Pharmacokinetic Methods Research Articles

Geriatric Drug Evaluation

The older population is currently the fastest growing age group in the United States, and this trend is expected to continue for several decades. Older individuals, in general, have a higher disease burden compared with younger adults and are the major users of medications, yet premarketing drug clinical trials have often excluded them even for the drugs that have high utility in this age group. Extrapolation of clinical results from younger to older individuals does not provide adequate benefit-risk estimation, and the frequent need for dose adjustment in older patients from initially approved doses exemplifies the current lack of adequate clinical data in the elderly. Herein, we discuss the information gap for older individuals and the need for a better understanding of the effect of aging on drug responses. We also present cases for future directions, urging the implementation of improved clinical trial designs using new and emerging pharmacokinetic and pharmacodynamic methods to allow the provision of evidence-based individualized treatment to this high drug use group.

Abstract 3167: Comparison of the pharmacokinetics of phenanthrene in smokers after oral ingestion or inhalation through cigarettes for potential lung cancer susceptibility assessment

Abstract Polycyclic aromatic hydrocarbons (PAHs) are believed to be among the critical causative agents for lung cancer in smokers. PAHs require metabolic activation to elicit carcinogenic effects. Our hypothesis is that individuals who metabolically activate PAH more effectively will be at higher risk for lung cancer. Many studies investigated PAHs’ metabolism in human tissue in vitro or in animals. However, direct pharmacokinetics data in human are lacking. There are to our knowledge no data on human PAH pharmacokinetics after exposure by inhalation, from a cigarette or from any other source. We used a unique approach employing a stable isotope labeled phenanthrene (Phe), the simplest PAH with a bay region, a feature closely associated with PAH carcinogenicity. Deuterated Phe ([D10]Phe) was administered to 15 subjects in a within-subject crossover and randomized clinical study, either by oral administration or by incorporation into cigarettes. Serial blood samples were taken at baseline and over 24 h after [D10]Phe administration. Urine was collected during 8 intervals over 48 h after dosing. Deuterated r,1-t-2,3, c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene ([D10]PheT), the metabolic activation end product, in blood and urine samples, was analyzed by GC-MS/MS. Two pharmacokinetic (PK) methods including plasma AUCs and the total amount of [D10]PheT excreted in the urine were used to determine the exposure to [D10]PheT after the two routes of administration. Levels of [D10]PheT in plasma of all subjects were maximal 15-30 min after smoking a cigarette containing [D10]Phe, and decreased thereafter, which suggested that there was significant pulmonary “first-pass” formation of [D10]PheT. Maximum levels of [D10]PheT in plasma occurred between 30 to 150 min after oral ingestion. The relative exposure to [D10]PheT from oral dosing vs smoking was 0.92 ± 0.24 and 0.83 ± 0.28, based on the ratio of plasma AUCs and the ratio of the amount of PheT excreted in the urine, respectively. There was no statistically significant difference in [D10]PheT after two administration routes. There was large inter-individual variation in the capacity of generating [D10]PheT. The AUC ranged from 6560 to 92200 fmol-min/ml with a terminal elimination half-life of 290-681 min. Total urinary excretion ranged from 0.72% to 20.51% of initial dosing. This study showed for the first time that the formation of PAH diol epoxides, as monitored by [D10]PheT, occurred with remarkable rapidity in all subjects after smoking. Oral dosing of [D10]Phe with subsequent urine collections will adequately reflect individual capacity to metabolically activate [D10]Phe. The results demonstrate that this approach is feasible for potentially identifying those individuals who have particularly high capacity to metabolic activate bay region-PAH. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3167. doi:10.1158/1538-7445.AM2011-3167

Pharmacokinetic study of Rhizoma Curcumae Oil and Rhizoma Curcumae Oil‐β‐cyclodextrin inclusion complex in pigs after oral administration

Pharmacokinetics of rhizoma Curcumae oil-pure drug (RCO-PD) and its β-cyclodextrin inclusion complex (RCO-βCD) were studied in a randomized two-way crossover design following a single oral administration of the two formulations. Germacrone concentrations in plasma were determined by high-performance liquid chromatography with UV detector. The concentrations vs. time data were analyzed by a noncompartmental pharmacokinetic method. The result showed that germacrone in both groups was rapidly absorbed followed by a slow elimination. The main parameters in RCO-PD group were as follows: t(1/2λz) 6.63±1.08 h, C(max) 2.50±0.34 μg/mL, MRT 7.19±0.93 h, and AUC(0-∞) 13.92±2.75 mg/L·h, while in RCO-βCD group, t(1/2λz) 6.77 ± 0.67 h, C(max) 2.98±0.24 μg/mL, MRT 8.87±0.76 h, and AUC(0-∞) 21.60 ± 1.95 mg/L·h, respectively. The above results indicated that C(max), T(max), AUC(0-t), AUC(0-∞), and MRT in RCO-βCD group were significantly different from RCO-PD group, and the relative bioavailability of RCO-βCD group is significantly higher while compared to RCO-PD group (F=156%, with its 90% confidence interval of 145-169%).

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

The aim of the study was to determine the relative lung and systemic bioavailability of terbutaline. 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. 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. The urinary salbutamol pharmacokinetic method post inhalation applies to terbutaline. Terbutaline study doses can replace routine salbutamol during these studies when patients are studied.

A bio-activity guided in vitro pharmacokinetic method to improve the quality control of Chinese medicines, application to Si Wu Tang

The purpose of this study was to demonstrate the feasibility of using a bio-activity guided in vitro pharmacokinetic (BAPK) method in identifying relevant (absorbable and bioactive) markers for quality control (QC) of Chinese medicines (CM), using Si Wu Tang (SWT), a popular CM for women's health, as an example. A stepwise BAPK approach was utilized for relevant marker determination and evaluating of six SWT products: (1) data mining to identify active components of SWT, (2) quantification of the identified active components in each SWT product, (3) determination of in vitro dissolution and metabolism of the components under simulated gastrointestinal conditions, (4) identification of absorbable components or marker(s) via in vitro Caco-2 cell model, (5) stability testing of the permeable marker(s). Our results showed considerable variations in the amount of active components in different SWT products. Of the nine active components identified from data mining, three (ferulic acid, ligustilide, senkyunolide A) were found to be well permeated and stable over three months. Paeoniflorin, the marker designated by Chinese Pharmacopoeia, was poorly permeable and thus could not be considered a relevant marker for SWT. Our preliminary evaluation of the BAPK method appears to be feasible and may offer as a useful approach for identifying relevant markers of other TCM products in the future.

Enhanced elimination in acute barbiturate poisoning – A systematic review

Context. Despite a worldwide decline in barbiturate use, cases of acute poisoning with severe toxicity are still noted, particularly in developing countries. Severe poisonings often require prolonged admission to an intensive care unit, so enhanced elimination might be useful to hasten recovery. Information regarding the efficacy of these techniques for individual barbiturates is not available in standard textbooks. Objective. To determine the evidence supporting the effect of enhanced elimination and its role in the management of acute barbiturate poisoning. Methods. A systematic review was conducted using broad search criteria in three databases. All potentially relevant articles were obtained, and reference lists were manually reviewed. Ninety-four publications fulfilling inclusion criteria were located. Studies were classified as controlled or uncontrolled, and clinical and pharmacokinetic end points were manually extracted. If not directly stated, standard pharmacokinetic methods were used to calculate the clearance and efficiency of enhanced elimination techniques for each barbiturate and tabulated for direct comparison. Prospective controlled clinical trials. Two of the 94 publications were prospective controlled studies (only one stated that allocation was via blinded randomisation), and both assessed the effect of multiple-dose activated charcoal for acute phenobarbital poisoning. These studies demonstrated enhanced elimination with a decrease in elimination of half-life from approximately 80 to 40 h, but only one study reported clinical benefits. Uncontrolled series and single case reports. Sufficient data to determine the clearance due to enhanced elimination were available in only 52 of these papers. Barbiturate clearances by enhanced elimination varied markedly among studies. While extracorporeal modalities appeared to increase the direct clearance of many barbiturates, there was insufficient information to confirm a clinical benefit. Conclusions. There is limited evidence to support the use of enhanced elimination in the treatment of poisoning with most barbiturates. There is no role for urine alkalinisation, while multiple-dose activated charcoal may be useful for most phenobarbital and possibly primidone poisonings. Extracorporeal techniques appear to enhance elimination, but the clinical benefits, relative to the potential complications and cost, are poorly defined. Extracorporeal techniques such as haemodialysis and haemoperfusion can be considered for patients with life-threatening barbiturate toxicity such as refractory hypotension.

Deposition, Imaging, and Clearance: What Remains to be Done?

Deposition and clearance studies are used during product development and in fundamental research. These studies mostly involve radionuclide imaging, but pharmacokinetic methods are also used to assess the amount of drug absorbed through the lungs, which is closely related to lung deposition. Radionuclide imaging may be two-dimensional (gamma scintigraphy or planar imaging), or three-dimensional (single photon emission computed tomography and positron emission tomography). In October 2009, a group of scientists met at the "Thousand Years of Pharmaceutical Aerosols" conference in Reykjavik, Iceland, to discuss future research in key areas of pulmonary drug delivery. This article reports the session on "Deposition, imaging and clearance." The objective was partly to review our current understanding, but more importantly to assess "what remains to be done?" A need to standardize methodology and provide a regulatory framework by which data from radionuclide imaging methods could be compared between centers and used in the drug approval process was recognized. There is also a requirement for novel radiolabeling methods that are more representative of production processes for dry powder inhalers and pressurized metered dose inhalers. A need was identified for studies to aid our understanding of the relationship between clinical effects and regional deposition patterns of inhaled drugs. A robust methodology to assess clearance from small conducting airways should be developed, as a potential biomarker for therapies in cystic fibrosis and other diseases. The mechanisms by which inhaled nanoparticles are removed from the lungs, and the factors on which their removal depends, require further investigation. Last, and by no means least, we need a better understanding of patient-related factors, including how to reduce the variability in pulmonary drug delivery, in order to improve the precision of deposition and clearance measurements.

Flip-flop kinetics of ropivacaine during continuous epidural infusion influences its accumulation rate

Ropivacaine has an optimal toxicity profile for epidural anesthesia in adults, but there are currently no studies concerning its pharmacokinetics during continuous infusion. The primary objective of this study was to evaluate the pharmacokinetics and safety of ropivacaine in adults during a 48-h continuous epidural infusion. We enrolled 43 adults (ASA I-II) scheduled for major abdominal or urologic surgery with postoperative continuous epidural analgesia with ropivacaine 0.2% (5 mL/h) and sufentanil 0.75 μg/mL for 48 h. Ropivacaine blood samples were collected during continuous epidural infusion before the bolus and 3, 6, 12, 24, 48, 54, 60 h after the bolus; plasma concentrations were measured on HPLC-UV. The concentration-time relationship of ropivacaine levels was analyzed using a population pharmacokinetic method based on a mixed-effect-model approach (P-PHARM software). Mean plasma concentration of ropivacaine at the end of epidural infusion (C(48 h)) was 1.69 μg/mL (0.21-3.8 μg/mL). Mean (range) C(max) was 1.82 μg/mL (0.61-4.0 μg/mL); the area under the plasma concentration curve, AUC ((0-60)), was 67.48 ± 30.60 μg·h/mL. Total plasma ropivacaine concentrations fell mainly within (84%) or below (12%) the range reported to be safe in adults (1.0-3.0 μg/mL). Only two patients (5%) reached ropivacaine plasma levels higher than 3 μg/mL, namely 3.8 and 4.0 μg/mL at 48 and 54 h, respectively. Total ropivacaine concentrations up to 4.0 μg/mL were tolerated during long-term epidural ropivacaine infusion. Mean clearance for total ropivacaine was 5.33 L/h. Age was the only covariable to significantly reduce clearance variability: CL (L/h)=15.04-0.148 × age (years). The volume of distribution (Vd) was 92.15 L. The infusion dosing period half-life (t(1/2,DP)=0.693 × Vd/CL) was 10.8 h. Exposure to ropivacaine during epidural infusion is highly variable. The apparent infusion dosing half-life t(1/2,DP) is the most appropriate parameter to predict drug accumulation upon epidural infusion since it appears to better reflect the interplay interference between volume distribution and absorption rate during the accumulation phase. Prediction of ropivacaine accumulation can be improved by considering patient age.

Survey of the current use of pharmacokinetic model-driven drug delivery in small animal anaesthesia and analgesia in Italy

Veterinary surgeons in Italy were surveyed about their current practice with regard to the use of propofol and intravenous opioids during anaesthesia and for treatment of acute pain in small...

Population pharmacokinetics of mycophenolic acid in pediatric renal transplant patients using parametric and nonparametric approaches

Mycophenolic acid (MPA) is an immunosuppressive drug widely used in the prevention of acute rejection in pediatric renal transplant recipients and is characterized by a wide inter-individual variability in its pharmacokinetics. The aim of this study was to compare population pharmacokinetic modeling of MPA in pediatric renal transplant recipients given mycophenolate mofetil, the ester prodrug of MPA, using parametric and nonparametric population methods. The data from 34 pediatric renal transplants (73 full pharmacokinetic profiles obtained on day 21, months 3, 6 and 9 post-transplant) were analyzed using both the nonlinear mixed-effect modeling (NONMEM) and nonparametric adaptive grid (NPAG) approaches, based on a two-compartment model with first order lagged time absorption and first order elimination. The predictive performance of the two models was evaluated in a separate group of 32 patients. Higher mean population parameter values and ranges of individual pharmacokinetic parameters were obtained with NPAG, especially for the elimination constant ke: mean 1.16 h −1 (0.26–4.33 h −1) and 0.78 h −1 (0.66–1.15 h −1) with NPAG and NONMEM, respectively. With NPAG, the skewness and kurtosis values for ke (2.03 and 7.80, respectively) were far from the theoretical values expected for normal distributions. Such a non-normal distribution could explain the high value of shrinkage (35%) obtained for this parameter with the parametric NONMEM method. Bayesian forecasting of mycophenolic acid exposure using the NPAG population pharmacokinetic parameters as priors yielded a better predictive performance, with a significantly smaller bias than with the NONMEM model (−1.68% vs −9.53%, p < 0.0001). In conclusion, in the present study, NPAG was found to be the most adequate population pharmacokinetic method to describe the pharmacokinetics of MPA in pediatric renal transplant recipients.

Dietary Fiber Supplementation With Wheat Dextrin Does Not Inhibit Calcium and Magnesium Absorption in Pre and Post Menopausal Women: 2010 Presidential Poster

Purpose: Previous studies have indicated that some dietary fibers may interfere with calcium absorption and few studies have been done on fiber's effect on magnesium absorption. Some dietary fibers with high viscosity may interfere with the absorption of drugs and vitamins. Wheat dextrin is a soluble fiber used as a dietary supplement. The purpose of this study was to examine the effect of chronic wheat dextrin intake on calcium and magnesium absorption in a placebo controlled, randomized crossover clinical trial. Methods: Study subjects consisted of 20 premenopausal (age 42.6±5.0 yrs) and 20 postmenopausal Caucasian women (age 57.0±7.6 yrs). Each of the subjects consumed 5 grams of wheat dextrin or placebo in the form of cookies, three times daily for 2 weeks prior to measuring their calcium and magnesium absorption. On the day of testing, a standardized breakfast containing 300 mg calcium (in calcium fortified orange juice) extrinsically labeled with 45Ca and 26Mg was consumed by the subjects. Blood samples were obtained for 45Ca at 0, 1, 3, 5, 7, and 9 hours. Urine samples were obtained for 2 subsequent nights for 26Mg measurement. 45Calcium was measured by atomic absorption spectrophotometer and 26Mg isotope ratios were analyzed using inductively coupled plasma mass spectrometry. Area under the curve to 9 hours AUC9) was calculated for increment of serum calcium and for 45Calcium specific activity. The enrichment of the 26Mg isotope was determined as the “percent excess” of 26Mg above the naturally occurring 26Mg/24Mg ratio. Results: In the study population the mean (±SD) AUC9 for increment in serum calcium was 1.57 (±1.29) for wheat dextrin and 1.61 (±1.25) for placebo (p=0.82) indicating no effect on calcium absorption with wheat dextrin treatment. The mean (±SD) AUC9 measured from the 45Ca specific activity was 0.81 (± 0.21) for wheat dextrin and was 0.82 (±0.22) for placebo (p=0.34) demonstrating no effect on 45Ca absorption. There was good agreement between pharmacokinetic and tracer methods used in determining calcium absorption (R2=0.6231). The percent excess of 26Mg/24Mg was 7.8% (SD±2.1%) for wheat dextrin and was 7.9% (SD±2.6%) for placebo (p=0.827) demonstrating no effect on magnesium absorption. Conclusion: The study demonstrates that chronic supplementation with wheat dextrin for the increase of dietary fiber does not inhibit calcium or magnesium absorption from the gastrointestinal tract in both pre and postmenopausal women. Disclosure: Ashok Hospattankar is an employee of Novartis Consumer Health, Inc. Laura Armas has grant/research support from Novartis Consumer Health, Inc. This research was supported by an industry grant from Novartis Consumer Health, Inc.

ORIGINAL ARTICLE: Investigation of the prediction accuracy of vancomycin concentrations determined by patient-specific parameters as estimated by Bayesian analysis

There have been many studies of therapeutic drug monitoring (TDM) of vancomycin (VCM) based on Bayesian analysis, but there have been no reports of the accuracy of prediction based on Bayesian-estimated patient-specific parameters. This study was conducted to compare the accuracy of prediction based on the population pharmacokinetic (PPK) method and Bayesian-estimated parameters. The subjects were 22 patients who were treated with VCM for MRSA infection and whose blood was sampled twice or more during the administration period. The concentrations between the blood samples were predicted based on the concentrations in the first blood samples based on the PPK method using mean parameters for the Japanese population and Bayesian-estimated patient-specific pharmacokinetic parameters. The mean prediction error (ME), mean absolute error (MAE) and root mean squared error (RMSE) were compared to examine the accuracy of prediction based on Bayesian-estimated patient-specific parameters. The mean measured VCM concentration was 10·43±5·19 μg/mL, whereas the mean concentration predicted based on the PPK method was 8·52±4·34 μg/mL, with an ME of -1·91, MAE of 2·93 and RMSE of 3·21. The mean concentration predicted based on patient-specific parameters was 9·62±4·95 μg/mL with ME of -0·81, MAE of 1·38 and RMSE of 1·74. The ME and MAE for the concentrations predicted using patient-specific parameters were smaller compared with those predicted using the PPK method (P=0·0471 and 0·0003, respectively), indicating superior prediction with a significant difference between approaches. Prediction using Bayesian estimates of patient-specific parameters was better than by the PPK method. However, when using patient-specific parameters it is still necessary to fully understand the clinical status of the patient and frequently determine VCM concentrations.

Evaluation of transcorneal permeability of hyaluronic acid-assistant Gd-DTPA using MRI

目的 利用磁共振成像(MRI)及其造影剂,探讨加入增黏剂透明质酸钠对钆喷酸葡胺(Gd-DTPA)角膜渗透性的影响.方法 16只新西兰白兔按随机数字表法分为2组,每组8只兔,均取右眼为实验眼,分别点用质量分数23.45%Gd-DTPA滴眼液为Gd-DTPA组、23.45%Gd-DTPA+质量分数0.2%透明质酸钠滴眼液为透明质酸钠组,每 5 min 点眼1次,每次50 μL,共6次.左眼为正常对照眼,不做任何处理.此后进行MRI连续扫描,观察用药前后兔眼结膜囊、前房、后房及玻璃体内示踪剂的信号变化.结果 正常兔眼前房MRI平扫呈均匀低信号.Gd-DTPA组结膜囊信号在用药40 min消失,透明质酸钠组结膜囊内Gd-DTPA信号在用药后60 min消失.与Gd-DTPA组比较,透明质酸钠组结膜囊内和前房示踪剂信号增强明显,60 min时Gd-DTPA组前房信号增强率为19.63%,透明质酸钠组为53.42%.2组兔点眼后后房及玻璃体信号强度均无变化.结论 透明质酸钠可提高与Gd-DTPA性质类似药物的角膜通透性,MRI能够在活体内动态、实时地检测滴眼液的角膜渗透性,是对传统药物代谢检测方法的补充。

Effects of Compounding on Pharmacokinetics of Itraconazole in Black-Footed Penguins (Spheniscus demersus)

Itraconazole is used to treat and prevent aspergillosis in captive penguin colonies. Although commercial formulations of itraconazole are available, compounding is sometimes performed to decrease cost or to provide a different concentration of the drug. Using a two-way crossover design, the pharmacokinetics of both a commercially available oral itraconazole solution and a compounded oral itraconazole solution were compared in six black-footed penguins (Spheniscus demersus). Each itraconazole formulation was administered orally in frozen-thawed capelin at 7 mg/kg. Plasma itraconazole concentrations at time 0 (pretreatment), 20 and 40 min post-drug administration, and 1, 2, 4, 6, 8, and 12 hr post-drug administration were determined using reverse-phase high-performance liquid chromatography. Drug concentrations were analyzed using standard pharmacokinetic methods. Plasma clearance of the commercial itraconazole solution was more rapid than the clearance published for other species, possibly warranting more frequent dosing in black-footed penguins. Absorption of itraconazole, as determined by peak concentration and area under the curve, was significantly higher for the commercial formulation when compared to the compounded formulation, likely as a result of the presence of cyclodextrin, a carrier compound shown to improve oral absorption, in the commercial formulation. Extrapolating dosing regimens for compounded itraconazole formulations from regimens determined for commercial formulations warrants caution as a result of the significant differences in pharmacokinetics.

Pharmacokinetic immunoassay methods in the presence of soluble target

Soluble targets represent a special challenge when employing ligand binding assays to support pharmacokinetic analysis of monoclonal therapeutics. Target-engaged antibody is not available for binding in immunoassays employing anti-idiotype-specific antibodies or target for capture. We investigated several formats of total antibody assays that show reduced interference of soluble targets: direct target capture, indirect target capture and acid dissociation. While indirect target capture worked well for a regular affinity antibody against DKK1, a high affinity antibody against PCSK9 required an additional acid dissociation step. The choice of a suitable format was antibody and target dependent. Our results offer several choices to approach immunoassay development for soluble targets.

A model-constrained Monte Carlo method for blind arterial input function estimation in dynamic contrast-enhanced MRI: I. Simulations

Widespread adoption of quantitative pharmacokinetic modeling methods in conjunction with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has led to increased recognition of the importance of obtaining accurate patient-specific arterial input function (AIF) measurements. Ideally, DCE-MRI studies use an AIF directly measured in an artery local to the tissue of interest, along with measured tissue concentration curves, to quantitatively determine pharmacokinetic parameters. However, the numerous technical and practical difficulties associated with AIF measurement have made the use of population-averaged AIF data a popular, if sub-optimal, alternative to AIF measurement. In this work, we present and characterize a new algorithm for determining the AIF solely from the measured tissue concentration curves. This Monte Carlo blind estimation (MCBE) algorithm estimates the AIF from the subsets of D concentration–time curves drawn from a larger pool of M candidate curves via nonlinear optimization, doing so for multiple (Q) subsets and statistically averaging these repeated estimates. The MCBE algorithm can be viewed as a generalization of previously published methods that employ clustering of concentration–time curves and only estimate the AIF once. Extensive computer simulations were performed over physiologically and experimentally realistic ranges of imaging and tissue parameters, and the impact of choosing different values of D and Q was investigated. We found the algorithm to be robust, computationally efficient and capable of accurately estimating the AIF even for relatively high noise levels, long sampling intervals and low diversity of tissue curves. With the incorporation of bootstrapping initialization, we further demonstrated the ability to blindly estimate AIFs that deviate substantially in shape from the population-averaged initial guess. Pharmacokinetic parameter estimates for Ktrans, kep, vp and ve all showed relative biases and uncertainties of less than 10% for measurements having a temporal sampling rate of 4 s and a concentration measurement noise level of σ = 0.04 mM. A companion paper discusses the application of the MCBE algorithm to DCE-MRI data acquired in eight patients with malignant brain tumors.

Developing a Safe Intravenous Sotalol Dosing Regimen

Recently, an intravenous formulation of sotalol has been approved by the food and drug administration for substitution for oral therapy in patients who are unable to take oral sotalol. The purpose of this randomized, 2-treatment, 2-period, crossover study was to develop a safe dosing regimen for intravenous sotalol that provides similar blood levels and therefore similar efficacy and safety to orally administered sotalol. Fifteen healthy subjects received 75 mg intravenous sotalol infusion administered over 2.5 hours and 80 mg oral sotalol. Standard pharmacokinetic methods were used to obtain maximum serum concentrations (Cmax) and areas under the concentration-time curves (AUC). Individual pharmacokinetic parameters were used in simulation studies to determine the optimal intravenous administration regimen. Intravenous sotalol administered over 2.5 hours resulted in a significantly greater Cmax than oral administration (830 +/- 391 vs. 601 +/- 289 ng/mL, P < 0.001). With increasing the length of infusions to 3, 4, and 5 hours, simulation studies showed that the Cmax decreased to 128%, 113%, and 102% of the oral Cmax. The length of infusion did not affect AUC. Based on these studies, a safe intravenous regimen for the replacement of 80-mg oral therapy requires 75 mg intravenous sotalol administered as a 5-hour infusion. Because the pharmacokinetics of sotalol are linear and dose proportional, 150 mg intravenous sotalol administered over 5 hours will provide similar Cmax and AUC as 160 mg oral sotalol. The food and drug administration-approved dosing regimen is 75 mg intravenous sotalol to replace 80 mg oral sotalol and 150 mg intravenous sotalol to replace 160 mg oral sotalol, both administered over 5 hours.

Pharmacokinetics and milk penetration of difloxacin after a long-acting formulation for subcutaneous administration to lactating goats

The single-dose disposition kinetics of difloxacin were determined in clinically normal lactating goats (n=6) after intravenous (IV) and subcutaneous (SC) administration and subcutaneous administration of a long-acting poloxamer 407 gel formulation (P407). Difloxacin concentrations were determined by HPLC with fluorescence detection. Minimum inhibitory concentrations of difloxacin against 14 strains of Staphylococcus aureus isolated from mastitic goats’ milk in Spain were determined to compute pharmacodynamic surrogate markers. The concentration-time data were analyzed by compartmental and noncompartmental pharmacokinetic methods. Following SC and P407 administration, difloxacin achieved maximum milk concentrations of 1.34±0.12 and 2.97±1.18mg/L, respectively, at 4.00±0.00h (SC) and 3.60±0.89h (P407) after administration. The absolute bioavailabilities after SC and P407 administration were 81.74±15.60% and 72.58±20.45%, respectively. Difloxacin penetration from the blood into the milk was good and high concentrations were found in milk secretions. From these data, a 15mg/kg dose of difloxacin P407 would appear to be effective against Staphylococcus aureus isolated from mastitic goats’ milk with minimum inhibitory concentrations ≤0.25mg/L.

An overview of glomerular filtration rate testing in dogs and cats.

Determination of glomerular filtration rate (GFR) is a valuable, yet underused, diagnostic tool for evaluating renal function in dogs and cats. This article first reviews the hormonal and hemodynamic factors which contribute to GFR, followed by a description of considerations when selecting a pharmacokinetic model and methods of animal-to-animal standardization. The best-characterized existing GFR markers, including creatinine, radiolabeled markers, and iohexol, are reviewed in depth, as well as alternative but lesser used techniques. A weighted means analysis of reported GFR measurements in healthy dogs and cats and a review of selected studies that have examined GFR alterations in animals with naturally occurring and experimental diseases provide the reader with preliminary guidelines on expected GFR results in these species and disease conditions.

Authors' Reply to Maintenance Immunosuppressive Agents as Risk Factors for BK Virus Nephropathy

We appreciate the comments by Kuypers et al. regarding our study on the association of maintenance immunosuppressive agents and BK nephropathy (BKN) (1). We are in an agreement with the authors that mycophenolate mofetil (MMF) dose is not a reliable surrogate for drug exposure, and multiple factors, such as renal dysfunction, serum albumin level, and concomitant medications, could significantly affect the concentration of its metabolites (2–6). However, the clinical value of mycophenolic acid (MPA) therapeutic drug monitoring remains a controversial and supportive evidence regarding its added benefit is conflicting (7). Although, many retrospective studies found an association between the risk of acute rejection and total MPA area under the curve (AUC0–12 h) (7–9), the relationship between adverse effects of MMF, such as anemia, leukopenia, gastrointestinal symptoms, and infection, and the AUC0–12 h is less well established (7, 9, 10). Some studies have found better correlation between the incidence of infection or leucopenia with free rather than total MPA level (2–4). Others have suggested that adverse events are better predicted by MMF dose, rather than blood concentration (8, 11). We agree with the authors that the wide interindividual and intraindividual variability in MMF pharmacokinetics makes its dose a less than optimal indicator of its effect at the cellular level. For the same reason, a single MPA trough level suffers from similar shortcomings and is the reason that there is no consensus on its use for drug monitoring or its optimal target level. Therefore, acknowledging the pitfall of using the drug dose, we are not sure that MPA trough level is a better surrogate for drug exposure and effect. Moreover, the use of complete or abbreviated AUC for comparing the drug exposure between the cases and controls in this setting is not practically feasible, because a single testing after the diagnosis may not reflect the exposure over time, and retrospective AUC measurements at different time points would not be possible. To better study this matter, a prospective cohort study would be a much better design, but the relatively low incidence of the disease would require enrolment of a large cohort, which would make it an expensive study and impair its feasibility. Published guidelines advocate reduction in immunosuppression as the first step after a diagnosis of BKN (12). However, no specific approach has been established regarding whether calcineurin inhibitors (CNI) or antiproliferative agents should be reduced first. Clinical trials to validate different strategies are lacking and published reports on different immunosuppression reduction protocols contain mixed results (13). Therefore, the question on how to manage immunosuppressive agents in this patient population remains uncertain. In our study, we suggested reduction in tacrolimus level as the first step, while maintaining the MMF dose, based on our observation of a significant association between BKN and tacrolimus level (1). Even though, similar to other strategies, there is no clinical trial to support this recommendation, evidence continue to accumulate supporting the benefit of significant reduction in CNI. Recently, Egli et al. (14) explored BK virus-specific T-cell response as a marker of antiviral immune protection. The study found that BK virus-specific T-cell response in vitro inversely correlated with tacrolimus concentration, although there was no relationship with MMF concentration. This further supports the idea that reduction in CNI level would be a better first step for the management of BKN. The risk of rejection after reduction in immunosuppression remains a valid concern, as acute rejection rates as high as 75% have been reported after reduction in immunosuppression with various protocols (13). However, we believe that with our suggested strategy, this risk will not be higher than the traditional reduction in MPA and maintenance of CNI as the first step. In this setting, we agree that the therapeutic drug monitoring for MPA level might have a role in the prevention of acute rejection (7–9). In conclusion, we admit that well-designed clinical trials would be the best way of studying the role of differential reduction in immunosuppressive agents in patients with BKN and use of standard pharmacokinetic methods to examine the drug exposure provides more accurate data; however, in the absence of such studies, the use of observational clinical data such as ours and in vitro studies would provide a better rationale for a therapeutic approach than following practices that are not based on tangible evidence. Wana Manitpisitkul1 Abdolreza Haririan2 1Department of Pharmacy, University of Maryland Medical Center Baltimore, Maryland 2 Division of Nephrology University of Maryland Medical Center Baltimore, Maryland