Population PKPD of voclosporin in renal allograft patients.

The aims of this population-pharmacokinetic/pharmacodynamic (POP-PKPD) analysis of voclosporin in renal allograft patients were to build a POP-PKPD model for voclosporin and calcineurin activity (CNa) and identify clinically relevant covariates that could assist dosing of the drug. POP-PKPD modeling was performed using a stochastic approximation of the standard expectation maximization (SAEM) algorithm for nonlinear mixed-effects as implemented in Monolix™ 3.2. Voclosporin whole blood concentrations were obtained from de novo renal allograft patients and assayed using a validated LC/MS/MS assay. CNa was measured using a (32)P-radiolabeled assay. A two-compartment model with simultaneous sigmoid inhibitory Emax model was used to describe the PKPD relationship between voclosporin concentration and CNa. The POP-PKPD model was then utilized to simulate an optimal initial dosing strategy. Eighty-seven patients were included in the POP-PKPD study. Population mean estimates (relative standard error, rse) for oral clearance (CL/F) and first compartment volume of distribution (V1), were 717 mL min(-1) (35%) and 2010 mL (17%), respectively. Maximum CNa Inhibition (Imax), effective concentration (C50), and baseline immunosuppression (S0) were 0.87 pmol/min/mg (8.0%), 123 ng/mL (10%), and 1.15 pmol/min/mg (4.0%), respectively. Covariate analyses demonstrated that age and body surface area significantly influenced CL/F: CLi=717(Agei/48.8)-0.57(BSAi/1.99)1.1, while serum triglycerides significantly altered S0: S0i=1.15(TRIGi/1.97)0.15.

Pharmacokinetics of voclosporin in renal impairment and hepatic impairment.

Voclosporin is a novel calcineurin inhibitor intended for prevention of organ graft rejection and treatment of lupus nephritis. These studies evaluated the effect of renal or hepatic impairment on pharmacokinetics of voclosporin. Thirty-three subjects were enrolled into 1 of 4 groups based on renal function as defined by creatinine clearance and 18 subjects were enrolled into 1 of 3 groups based on hepatic function defined by Child-Pugh classes. Voclosporin 0.4 mg/kg was administered orally. Geometric mean ratios (renal/hepatic impairment-to-normal) and 90% confidence intervals for Cmax and AUC were calculated. A default no-effect interval of 80-125% was set. Although 90% confidence intervals exceeded the no-effect intervals for both parameters, individual Cmax and AUC plots indicate almost complete overlapping range of values for mild and moderate renal impairment and normal subjects. Severe renal impairment resulted in a 1.5-fold increase in AUC without an increase in Cmax . Mild to moderate hepatic impairment resulted in a 1.5- to 2-fold increase in voclosporin exposure. Voclosporin can be administered safely to patients with mild to moderate renal impairment without dose modification. Appropriate safety monitoring with concentration-based adjustments in transplantation are recommended for patients with severe renal impairment, and for patients with hepatic impairment.

The PROMISE study: a phase 2b multicenter study of voclosporin (ISA247) versus tacrolimus in de novo kidney transplantation.

Voclosporin (VCS, ISA247) is a novel calcineurin inhibitor being developed for organ transplantation. PROMISE was a 6-month, multicenter, randomized, open-label study of three ascending concentration-controlled groups of VCS (low, medium and high) compared to tacrolimus (TAC) in 334 low-risk renal transplant recipients. The primary endpoint was demonstration of noninferiority of biopsy proven acute rejection (BPAR) rates. Secondary objectives included renal function, new onset diabetes after transplantation (NODAT), hypertension, hyperlipidemia and pharmacokinetic-pharmacodynamic evaluation. The incidence of BPAR in the VCS groups (10.7%, 9.1% and 2.3%, respectively) was noninferior to TAC (5.8%). The incidence of NODAT for VCS was 1.6%, 5.7% and 17.7% versus 16.4% in TAC (low-dose VCS, p = 0.03). Nankivell estimated glomerular filtration rate was respectively: 71, 72, 68 and 69 mL/min, statistically lower in the high-dose group, p = 0.049. The incidence of hypertension and adverse events was not different between the VCS groups and TAC. VCS demonstrated an excellent correlation between trough and area under the curve (r(2) = 0.97) and no difference in mycophenolic acid exposure compared to TAC. This 6-month study shows VCS to be as efficacious as TAC in preventing acute rejection with similar renal function in the low- and medium-exposure groups, and potentially associated with a reduced incidence of NODAT.

Emissions of size-segregated aerosols from on-road vehicles in the Caldecott tunnel.

Particulate matter emissions from the California in-use vehicle fleet were measured as 37,500 vehicles traveled through two bores of the Caldecott Tunnel located in the San Francisco Bay area. Microorifice cascade impactors and filter-based samplers were used to determine the particle chemical composition as a function of particle size. Ammonia emissions from the vehicle fleet were measured as well. Concentrations of aerosol mass, organic carbon, elemental carbon, sulfate ion, nitrate ion, and ammonium ion, as well as 13 elements are reported. The particle mass distribution peaks in the particle size range 0.1-0.18 microm aerodynamic diameter (Da). Elemental carbon and organic matter were the largest components of particle mass in all the size ranges studied. The Caldecott Tunnel bores studied include one which carries light-duty vehicle traffic and one which carries a mixture of light- and heavy-duty vehicle traffic. From experiments conducted in both bores, estimates are made of the size distribution and chemical composition of particulate matter emissions extrapolated to the 100% light-duty and 100% heavy-duty vehicle fleets. The heavy-duty vehicle fleet emitted 1285 +/- 237 mg of fine particulate matter (Da < 1.9 microm)/kg of C contained in the fuel burned (corresponding to approximately 430 +/- 79 mg/km driven). Light-duty vehicles emitted less than 85 +/- 6 mg/kg of C in the fuel burned (corresponding to less than approximately 5.5 +/- 0.4 mg/km driven). Emissions of gas-phase ammonia in the Caldecott Tunnel were measured to be 194 and 267 mg/L of gasoline-equivalent fuel burned in the tunnel. The ammonia emissions are attributed to automobiles that were equipped with 3-way catalysts and operating fuel rich.

Effect of passive smoking on theophylline clearance in children.

The author investigated the effects of passive tobacco smoking on the metabolism of theophylline in a pediatric population. In a retrospective analysis of 201 children admitted to a pediatric unit for asthma, 31 were identified with an acute exacerbation of asthma of noninfectious origin in which environmental exposure to tobacco smoke could be established. The parents were known smokers with a minimum 1-pack-per-day habit. An age-and gender-matched control population of children was then identified who had an acute exacerbation of asthma without any environmental exposure to tobacco smoke. In addition, the patients in both groups received the same dose of intravenous aminophylline for a minimum of 48 hours to ensure steady-state conditions. Total body clearance of theophylline was significantly elevated in the children exposed to environmental tobacco smoke (1.36 +/- 0.09 vs. 0.90 +/- 0.04 mL/min per kg, p < 0.0001). Steady-state serum levels were significantly lower in the passive smoking group (55.3 +/- 2.8 vs. 73.2 +/- 3.3 p < 0.00001) for those receiving nearly identical intravenous doses. The length of hospital stay was longer in the group exposed to passive smoke (4.4 +/- 2.6 vs. 2.9 +/- 1.3 days, p < 0.05). The clearance of theophylline is greater in asthmatic children exposed to passive tobacco smoke than in asthmatic children not exposed to passive tobacco smoke. These findings suggest that passive smoking may increase the clearance of other drugs metabolized in a manner similar to theophylline.

Decreased dromotropic response to verapamil despite pronounced increased drug concentration in rheumatoid arthritis.

AIMS: Inflammation reduces hepatic clearance of many drugs with unknown therapeutic consequences. This study was carried out to examine the effect of rheumatoid arthritis (RA) on the pharmacokinetics and pharmacodynamics of verapamil. METHODS: Eight RA patients were age- and sex-matched with eight healthy volunteers. The disease severity was assessed, and ECG, blood pressure and verapamil enantiomers concentrations were measured for 12 h post 80 mg oral verapamil. Serum interleukin-6 (IL-6) and nitrite (NO2-) were measured in predose samples. RESULTS: IL-6 and NO2- concentrations were significantly increased in parallel with disease severity. Oral clearance of both S- and R-verapamil was significantly decreased by RA. While the unbound fraction of S- and R-verapamil decreased by 5 and 7-fold, respectively, the unbound AUC remained unchanged for the more potent enantiomer, S-verapamil. AUC of norverapamil enantiomers was increased 2-3-fold. Despite elevated serum drug concentrations in RA, the potential to prolong the PR-interval was significantly reduced by one fold and the effect on the heart rate and blood pressure did not increase. CONCLUSIONS: RA results in increased verapamil concentrations due likely to changes in protein binding, decreased clearance and/or altered hepatic blood flow. A significant decrease in dromotropic effect, despite increased serum drug concentrations, may be attributed to receptor down regulation caused by pro-inflammatory cytokines and/or NO.

Methoxyflurane anesthesia augments the chronotropic and dromotropic effects of verapamil.

INTRODUCTION: Inhalation anesthetics have been shown to have electrical suppressant effects on excitable membranes such as the cardiac conduction system. Therefore, the anesthetized patient or laboratory animal may respond differently to cardiac drugs when compared with their conscious counterparts. The purpose of this study was to assess the effects of anesthesia with methoxyflurane (MF) on the dromotropic and chronotropic effects of verapamil (VER) in the rat. METHODS: A lead I ECG was measured using subcutaneous electrodes placed both axilli and over the xyphoid process in male Sprague-Dawley rats. Dromotropic effect was measured using the PR-interval which indicated the electrical spread across the atria to the AV-node and chronotropic effects were determined using RR-interval. A total of six animals were randomized to receive 10 mg/kg s.c. of verapamil in the presence or absence of general anesthesia containing methoxyflurane. In addition, PR-interval and RR-intervals were determined in the presence of only methoxyflurane and at rest without any drug exposure. The time for the ECG to normalize after exposure to methoxyflurane and/or verapamil was also determined. RESULTS: Exposure to verapamil alone resulted in a 5% prolongation in PR-interval and 6% prolongation in RR-interval. Methoxyflurane alone had a larger effect than verapamil demonstrating a 14.5% prolongation in PR-interval and a 12.3% in RR-interval which was statistically significant. The combination of MF + VER resulted in a synergistic prolongation in PR-interval to 28. 7% while the effect on RR-interval was additive with an increase to 17.6%. The time for the ECG to normalize after exposure to VER, MF and VER + MF was 37.5 15.1 min, 69.8 5.3 min, and 148.5 +/- 6.6 min respectively. CONCLUSION: General anesthesia with MF enhances the dromotropic and chronotropic effect of VER. This should be considered when MF-anesthesia is used in experimental procedure.

Application of a neural network for gentamicin concentration prediction in a general hospital population.

Neural network (NN) computation is computer modeling based in part on simulation of the structure and function of the brain. These modeling techniques have been found useful as pattern recognition tools. In the present study, data including age, sex, height, weight, serum creatinine concentration, dose, dosing interval, and time of measurement were collected from 240 patients with various diseases being treated with gentamicin in a general hospital setting. The patient records were randomly divided into two sets: a training set of 220 patients used to develop relationships between input and output variables (peak and trough plasma concentrations) and a testing set (blinded from the NN) of 20 to test the NN. The network model was the back-propagation, feed-forward model. Various networks were tested, and the most accurate networks for peak and trough (calculated as mean percent error, root mean squared error of the testing group, and tau value between observed and predicted values) were reported. The results indicate that NNs can predict gentamicin serum concentrations accurately from various input data over a range of patient ages and renal function and may offer advantages over traditional dose prediction methods for gentamicin.

Can psychotherapy help patients with psoriasis?

Two groups of people with psoriasis attended a short series of meetings conducted by a clinical psychologist. During these sessions the patients were given the opportunity to discuss between themselves problems created by their skin complaint and they were taught specific relaxation techniques for use whenever they felt under stress. Psychological tests showed that the participants were a noticeably anxious group compared to the general population. However, their levels of anxiety were significantly reduced by the end of the study. There was also a modest trend towards physical improvement. No such changes were seen in a matched control group.