ng/mL, and 500 ng/mL were in the range of 91.0%−96.2% for intra-assay and 89.0%–92.0% for inter-assay. The coefficients of variation (CV%) for intra- and inter-assays at the three different sarsasapogenin levels were 3.1%–8.3% (n=6) and 6.0%-14.1% (n=6), respectively.

Conclusion:

The IC-ELISA method is a sensitive test for the determination of sarsasapogenin concentration in rat plasma and for pharmacokinetic (PK) studies.     

Pharmacokinetics of tacrolimus converted from twice-daily formulation to once-daily formulation in Chinese stable liver transplant recipients

Aim:

To evaluate the pharmacokinetics of tacrolimus in Chinese stable liver transplant recipients converted from immediate release (IR) tacrolimus-based immunosuppression to modified release (MR) tacrolimus-based immunosuppression.

Methods:

Open-label, multi-center study with a one-way conversion design was conducted. Eighty-three stable liver recipients (6–24 months post-transplant) with normal renal and stable hepatic function were converted from IR tacrolimus twice-daily treatment to MR tacrolimus once-daily treatment on a 1:1 (mg: mg) total daily dose basis. Twenty-four hour pharmacokinetic studies were carried out on d 0 (pre-conversion), d 1, and d 84 (post-conversion).

Results:

The area under the blood concentration–time curve of MR tacrolimus from 0 to 24 h (AUC_0–24) on d 1 was comparable to that of IR tacrolimus on d 0, with a 90% confidence interval (CI) for MR/IR tacrolimus of 92%–97%. The AUC_0–24 value for MR tacrolimus on d 84 with the daily dose increased by 14% was approximately 17% lower than that for IR tacrolimus. The 90% CI was 77%–90%, outside the bioequivalence range of 80%–125%. There was a good correlation between AUC_0–24 and concentration at 24 h (C₂₄) for IR tacrolimus (d 0, r=0.930) and MR tacrolimus (d 1, r=0.936; d 84, r=0.903).

Conclusion:

The exposure to tacrolimus when administered MR tacrolimus once daily is not equivalent to that for IR tacrolimus twice daily after an 84-day conversion in Chinese stable liver transplant recipients. The dose should be adjusted on the basis of trough levels. The therapeutic drug monitoring for patients treated with IR tacrolimus is considered to be applicable to MR tacrolimus.     

Preparation, characterization and in vivo evaluation of bergenin-phospholipid complex

Aim:

To prepare a bergenin-phospholipid complex (BPC) to increase oral bioavailability of the drug.

Methods:

In order to obtain the acceptable BPC, a spherical symmetric design-response surface methodology was used for process optimization. The influence of reaction medium, temperature, drug concentration and drug-to-phospholipid ratio on the combination percentage and content of bergenin in BPC were evaluated. BPC was then characterized by thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC), ultra-violet (UV) spectroscopy, fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC) and X-ray powder diffraction. The physicochemical properties such as microscopic shape, particle size, zeta-potential, solubility, crystalline form, and hygroscopicity were tested. The pharmacokinetic characteristics and bioavailability of BPC were investigated after oral administration in rats in comparison to bergenin and the physical mixture (bergenin and phospholipids).

Results:

BPC was successfully prepared under the optimum conditions [temperature=60 °C, drug concentration=80 g/L and drug-to-phospholipids ratio=0.9 (w/w)]. The combination percentage was 100.00%±0.20%, and the content of bergenin in the complex was 45.98%±1.12%. Scanning electron microscopy and transmission electron microscopy of BPC showed spherical particles. The average particle size was 169.2±20.11 nm and the zeta-potential was -21.6±2.4 mV. The solubility of BPC in water and in n-octanol was effectively enhanced. The C_max and AUC_0→∞ of BPC were increased, and the relative bioavailability was significantly increased to 439% of bergenin.

Conclusion:

The BPC is a valuable delivery system to enhance the oral absorption of bergenin.     

Single and multiple dose intravenous and oral pharmacokinetics of the hedgehog pathway inhibitor vismodegib in healthy female subjects

AIM

Vismodegib has demonstrated clinical activity in patients with advanced basal cell carcinoma. The pharmacokinetics (PK) of vismodegib are non-linear. The objective of this study was to determine whether vismodegib PK change following repeated dosing by administering a tracer intravenous (i.v.) dose of ¹⁴C-vismodegib with single and multiple oral doses.

METHODS

Healthy post menopausal female subjects (n= 6/group) received either a single or daily 150 mg vismodegib oral dose with a ¹⁴C-labelled 10 µg i.v. bolus dose administered 2 h after the single or last oral dose (day 7). Plasma samples were assayed for vismodegib by LC-MS/MS and for ¹⁴C-vismodegib by accelerator mass spectrometry.

RESULTS

Following a single i.v. dose, mean clearance, volume of distribution and absolute bioavailability were 43.4 ml h⁻¹, 16.4 l and 31.8%, respectively. Parallel concentration–time profiles following single oral and i.v. administration of vismodegib indicated elimination rate limited PK. Following i.v. administration at steady-state, mean clearance and volume of distribution were 78.5 ml h⁻¹ and 26.8 l, respectively. Comparison of i.v. PK parameters after single and multiple oral dosing showed similar half-life, increased clearance and volume of distribution (81% and 63% higher, respectively) and decreased bioavailability (77% lower) after repeated dosing. Relative to single dose, the unbound fraction of vismodegib increased 2.4-fold with continuous daily dosing.

CONCLUSION

Vismodegib exhibited a long terminal half-life after oral and i.v. administration, moderate absolute bioavailability and non-linear PK after repeated dosing. Results from this study suggest that the non-linear PK of vismodegib result from two separate, non-linear processes, namely solubility limited absorption and high affinity, saturable plasma protein binding.     

Lopinavir/ritonavir population pharmacokinetics in neonates and infants

AIMS

Because of immature hepatic metabolism, lopinavir could present specific pharmacokinetics in the first weeks of life. We aimed at determining the optimal dosing regimen in neonates and infants weighing 1 to 10.5 kg.

METHODS

Lopinavir/ritonavir (LPV/r) pharmacokinetics were studied in 96 infants using a population approach.

RESULTS

A one-compartment model described LPV/r pharmacokinetics. Normalized to a 70 kg adult using allometry, clearance (CL/F) and distribution volume (V/F) estimates were 5.87 l h⁻¹ 70 kg⁻¹ and 91.7 l 70 kg⁻¹. The relative bioavailabilty, F, increased with post-menstrual age (PMA) and reached 50% of the adult value at 39.7 weeks.

CONCLUSIONS

Size and PMA explained some CL/F and V/F variability in neonates/infants. Based upon trough concentration limitations, suggested LPV/r dosing regimens were 40 mg 12 h⁻¹, 80 mg 12 h⁻¹ and 120 mg 12 h⁻¹ in the 1–2 kg, 2–6 kg and 6–10 kg group, respectively.     

Pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of ticagrelor in healthy volunteers

AIM

To determine the pharmacokinetics, pharmacodynamics, safety and tolerability of multiple oral doses of ticagrelor, a P2Y₁₂ receptor antagonist, in healthy volunteers.

METHODS

This was a randomized, single-blind, placebo-controlled, ascending dose study. Thirty-two subjects received ticagrelor 50–600 mg once daily or 50–300 mg twice daily or placebo for 5 days at three dose levels in two parallel groups. Another group of 16 subjects received a clopidogrel 300 mg loading dose then 75 mg day⁻¹, or placebo for 14 days.

RESULTS

Ticagrelor was absorbed with median t_max 1.5–3 h, exhibiting predictable pharmacokinetics over the 50–600 mg dose range. Mean C_max and AUC for ticagrelor and its main metabolite, AR-C124910XX, increased approximately dose-proportionately (approximately 2.2- to 2.4-fold with a twofold dose increase) over the dose range. Inhibition of platelet aggregation (IPA) with ticagrelor was greater and better sustained at high levels with ticagrelor twice daily vs. once daily regimens. Throughout dosing, more consistent IPA was observed at doses ≥300 mg once daily and ≥100 mg twice daily compared with clopidogrel. Mean IPA with ticagrelor ≥100 mg twice daily was greater and less variable (93–100%, range 65–100%) than with clopidogrel (77%, range 11–100%) at trough concentrations. No safety or tolerability issues were identified.

CONCLUSIONS

Multiple dosing provided predictable pharmacokinetics of ticagrelor and its metabolite over the dose range of 50–600 mg once daily and 50–300 mg twice daily with C_max and AUC(0,t) increasing approximately dose-proportionally. Greater and more consistent IPA with ticagrelor at doses ≥100 mg twice daily and ≥300 mg once daily were observed than with clopidogrel. Ticagrelor at doses up to 600 mg day⁻¹ was well tolerated.     

An open-label, single-dose bioavailability study of the pharmacokinetics of CAT-354 after subcutaneous and intravenous administration in healthy males

AIM

To assess the bioavailability and pharmacokinetics of CAT-354, an anti-IL-13 human monoclonal IgG4 antibody, following subcutaneous (s.c.) and intravenous (i.v.) administration.

METHODS

This was a single-dose, randomized, open-label, parallel-group bioavailability study. Healthy male subjects aged 20–54 years were randomly assigned to one of three dose groups (n= 10/group) to receive CAT-354: 150 mg i.v.; 150 mg s.c. or 300 mg s.c. (two 150 mg injections). Serum pharmacokinetics, adverse events (AEs), vital signs, electrocardiograms and laboratory parameters were assessed.

RESULTS

CAT-354 showed bioavailability of 62% and 60% after 150 mg and 300 mg s.c. doses, respectively, and linear pharmacokinetics over the dose range tested. Peak serum concentrations in the s.c. groups occurred after 3–9 (median 5) days, with a mean elimination half-life of 19.2 ± 3.1 days (150 mg) and 19.4 ± 3.59 days (300 mg) after s.c. and 21.4 ± 2.46 days after i.v. administration. Volume of distribution at steady state (V_ss) was 4960 ± 1440 ml kg⁻¹ after i.v. (slightly greater than plasma volume). Average apparent clearances (CL/F) were 292 ± 82.3 and 307 ± 109 ml day⁻¹ after 150 and 300 mg s.c., respectively; systemic CL of 188 ± 84.0 ml day⁻¹ after i.v. dosing was consistent with endogenous IgG and reticuloendothelial elimination. No severe or serious AEs occurred. Among 40 reported AEs, 25 were headache, sinus disorders/respiratory symptoms and changes in body temperature perception.

CONCLUSIONS

CAT-354 exhibited bioavailability of approximately 60% when given s.c. to healthy male subjects.     

Hormonal and metabolic effects of morning or evening dosing of the dipeptidyl peptidase IV inhibitor vildagliptin in patients with type 2 diabetes

AIM

This randomized, double-blind, crossover study compared post-prandial hormonal and metabolic effects of vildagliptin, (an oral, potent, selective inhibitor of dipeptidyl peptidase IV [DPP-4]) administered morning or evening in patients with type 2 diabetes.

METHODS

Forty-eight patients were randomized to once daily vildagliptin 100 mg administered before breakfast or before dinner for 28 days then crossed over to the other dosing regimen. Blood was sampled frequently after each dose at baseline (day −1) and on days 28 and 56 to assess pharmacodynamic parameters.

RESULTS

Vildagliptin inhibited DPP-4 activity (>80% for 15.5 h post-dose), and increased active glucagon-like peptide-1 compared with placebo. Both regimens reduced total glucose exposure compared with placebo (area under the 0–24 h effect–time curve [AUE(0,24 h)]: morning −467 mg dl⁻¹ h, P = 0.014; evening −574 mg dl⁻¹ h, P = 0.003) with no difference between regimens (P = 0.430). Reductions in daytime glucose exposure (AUE(0,10.5 h)) were similar between regimens. Reduction in night-time exposure (AUE(10.5,24 h) was greater with evening than morning dosing (−336 vs. −218 mg dl⁻¹ h, P = 0.192). Only evening dosing significantly reduced fasting plasma glucose (−13 mg dl⁻¹, P = 0.032) compared with placebo. Insulin exposure was greater with evening dosing (evening 407 µU ml⁻¹ h; morning 354 µU ml⁻¹ h, P = 0.050).

CONCLUSIONS

Both morning and evening dosing of once daily vildagliptin 100 mg significantly reduced post-prandial glucose in patients with type 2 diabetes; only evening dosing significantly decreased fasting plasma glucose. Although evening dosing with vildagliptin 100 mg tended to decrease night-time glucose exposure more than morning dosing, both regimens were equally effective in reducing 24 h mean glucose exposure (AUE(0,24 h)) in patients with type 2 diabetes.     

Novel gastroretentive sustained-release tablet of tacrolimus based on self-microemulsifying mixture: in vitro evaluation and in vivo bioavailability test

Aim:

To develop a novel gastroretentive drug delivery system based on a self-microemulsifying (SME) lipid mixture for improving the oral absorption of the immunosuppressant tacrolimus.

Methods:

Liquid SME mixture, composed of Cremophor RH40 and monocaprylin glycerate, was blended with polyethylene oxide, chitosan, polyvinylpyrrolidone and mannitol, and then transformed into tablets via granulation, with ethanol as the wetting agent. The tablets were characterized in respect of swelling, bioadhesive and SME properties. In vitro dissolution was conducted using an HCl buffer at pH 1.2. Oral bioavailability of the tablets was examined in fasted beagle dogs.

Results:

The tablet could expand to 13.5 mm in diameter and 15 mm in thickness during the initial 20 min of contact with the HCl buffer at pH 1.2. The bioadhesive strength was as high as 0.98±0.06 N/cm². The SME gastroretentive sustained-release tablets preserved the SME capability of the liquid SME formations under transmission electron microscope. The drug-release curve was fit to the zero-order release model, which was helpful in reducing fluctuations in blood concentration. Compared with the commercially available capsules of tacrolimus, the relative bioavailability of the SME gastroretentive sustained-release tablets was 553.4%±353.8%.

Conclusion:

SME gastroretentive sustained-release tablets can enhance the oral bioavailability of tacrolimus with poor solubility and a narrow absorption window.     

Ginsenoside Rbl protects cardiomyocytes against CoCl2-induced apoptosis in neonatal rats by inhibiting mitochondria permeability transition pore opening

Aim:

To investigate whether mitochondria permeability transition pore (mPTP) opening was involved in ginsenoside Rb1 (Gs-Rb1) induced anti-hypoxia effects in neonatal rat cardiomyocytes ex vivo.

Methods:

Cardiomyocytes were randomly divided into 7 groups: control group, hypoxia group (500 μmol/L CoCl₂), Gs-Rb1 200 μmol/L group (CoCl₂ intervention+Gs-Rb1), wortmannin (PI3K inhibitor) 0.5 μmol/L group, wortmannin+Gs-Rb1 group, adenine 9-β-D-arabinofuranoside (Ara A, AMPK inhibitor) 500 μmol/L group, and Ara A and Gs-Rb1 group. Apoptosis rate was determined by using flow cytometry. The opening of the transient mPTP was assessed by using co-loading with calcein AM and CoCl₂ in high conductance mode. Expression of GSK-3β, cytochrome c, caspase-3 and poly (ADP-ribose) polymerase (PARP) was measured by using Western blotting. ΔGSK-3β was defined as the ratio of p-Ser9-GSK-3β to total GSK-3β.

Results:

CoCl₂ significantly stimulated mPTP opening and up-regulated the level of ΔGSK-3β. There was a statistically significant positive correlation between apoptosis rate and mPTP opening, between apoptosis rate and ΔGSK-3β, and between mPTP opening and ΔGSK-3β. Gs-Rb1 significantly inhibited mPTP opening induced by hypoxia (41.3%±2.0%, P<0.001) . Gs-Rb1 caused a 77.3%±3.2% reduction in the expression of GSK-3β protein (P<0.001) and a significant increase of 1.182±0.007–fold (P=0.0001) in p-Ser9-GSK-3β compared with control group. Wortmannin and Ara A significantly inhibited the effect of Gs-Rb1 on mPTP opening and ΔGSK-3β. Gs-Rb1 significantly decreased expression of cytochrome c (66.1%±1.7%, P=0.001), caspase-3 (56.5%±2.7%, P=0.001) and cleaved poly ADP-ribose polymerase (PARP) (57.9%±1.4%, P=0.001).

Conclusion:

Gs-Rb1 exerted anti-hypoxia effect on neonatal rat cardiomyocytes by inhibiting GSK-3β-mediated mPTP opening.     

Relative bioavailability of terbutaline to the lung following inhalation, using urinary excretion

AIMS

The aim of the study was to determine the relative lung and systemic bioavailability of terbutaline.

METHODS

On separate days healthy volunteers received 500 µg terbutaline study doses either inhaled from a metered dose inhaler or swallowed as a solution with and without oral charcoal. Urine samples were provided at timed intervals post dosing.

RESULTS

Mean (SD) urinary terbutaline 0.5 h post inhalation, in 12 volunteers, with (IC) and without (I) oral charcoal and oral (O) dosing was 7.4 (2.2), 6.5 (2.1) and 0.2 (0.2) µg. I and IC were similar and both significantly greater than O (P < 0.001). Urinary 24 h terbutaline post I was similar to IC + O. The method was linear and reproducible, similar to that of the urinary salbutamol method.

CONCLUSIONS

The urinary salbutamol pharmacokinetic method post inhalation applies to terbutaline. Terbutaline study doses can replace routine salbutamol during these studies when patients are studied.     

Cytotoxic effect of trans-cinnamaldehyde on human leukemia K562 cells

Aim:

To investigate the effects of trans-cinnamaldehyde (TCA) on the human leukemia K562 cell line and the cytotoxicity of cytokine-induced killer (CIK) cells against K562 cells.

Methods:

Apoptosis, Fas expression, and mitochondrial transmembrane potential in K652 cells were analyzed using flow cytometry. K562 cells were labeled with CFSE. The cytotoxic effect of expanded CIK cells on CFSE-labeled K562 cells was determined by FACS flow cytometry.

Results:

Treatment with TCA 180 μmol/L for 9 h induced apoptosis in 8.9%±1.23% of K562 cells. Treatment with 120 or 180 μmol/L TCA for 24 h significantly increased the apoptotic cells to 18.63%±1.42 % and 38.98%±2.74%, respectively. TCA significantly upregulates Fas expression and decreases mitochondrial transmembrane potential in K562 cells. TCA treatment at 120 and 180 μmol/L for 9 h enhanced the percentage of lysis of K562 cells by expanded CIK cells from 34.84%±2.13% to 48.21%±2.22 % and 64.81%±3.22% at the E:F ratio of 25:1 and from 49.26%±3.22% to 57.81%±5.13% and 73.36%±5.98% at E:F ratio of 50:1.

Conclusion:

TCA exerts cytotoxic effects on human leukemia K562 cells by inducing apoptosis and synergizing the cytotoxicity of CIK cells against K562 cells. These properties of TCA are beneficial to the treatment of leukemia, even in the patients who have received hematopoietic stem cells transplantation (HSCT).     

Point-of-care test of heart-type fatty acid-binding protein for the diagnosis of early acute myocardial infarction

Aim:

To investigate the efficacies of point-of-care test of heart-type fatty-acid binding protein (H-FABP) and its combinations with the conventional biomarkers in the diagnosis of early acute myocardial infarction (AMI).

Methods:

227 patients suspected of AMI were consecutively recruited in two centers. Biomarkers including H-FABP, myoglobin (MYO), creatine kinase-myocardial band (CK-MB) and cardiac troponin T (cTnT) were determined simultaneously at admission. AMI was defined according to the universal definition of myocardial infarction. Chi-Square test was adopted for the analysis.

Results:

In patients presenting within 12 h of symptom onset, the sensitivity of H-FABP[93.0% (95% CI: 86.6%−96.9%)] was significantly higher than that of initial CK-MB [67.5% (95% CI: 58.1%−76.0%), P<0.0001], cTnT [69.3% (95%CI: 60.0%−77.6%), P<0.0001] and MYO [68.6% (95% CI: 54.1%−80.9%), P<0.05]. The negative predictive value of H-FABP [92.8% (95%CI: 86.3%−96.8%)] was significantly higher than that of initial CK-MB [74.7% (95% CI: 66.8%−81.5%), P<0.001] and cTnT [75.9% (95% CI: 68.1%−82.6%), P<0.001]. The sensitivity of H-FABP+cTnT combination [94.7% (95% CI: 88.9%−98.0%)] was significantly higher than that of admission cTnT [69.3% (95% CI: 60.0%−77.6%), P<0.0001], CK-MB+cTnT [75.4% (95% CI: 66.5%−83.0%), P<0.0001] and MYO+CK-MB+cTnT [74.5% (95% CI: 60.4%−85.7%), P<0.05]. The negative predictive value of H-FABP+cTnT [94.5% (95% CI: 88.4%−98.0%] was significantly higher than that of initial cTnT [75.9% (95% CI: 68.1%−82.6%), P<0.001] and CK-MB+cTnT [79.1% (95% CI: 71.2%−85.6%), P<0.001]. Subgroup analysis showed that the superiorities of both the sensitivities and the negative predictive values of H-FABP and H-FABP+cTnT combination occurred only in patients who presented within 6 h of the symptom onset.

Conclusion:

Point-of-care test of H-FABP can be used as a valuable biomarker to detect or exclude an early-stage AMI. Combining H-FABP and cTnT provides the best performance for early AMI diagnosis.     

Polymorphisms of VEGFA gene and susceptibility to hemorrhage risk of brain arteriovenous malformations in a Chinese population

Aim:

To evaluate the influence of the vascular endothelial growth factor A (VEGFA) polymorphisms on risk of presentation with intracerebral hemorrhage (ICH).

Methods:

Nine selected VEGFA single-nucleotide polymorphisms (SNPs) were genotyped in 311 patients with brain arteriovenous malformations (BAVM) in a Chinese population. Associations between individual SNPs/haplotypes and the hemorrhage risk of BAVMs were evaluated using logistic regression analysis.

Results:

In the single-locus analysis, rs1547651 was associated with increased risk of ICH (adjusted OR=2.11, 95% CI=1.01–4.42 compared with the AA genotype). In particular, an increased risk for ICH was associated with this variant in female patients (adjusted OR=3.21, and 95% CI=0.99–10.36). Haplotype-based analyses revealed that haplotype ''GC'' in block 1 and haplotype ''ACC'' in block 2 were associated with a 30%–38% reduction in the risk of ICH in patients with BAVMs compared to the most common haplotype (P_sim=0.033 and P_sim=0.005, respectively). The protective effect of haplotype ''ACC'' in block 2 was more evident in male patients and subjects with BAVMs of a size ≥3 cm (adjusted OR=0.57, 95% CI=0.34–0.97 and adjusted OR=0.57, 95% CI=0.31–0.86, respectively).

Conclusion:

The results suggest that VEGFA gene variants may contribute to ICH risk of BAVM.     

Initial vancomycin dosing recommendations for critically ill patients undergoing continuous venovenous hemodialysis

Background:

Delaying appropriate antimicrobial therapy for critically ill patients increases the risk of death. Currently, there are insufficient data to guide initial vancomycin dosing for patients undergoing continuous venovenous hemodialysis (CVVHD).

Objective:

To develop practical recommendations for initial dosing of vancomycin, based on the pharmacokinetics of this drug in critically ill patients undergoing CVVHD.

Methods:

A chart review was conducted for 24 critically ill adult patients who had undergone concurrent CVVHD and vancomycin therapy. Mean pharmacokinetic parameters were determined, along with practical recommendations for initial vancomycin dosing that targeted steady-state trough concentrations for patients receiving intermittent infusions and steady-state levels for those receiving continuous infusions between 15 and 20 mg/L. Monte Carlo simulation was used to develop the initial vancomycin dosing recommendations.

Results:

The mean (95% confidence interval) pharmacokinetic parameters for vancomycin (elimination rate constant 0.0315 [0.0254–0.0391], half-life 22.0 h [17.72–27.24 h], volume of distribution 0.96 L/kg [0.77–1.20 L/kg], and clearance 2.4 L/h [1.97–2.92 L/h]) indicated that initial intermittent IV dosing of 1.25–1.5 g q24h or 15 mg/kg q24h would be suitable. For continuous infusion, a 1.5-g IV loading dose followed by continuous infusion of 1–1.5 g IV over 24 h (42–62 mg/h) would be recommended. However, Monte Carlo simulation revealed that the probability of achieving desired concentrations between 15 and 20 mg/L with any of these initial regimens is low.

Conclusions:

There was considerable variation in vancomycin pharmacokinetics in this patient population. The observations reported here raise concerns about the reliability of numerous empiric dosing recommendations derived from small pharmacokinetic studies in heterogeneous populations. Follow-up therapeutic drug monitoring is essential to ensure that concentrations remain within the target range.     

A clinical study to assess CYP1A2 and CYP3A4 induction by AZD7325, a selective GABA(A) receptor modulator - an in vitro and in vivo comparison

AIM(S)

To investigate the potential of AZD7325 to induce CYP1A2 and CYP3A4 enzyme activities.

METHODS

Induction of CYP1A2 and CYP3A4 by AZD7325 was first evaluated using cultured human hepatocytes. The effect of multiple doses of 10 mg AZD7325 on the pharmacokinetics of midazolam and caffeine was then examined in healthy subjects.

RESULTS

The highest CYP1A2 and CYP3A4 induction responses were observed in human hepatocytes treated with 1 or 10 µm of AZD7325, in the range of 17.9%–54.9% and 76.9%–85.7% of the positive control responses, respectively. The results triggered the further clinical evaluation of AZD7325 induction potential. AZD7325 reached a plasma C_max of 0.2 µm after 10 mg daily dosing to steady-state. AZD7325 decreased midazolam geometric mean AUC by 19% (0.81-fold, 90% CI 0.77, 0.87), but had no effect on midazolam C_max (90% CI 0.82, 0.97). The mean CL/F of midazolam increased from 62 l h⁻¹ (midazolam alone) to 76 l h⁻¹ when co-administered with AZD7325. The AUC and C_max of caffeine were not changed after co-administration of AZD7325, with geometric mean ratios (90% CI) of 1.17 (1.12, 1.23) and 0.99 (0.95, 1.03), respectively.

CONCLUSIONS

While AZD7325 appeared to be a potent CYP3A4 inducer and a moderate CYP1A2 inducer from in vitro studies, the expected efficacious dose of AZD7325 had no effect on CYP1A2 activity and only a weak inducing effect on CYP3A4 activity. This comparison of in vitro and in vivo results demonstrates the critical role that clinical exposure plays in evaluating the CYP induction risk of a drug candidate.     

Pharmacokinetics, adverse effects and tolerability of a novel analogue of human pancreatic polypeptide, PP 1420

AIMS

The objectives of this phase 1 study were to confirm the tolerability of single ascending subcutaneous doses of PP 1420 in healthy subjects, to assess its adverse effects and to investigate the drug''s pharmacokinetics and dose proportionality.

METHODS

This was a double-blind, placebo-controlled, randomized study. There were three dosing periods. Each subject (n = 12) was randomized to receive one dose of placebo and two ascending doses of PP 1420, given as a subcutaneous injection. Blood samples were taken over 24 h to assess pharmacokinetics. Standard safety and laboratory data were collected. The primary endpoint was the tolerability of PP 1420. The secondary endpoint was exposure to PP 1420 as assessed by C_max and AUC(0,∞).

RESULTS

PP 1420 was well tolerated by all subjects with no serious adverse effects. Following single subcutaneous doses of PP 1420 at 2, 4 and 8 mg to male subjects, C_max was reached at a median t_max of approximately 1 h post dose (range 0.32–2.00 h). Thereafter, plasma concentrations of PP 1420 declined with geometric mean apparent terminal elimination t_1/2 ranging from 2.42–2.61 h (range 1.64–3.95 h) across all dose levels.

CONCLUSIONS

Subcutaneous PP 1420 was well tolerated in healthy human subjects at single doses between 2–8 mg, with no tolerability issues arising. Where observed, adverse events were not serious, and there was no evidence of a dose-relationship to frequency of adverse events. The results therefore support the conduct of clinical trials to investigate efficacy, tolerability and pharmacokinetics during repeated dosing.     

Pharmacokinetic and pharmacodynamic comparison of hydrofluoroalkane and chlorofluorocarbon formulations of budesonide

AIMS

A hydrofluoroalkane formulation of budesonide pressurized metered-dose inhaler has been developed to replace the existing chlorofluorocarbon one. The aim of this study was to evaluate the pharmacokinetic and pharmacodynamic characteristics of both formulations.

METHODS

Systemic bioavailability and bioactivity of both hydrofluoroalkane and chlorofluorocarbon pressurized metered-dose inhaler formulations at 800 µg twice daily was determined during a randomized crossover systemic pharmacokinetic/pharmacodynamic study at steady state in healthy volunteers. Measurements included the following: plasma cortisol AUC_24h[area under the concentration-time curve (0–24 h)], budesonide AUC_0–12h and C_max. Clinical efficacy was determined during a randomized crossover pharmacodynamic study in asthmatic patients receiving 200 µg followed by 800 µg budesonide via chlorofluorocarbon or hydrofluoroalkane pressurized metered-dose inhaler each for 4 weeks. Methacholine PC₂₀ (primary outcome), exhaled nitric oxide, spirometry, peak expiratory flow and symptoms were evaluated.

RESULTS

In the pharmacokinetic study, there were no differences in cortisol, AUC_0–12h[area under the concentration-time curve (0–12 h)], T_max (time to maximum concentration) or C_max (peak serum concentration) between the hydrofluoroalkane and chlorofluorocarbon pressurized metered-dose inhaler. The ratio of budesonide hydrofluoroalkane vs. chlorofluorocarbon pressurized metered-dose inhaler for cortisol AUC_24h was 1.02 (95% confidence interval 0.93–1.11) and budesonide AUC_0–12h was 1.03 (90% confidence interval 0.9–1.18). In the asthma pharmacodynamic study, there was a significant dose response (P < 0.0001) for methacholine PC₂₀ (provocative concentration of methacholine needed to produce a 20% fall in FEV₁) with a relative potency ratio of 1.10 (95% confidence interval 0.49–2.66), and no difference at either dose. No significant differences between formulations were seen with the secondary outcome variables.

CONCLUSIONS

Hydrofluoroalkane and chlorofluorocarbon formulations of budesonide were therapeutically equivalent in terms of relative lung bioavailability, airway efficacy and systemic effects.