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A novel transcutaneous chemical collection device (TCD) has been developed to study the phenomenon of outward transcutaneous chemical migration. The TCD is a Bandaid-like device containing an immobilized aqueous media and binding reservoir material to prevent back-transfer into the skin. This device, when placed against the skin, allows collection and quantitation of chemicals that diffuse directly through the skin from within the body. The relationship of the amount of drug collected in the TCD to the amount in the body available for collection (as represented by the area under the plasma-concentration time curve, AUC) and the effects of sweating, a potential confounding factor, on collection of drug in a TCD were studied, using caffeine as a model compound. TCD were placed on the skin of normal male volunteers. Twenty-four hours later subjects took caffeine by mouth. Blood samples were collected and TCD were removed at various times after drug intake and analyzed by HPLC for caffeine. Studies of the sweating effect were carried out in a similar manner, except that one arm of each subject was maintained at 40 degrees C to induce local sweating, the other arm acted as a non-sweating control. The amount of caffeine collected was linearly related to the AUC. Sweating seemed to have a large (40%) contribution to transdermal collection in the early period (5.5 h) of the study, but this difference was much less (14%) at longer collection times (10 h).

We characterized in vitro adsorption of representative chemicals in candidate gel/charcoal matrices being investigated for use in noninvasive transdermal chemical collection. Binding properties of three model compounds of widely varying water and lipid solubilities (theophylline, methotrexate, and parathion) were studied in hydrophilic (agarose, or polyvinyl alcohol/polyvinyl pyrrolidone) and lipophilic (silicone) gel/charcoal compositions. Analysis of adsorption isotherms indicate that agarose is the superior gel selection for hydrophilic compounds such as theophylline and methotrexate (greater than 90% uptake for each), and that a silicone lipogel allows for greatest lipophilic (parathion) adsorption (greater than 95% uptake).

Recent market withdrawals of prescription drug products have brought attention to premarketing safety research. Less known but related to some drug withdrawals are postmarketing dosage changes of newly marketed drugs, including both dosage reductions and increases. These events have serious effects on patients, manufacturers, and regulatory authorities. Most of these harmful events could be avoided by intensive employment of targeted clinical pharmacology investigations to optimize dosage prior to phase III testing and regulatory approval. In this paper, the frequency and implications of postmarketing dosing changes and market withdrawals are considered in light of approaches to preventing them.

Objective Our objective was to develop a population pharmacokinetic and pharmacodynamic model of etanercept in patients with rheumatoid arthritis, with the American College of Rheumatology response criterion of 20% improvement (ACR20) used as a binary clinical outcome variable. Methods Concentration-time profiles from 25 subjects, administered 25 mg subcutaneous etanercept twice weekly for 24 weeks, were pooled with data from 77 subjects, enrolled in a 24-week, randomized, double-blind study comparing 25 mg and 50 mg subcutaneous etanercept twice weekly. The cumulative area under the concentration-time curve (AUC) was used as the exposure variable, and ACR20 was the binomial clinical outcome. ACR20 data from another 80 placebo-treated patients enrolled in a randomized, double-blind phase III study were used to describe the placebo time course of ACR20. A logistic regression analysis with NONMEM was applied to describe the exposure-response relationship, and the 95% confidence intervals (95% CIs) were constructed by bootstrapping 1000 times. Results The population mean apparent clearance was 0.117 L/h (95% CI, 0.108-0.130 L/h) for white female patients and 0.138 L/h (95% CI, 0.118-0.163 L/h) for white male patients. Interindividual variability and interoccasion variability were 41.1% and 27.6%, respectively. The mean absorption half-life was 20.9 hours, and the elimination half-life was 95.4 hours. An improved response profile in male patients was shown, but the multiplicative factor between slope on cumulative AUC between male and female patients was not statistically significant (1.69; 95% CI, 0.37-9.99). The model-predicted percentage of patients achieving ACR20 at 6 months after dosing of 25 mg subcutaneously twice weekly was 54.9%, comparable to the observed 52.9%. Conclusion The population pharmacokinetic analysis confirmed that etanercept is slowly absorbed and eliminated after subcutaneous administration. The logistic model linking cumulative AUC with ACR20 adequately characterized the time course of clinical improvement in patients with rheumatoid arthritis receiving etanercept. Clinical Pharmacology & Therapeutics (2003) 73, 348–365; doi: 10.1016/S0009-9236(02)17635-1

A collaborative effort between pharmaceutical companies, regulatory agencies and academia to qualify biomarkers for kidney toxicity provides a model for investigating and identifying reliable safety markers for preclinical applications.

The integration of pharmacokinetic and pharmacodynamic principles into drug development has been proposed as a way of making it more rational and efficient. The use of these principles in drug development to make scientific and strategic decisions is defined as the ‘pharmacokinetic-pharmacodynamic guided approach to drug development’. The objectives of this survey were: (i) to assess the extent the pharmacokinetic-pharmacodynamic guided approach to drug development has been used in a large multinational pharmaceutical company: (ii) to evaluate the impact of pharmacokinetic and/or pharmacodynamic results on clinical drug development; and (iii) to identify factors which prevented the full application of the pharmacokinetic-pharmacodynamic guided approach. This was done by looking at 18 projects in the current development portfolio at Hoffman La Roche and evaluating the use of this approach by interviewing the responsible clinical pharmacologist using a standardised questionnaire. (i) Benefits from using the pharmacokinetic-pharmacodynamic guided approach were reported in every project, independent of development phase and therapeutic area. This approach was more extensively used in the recent projects. The selection of dosages in clinical studies was found to be the most important application of pharmacokinetic-pharmacodynamic results in terms of an impact on drug development, (ii) Time savings, up to several months, could be quantified in 8 projects during the entry-into-man studies and in 6 projects during the phase II or III studies. In 4 projects, 1 clinical study was avoided. (iii) The most important scientific factor preventing the full application of the approach was the lack of knowledge on the predictive value of the pharmacodynamic or surrogate marker for effect (6 projects). The results of the survey have shown that the use of the pharmacokinetic-pharmacodynamic guided approach has contributed to making clinical drug development more rational and more efficient. Opportunities to apply the pharmacokinetic-pharmacodynamic approach should be identified in each project and a project specific strategy for the pharmacokinetic-pharmacodynamic guided approach should be defined during phase 0 of drug development.

A Concentration-Controlled Trial (CCT) is one where subjects are assigned to predetermined levels of average plasma drug concentration. These target concentrations are achieved (within reasonable ranges) by an individualized pharmacokinetically (PK) controlled dosing scheme. In a recent paper (Sanathanan and Peck, 1991), we have investigated the sample size efficiency of the Randomized CCT (RCCT) design in comparison to the traditional Randomized Dose-Controlled Trial (RDCT). We have pointed out that in addition to safety concerns which strongly suggest the use of CCTs for drugs with narrow therapeutic windows, sample size considerations favor the choice of CCTs in many situations. In particular, substantially smaller sample sizes are possible with CCTs which are designed to minimize the interindividual PK variability within comparison groups and consequently decrease the variability in clinical response within these groups. In a subsequent paper (Sanathanan and co-workers, 1991), we proposed a Phase II randomized concentration-controlled titration design with the objective of streamlining the drug development process. In this chapter we present a brief overview of the basic concepts underlying the design and implementation of CCTs.

Premarketing development of new drugs is time-consuming, costly, and does not always lead to optimal dosages. DiMasi and coworkers (1991) estimate that the mean development time of new drugs approved during the mid-80’s was 11.8 years and the average direct cost was 117 million dollars. Despite such lengthy and costly premarketing research efforts, as of April 1991, 8.3% of 192 new drugs approved during the 1980’s had undergone significant dosage changes in the approved drug labels (examples: midazolam, zidovudine, buprenorphine, alprazolam). These dosage changes were prompted by a recognition that modifications in recommended doses or dosing intervals would lead to even more efficacious or safer therapy in individual patients. Thus, if efficiency in premarketing drug development is measured by its duration, cost and optimality of dosages, it appears that the process is often inefficient.

Suramin, a drug used in the treatment of parasitic diseases, is currently being evaluated in clinical trials as an antineoplastic agent. The use of therapeutic drug monitoring and adaptive control with feedback in clinical trials of suramin was initially motivated by an association between acute neurologic toxicity and plasma suramin concentrations in excess of 350 micrograms/ml. We have prospectively examined the performance of both two- and three-compartment population pharmacokinetic models in controlling plasma suramin concentrations and have found that a three-compartment model best describes this drug. No correlation was found between the clearance of suramin and creatinine clearance, as had been previously hypothesized. The low systemic clearance of suramin and the number of parameters required to describe the three-compartment model suggest the need for a bayesian approach to the estimation of individual pharmacokinetics.

A randomized concentration-controlled trial (RCCT) is one in which subjects are randomly assigned to predetermined levels of average plasma drug concentration. These target concentrations can be achieved (within reasonable ranges) by an individualized pharmacokinetically controlled dosing scheme. The RCCT is designed to minimize the interindividual pharmacokinetic (PK) variability comparison groups and consequently decrease the variability in clinical response within these groups. In this paper, we investigate the extent of improvement in sample size efficiency that can be gained from the RCCT design in comparison to the traditional randomized dose-controlled trial (RDCT) design. Our investigations involve both theoretical arguments and simulation studies, illustrated with data on PK and pharmacodynamic (PD) characteristics of antiasthma drug theophylline. Aside from safety concerns that strongly suggest the use of RCCT for drugs with narrow therapeutic windows, sample size considerations favor the choice of RCCT in many situations, as shown in this paper.

Transcutaneous collection of theophylline and its metabolite, caffeine, was undertaken in 33 preterm infants (2 to 89 days old) who were receiving routine theophylline therapy. Collection was done by means of a novel adhesive transcutaneous collection system. The transcutaneous collection system accumulated substances that migrated from the blood to the skin surface by trapping them in an activated charcoal-gel matrix. On one to three occasions, four transdermal collection systems were applied to the back or abdomen of each infant for 4 to 12 hours. During that time, blood samples were obtained for routine monitoring of plasma theophylline levels. Amounts of theophylline (95 +/- 198 ng) and caffeine (83 +/- 77 ng) in the transcutaneous collection system were significantly correlated with the respective average plasma drug concentration and postconceptional age (p less than 0.01). Skin reactions were limited to mild erythema. We concluded that theophylline and caffeine can be collected on the surface of the skin of preterm infants with a novel transcutaneous collection system. Amounts collected by means of the transcutaneous collection system correlated with plasma concentrations consistent with a diffusion process, but they were poor predictors of individual concentrations.

Determination of appropriate theophylline maintenance doses in preterm infants is confounded by interpatient variability. This study evaluated the performance of an IBM PC computer program applying Bayesian regression before and during steady state in 37 preterm infants. Prior population estimates of clearance and distribution volume in preterm infants and Bayesian estimates of clearance and distribution volume based on one to three theophylline plasma concentrations were used to predict subsequent concentrations (drawn 1-17 days later). We assessed the accuracy and precision of the predictive performance of the Bayesian program with the mean prediction error and the mean absolute prediction error. The absolute prediction error (mean absolute error +/- SEM) significantly decreased with increasing feedback concentrations from 3.54 +/- 0.45 micrograms/ml (population estimates) to 2.74 +/- 0.42 (one feedback) and 2.02 +/- 0.35 micrograms/ml (two feedback concentrations). Mean prediction errors (+/- SEM) based on one to three feedbacks (-1.5 +/- 0.40 micrograms/ml) were significant improvements over population predictions (-2.63 +/- 0.72 micrograms/ml, p less than 0.05), although a small but significant average overprediction remained. Absolute prediction error was correlated with postconceptional and postnatal age when zero or one but not two feedback concentrations were available. Computer program predictions based on one measured feedback concentration were more accurate and precise than population-based predictions. Refinement of population parameters or two feedback concentrations further improved performance.

Background Realistic PK-PD models should incorporate the perceived clinical outcome of drug treatment. In the case of JRA, therapeutic outcome is judged according to a dichotomous scale (improved or not). We developed a PK-PD model for etanercept using six clinical component variables, which comprise the definition of improvement (DOI), assessed as “improved” if three or more of the components decrease by more than 30% of baseline values. Methods Clinical trial data of etanercept in 69 patients with JRA were used. The six component variables were percentage changes from baselines of global assessments by the physician (MDGA), patients or guardians (PTGA), functional ability (FA), number of active joints (AJC), number of joints with limitation of motion (LOM) and erythrocyte sedimentation rate (ESR). Each variable was fitted using the Emax model with individual predicted etanercept concentration or cumulative AUC. (NONMEM Ver. 5.1.1.) The dichotomous DOI was determined according to the criterion of 30% improvement in at least 3 of the 6 individual predicted variables. Results Emax and EC50 estimates are shown in the table. Three hundred and thirty eight points out of 422 (80.1%) individual predicted DOI values matched with the observed DOI values. Conclusions A PK-PD model for a dichotomous PD parameter was developed using component variables. This approach will help researchers to quantify the pharmacologic effects assessed by dichotomous clinical outcome variables. (See Table) Clinical Pharmacology & Therapeutics (2005) 77, P92–P92; doi: 10.1016/j.clpt.2004.12.246 Table 1. Estimated Emax and EC50 Component Variable Pharmacokinetic Parameter Used Estimated Emax (%) Estimated EC50 MDGA Cumulative AUC 63.5 1510 mg/L × h FA Cumulative AUC 55.2 5250 mg/L × h AJC Cumulative AUC 54.5 1750 mg/L × h LOM Cumulative AUC 50.7 1260 mg/L × h PTGA Serum concentration 52.3 904 μg/L ESR Serum concentration 44.2 98.8 μg/L

Purpose To build a population pharmacodynamic (PD) model of zolmitriptan (ZOL) following administration of ZOL conventional tablets. Methods ZOL concentration and headache scores (HS) were obtained in 235 migraine patients from AstraZeneca studies 8311CIL/006, 311CIL/007 and 311CIL/017. NONMEM likelihood estimation method was used to build a population PD model. The individual probabilities of headache scores (HS)≤ 1 (no pain), 2 (mild pain), 3 (moderate pain), or 4 (severe pain) at various times following administration of the drug were modeled using a logistic model. The placebo (time) effect was modeled as a first-order increase with an upper bound. A sigmoidal Emax-type equation with a high sigmoidicity factor was chosen to mimic the step function of pain relief. Results The built population PD model yielded 78% perfect match, 10% under prediction and 12% over prediction of the observed HS, respectively. Baseline HS is a significant covariate for pain relief. Conclusions A logistic model adequately described the time courses of HS following the administration of ZOL conventional tablets. Patients with moderate baseline HS had a higher probability of improvement of pain. Demographic factors do not impact the PD relationship between HS and ZOL concentration. Clinical Pharmacology & Therapeutics (2005) 77, P90–P90; doi: 10.1016/j.clpt.2004.12.237

Background To develop a model describing the circadian rhythm of the 24-hour ambulatory blood pressure monitoring (ABPM) measured diastolic blood pressure (DBP) in patients with mild to moderate essential hypertension when no drug is present. Methods 3,771 ABPM measurements from 107 hypertensive patients in a randomized placebo-controlled study of an antihypertensive agent, assigned to the placebo group (n=24, 3 occasions) or in the placebo run-in period (n=83), were analyzed by nonlinear mixed effects regression using NONMEM. FOCE with interaction was the estimation method. Results The final model was a two-cosine term model (24- and 12-hour cycles) having phase shift on clock time, with interindividual variability on the 24-hour rhythm adjusted mean, the amplitudes of the cosine terms, phase shift, and clock time. Interoccasion variability was also included on the 24-hour rhythm adjusted mean, the amplitude of the cosine term by 24-hour cycle and the clock time. The population standard of the 24-hour rhythm adjusted mean was 95.6 mmHg[95% CI: 93.5–97.7] and its interindividual and interoccasion variability were 9.2 CV%[6.2–12.1] and 3.2 CV%[0.6–5.7], respectively. The residual error was 7.48 mmHg. Conclusions A two-cosine model was able to characterize the circadian rhythm of ABPM measured DBP in this patient population. This model can be used as the baseline model to characterize the exposure-response relationship of antihypertensive agents. Clinical Pharmacology & Therapeutics (2005) 77, P57–P57; doi: 10.1016/j.clpt.2004.12.109

Background: AMD3100 is a small molecule CXCR4 antagonist that has been shown to induce the mobilization of hematopoietic stem cells (CD34+) from the bone marrow to peripheral blood. The purpose of this study was to characterize the exposure-response (ER) relationship of AMD3100 in mobilizing CD34+ cells.

Purpose To develop a systematic approach to identify and model the source of nonlinearity, detected as non-constant AUC/dose and Cmax/dose ratios, observed in PK analyses of ascending dose exposures (6–100 mg) of talampanel, an innovative antiepileptic drug. Methods: Graphical evaluations of partial-AUC/dose ratios from a 4-arm single dose-escalation PK study (n=24), were followed by population PK analyses (NONMEM) using model discrimination criteria to identify the likely source of nonlinearity. Results: Graphical patterns of partial AUC/dose and Cmax/dose ratios revealed greatest non-linearity in the early post-dose time period, leading to the assumption that absorption is the most probable source of nonlinearity. Saturable first-pass bioavailability (F) was modeled as an asymptotic function of dose (F=Dose/(Kd+Dose). A parallel zero-/first-order absorption model coupled with a 1-compartment linear model adequately described the entire PK profile of talampanel. Kd (dose yielding 50% F) was 4.7 mg (intersubject variability of F=77%). A similar model was evaluated using Michaelis-Menten elimination, but was rejected due to a Km estimate 4–5 times higher than the highest Cmax, and little improvement of model fitting criteria (decreased objective function value, diagnostic plots). Conclusion: Graphical analyses of dose normalized AUC and Cmax values, coupled with population PK model testing can be used to identify and model the source of nonlinearity observed in PK analysis. Clinical Pharmacology & Therapeutics (2004) 75, P90–P90; doi: 10.1016/j.clpt.2003.11.346

Objectives To investigate new drug development programs, we piloted a method to assess “test-quality” of phase-3 trials. Methods. 40 phase-3 trial results, announced in 2001, were evaluated using standardized design, performance, and trial endpoint criteria, and available FDA reviews. Trials were reliable if scientifically designed, conducted according to GCP (presumptively reliable if GCP unconfirmed), and employed FDA-accepted endpoints; unconvincing if endpoints were unacceptable; and inconclusive if the design was scientifically weak or GCP was violated. Results. 34 trials (85%) were evaluable: 100% were scientifically sound, employing randomization, adequate blinding and power, and employed acceptable endpoints. GCP compliance was confirmed in 50%, unconfirmed in 47%; 3% were non-compliant. Using our taxonomy, 97% of trials were presumptively or definitely reliable, 3% were inconclusive, and none were unconvincing. Trial sponsors reported 82% of trials as “successful,” of which 57% were FDA approved/approvable by 2003. Implications. High test-quality of publicly announced phase-3 trials in 2001 was confirmed. About one-half of “successful” trials led to FDA approval within 2 years, usually in public companies or partnerships with prior drug approvals (81%). A “quality and completeness” assessment of pre-phase-3 programs will be applied to further investigate ability of phase-3 trials (publicly announced or private) to reliably demonstrate drug effectiveness. Clinical Pharmacology & Therapeutics (2004) 75, P8–P8; doi: 10.1016/j.clpt.2003.11.030

Objective To compare the time courses of concentrations between etanercept 0.8 mg/Kg once weekly and 0.4 mg/Kg twice weekly subcutaneous (SC) dosing in pediatric patients with JRA. Methods A Monte Carlo clinical trial simulation experiment was conducted to compare the PK profiles of 200 pediatric patients with JRA who randomly received either etanercept 0.4 mg/Kg SC twice weekly or 0.8 mg/Kg once weekly for 12 weeks. The population PK parameters and covariate distribution model derived from 69 JRA patients (age: 4-17), enrolled in a 3–month, PK incorporated, double-blind randomized phase III study, were used for simulation of 100 replicates with Pharsight Trial Simulator® (Pharsight Co., ver. 2.1.2, Mountain View, California). The parameter uncertainties were also incorporated. Results The mean±standard deviation values of simulated peak concentrations for 0.8 mg/kg once weekly dosing and 0.4 mg/kg twice weekly dosing were almost identical (2.92±1.41 mg/L and 2.62±1.23 mg/L, respectively). Trough concentrations during 0.8 mg/kg once weekly dosing (1.58±1.07 mg/L) is also comparable to those during 0.4 mg/Kg twice weekly dosing (1.92±1.09 mg/L). Conclusion This simulation study confirmed that 0.8 mg/Kg once weekly and 0.4 mg/Kg twice weekly SC regimen of etanercept will yield an overlapping steady-state time-concentration profile and are expected to yield equivalent clinical outcomes. Clinical Pharmacology & Therapeutics (2004) 75, P53–P53; doi: 10.1016/j.clpt.2003.11.201

Background Dose guidance is an essential element of drug package inserts (PIs) and is a common change made in PIs post approval. Methods: We reviewed 229 PIs for products mentioning “dose response” (N=300) in the electronic 2003 Physicians Desk Reference for date of last update (DU) and a dose response (DR) completeness score as a % of the maximum of 35 points (CS%). The CS comprised the scores (0–2 or 0–3) by each reviewer of the 15 data elements in 4 categories (see table). We performed duplicate reviews of 27 PIs to assess inter-rater correlation of the CS (Spearman rho). Variability was assessed via 95% confidence intervals (95% CI), [mean ± 1.96 std error of the mean] (SAS JMP ver 5.0.1a). Results: The DU, found in 224 (98%), ranged from 6/93 to 8/03. Inter-rater correlation (N=27) of the CS was rho = 0.53, p= 0.0045). (see Table Conclusions & Recommendations By these measures, there is limited dose response described in these PIs, especially DR of Adverse Events. Aware that recent NDA's contain FDA-encouraged DR trials, we recommend FDA and manufacturers incorporate useful DR data in drug labels and provide web-based access to DR data not presented in their PI. Clinical Pharmacology & Therapeutics (2004) 75, P9–P9; doi: 10.1016/j.clpt.2003.11.032 Table 1. DR Information Category Max CS% Median (range) CS% Mean [95% CI] DR in Development 15 36% (0%, 100%) 35% [31%, 38%] DR of Adverse Events 6 17% (0%, 100%) 31% [27%, 35%] DR for Efficacy 6 33% (0%, 100%) 33% [29%, 37%] Dose adjustment 12 42% (0%, 100%) 43% [39%, 46%] Total (CS%) 35 24% (0%, 93%) 37% [34%, 39%]

In 1989, the occurrence of a rare, life-threatening ventricular arrhythmia (torsades de pointes) in an otherwise healthy young woman led alert clinicians at the Naval Hospital in Bethesda, Md, to consider the possibility that the patient's near-fatal arrhythmia was triggered by a drug-drug interaction involving her antihistamine (terfenadine) and her antifungal (ketoconazole) medications. 1 Consulting clinical pharmacologists from the Uniformed Services University of the Health Sciences and the US Food and Drug Administration (FDA) suggested that ketoconazole inhibited the oxidative metabolism of terfenadine. Analysis of blood samples revealed that the patient had high levels of unmetabolized terfenadine, a compound not usually detectable in blood because it is metabolized so quickly. Review of reports to the FDA's spontaneous reporting system revealed that among additional cases of torsades de pointes in patients receiving terfenadine, many were also receiving ketoconazole. This evidence led the FDA to ask Marion Merrill Dow, Kansas City, Mo

Dr Kessler and Mr Pines 1 present a thoughtful and balanced review of the Food and Drug Administration's (FDA) regulation of prescription drug promotion. In their conclusion, the authors call to mind issues where the need for change is clear and other issues that have long vexed the agency. Mr Pines, a former FDA Associate Commissioner for Public Affairs, is intimately familiar with these issues and has chaired conferences on them in several forums. Many of the presentations from these conferences have been published. 2,3 The article makes some cogent observations. The need to revise the brief summary for use in advertising in a way that makes it readable and more useful is inescapable. The need for governmental oversight of promotional activities involving gifts and other financial inducements to health care providers, such as travel, was made clear in hearings conducted by Sen Edward Kennedy of Massachusetts as early as

The marginal viability of erythrocytes stored for 35 days as red blood cell concentrates in citrate-phosphate-dextrose-adenine-one (CPDA-1) was attributed to inadequate nutrient support with adenine and glucose. In an effort to improve the viability of red blood cells following extended storage, a new CPD-adenine and 1.4 times more glucose than CPDA-1. The efficacy of CPDA-2 was evaluated in vivo by measurement of 24-hour postinfusion recovery of 51Cr-labeled erythrocytes which had been stored as whole blood or red blood cell concentrates for 5 to 8 weeks. All red blood cell concentrates, and the whole blood units stored for 35 and 42 days, were held at room temperature for 8 hours prior to processing and/or refrigeration. CPDA-2 yielded significantly higher 51Cr survivals than CPDA-1 and exceeded the accepted criterion for anticoagulant preservative efficacy of 70 percent postinfusion survival of red blood cells after storage for a period of 42 days. Preliminary data supports possible usage to 49 days. Plasma glucose and red blood cell ATP concentration were maintained better in CPDA-2 than in CPDA-1. When compared to historical controls for CPD and CPDA-1 the data suggest that red blood cells stored in CPDA-02 will have superior viability throughout the entire storage period. CPDA-2 is a candidate to replace CPDA-1 as the anticoagulant-preservative solution of choice for red blood cell concentrates.

We performed two studies to assess the clinical utility of a Bayesian regression analysis computer program for phenytoin (PHT). In a randomized prospective study of 40 epileptic patients, the dosing program was significantly more accurate (p = 0.002) and less biased (p = 0.02) than a group of physicians at hitting a target PHT serum-concentration. Initial serum PHT concentrations that were not steady state were associated with the largest dosing errors by physicians but did not affect the accuracy of the dosing program. In a second study, we used the dosing program to predict 91 serum concentrations in 31 patients with PHT toxicity after the drug was stopped (initial concentration 26-69 micrograms/ml). The program predicted serum concentrations with a mean error of 3.49 +/- 0.29 micrograms/ml without significant tendency to over- or underpredict. We conclude that this dosing program may aid clinicians by improving dosing accuracy and predicting serum concentrations in patients with PHT toxicity.

In order to provide data in support of licensure applications for citrate-phosphate-dextrose (CPD) supplemented with adenine, a multi-institutional cooperative effort was organized to determine survivability of red blood cells subjected to prolonged liquid storage. Two manufacturers supplied plastic multiple bag blood storage containers prefilled with modified CPD (glucose 25% greater than the normal concentration) supplemented with adenine (17.0 to 17.3 mg per 63 ml of anticoagulant; 0.25 millimolar approximate final concentration when diluted with 450 ml of whole blood). Red blood cells from 32 units stored as whole blood for 35 days showed a mean survival of 80.53 + 6.44 per cent (1 SD). Both red blood cell and supernatant plasma biochemical characteristics were comparable to those reported for whole blood stored for 21 days in either acid-citrate-dextrose (ACD) or CPD. Red blood cells from 19 units stored as concentrates for 35 days (Hct 75.03 + 3.74%) had a mean survival of 71.38 + 10.3 per cent with considerable interdonor variation in survival and interlaboratory variation in some biochemical characteristics. Red blood cells from eight units stored as concentrates (Hct 75.38 + 4.30%) for 28 days showed a mean survival of 83.97 + 6.10 per cent and biochemical characteristics comparable to those reported for red blood-cell concentrates stored in CPD or ACD for 21 days. Modified CPD with adenine as formulated offers an improved anticoagulant for blood banking by extending the permissible red blood cell storage period.

Intravenous immunoglobulin (IVIG) may be a therapeutic adjunct to antibiotic treatment of neonatal infections. We examined the pharmacokinetics and safety of IVIG in human neonates. Thirty neonates with suspected sepsis were randomly assigned either to a treatment (receiving either 250, 500, or 1,000 mg/kg of IVIG plus antibiotics) or control (antibiotics alone) group. The 500 mg/kg dose produced a rise in total IgG for greater than 8 and in group B streptococcus (GBS) type-specific IgG for greater than 4-14 days. The type-specific antibody elevation varied with the amount of pathogen-specific antibody and dose of IVIG. Pharmacokinetic analysis suggests a Vdss of 42 ml/kg, Cl of 3.0 ml/kg/day, a biphasic elimination curve, and a terminal elimination half-life of 24.2 days. No toxicity was observed. These data may be valuable in determining optimal dosing schedules for IVIG in treating or preventing neonatal infections.

To evaluate the efficacy of lithium in chronic alcoholism, we enrolled 47 male alcoholics in a prospective double-blind two-period crossover study. Nineteen subjects completed the 6-mo study during which they received lithium and placebo each for a 3-mo period. Self-reported alcohol intake and social and psychological factors were monitored. Three subjects claimed that they did not drink during the study. Mean self-reported alcohol intake of the remaining 16 was less during lithium therapy but was also less during the first treatment period. Neither of these differences reached statistical significance. The nine depressed patients, diagnosed from their profiles on the Minnesota Multiphasic Personality Inventory did not consume significantly less alcohol and did not change scores for depression significantly during lithium therapy. We could not demonstrate that lithium therapy was of benefit in our group of alcoholic patients.

Continuous transepidermal drug collection (CTDC) has been proposed for use in assessing ethanol intake and in monitoring compliance with therapeutic regimens. Exploration of a theoretical basis for use of CTDC in these circumstances and for its use in assessing other aspects of drug disposition kinetics was undertaken. Effects of single and multicompartmental drug disposition models, single dose and multiple dose regimens, with regular and irregular doses and dosing intervals, and zero-order, first-order, and Michaelis-Menten excretion patterns were explored. First-order transepidermal drug transfer was assumed with and without back transfer from the collection device. These analyses suggest that the utility of CTDC is severely restricted when back transfer from the collection device is substantial. With back transfer minimized, CTDC may be a useful tool for assessing amount of drug exposure, compliance with therapeutic regimens, and relative bioavailability, but offers little advantage over discrete sampling of other body fluids in the study of other aspects of drug disposition kinetics.