Applying real-world data from expanded-access (“compassionate use”) patients to drug development

Our drug development process has produced many life-saving medications, but patients experiencing rare diseases and similar conditions often are left with limited options for treatment. For an approved treatment to be developed, research on a new candidate or existing drug must validate safety and efficacy based on contemporary research expectations. Randomized clinical trials are conducted for this purpose, but they are also costly, laborious, and time-consuming. For this reason, The 21st Century Cures Act mandates that the US Food and Drug Administration look for alternative methods for approving drugs, in particular exploring the uses of real-world data and evidence. Expanded access (“compassionate use”) is a pathway for the clinical treatment of patients using drugs that are not yet approved for prescribing in the United States. Using real-world evidence generated from expanded-access patients presents an opportunity to provide critical data on patient outcomes that can serve regulatory approval in conjunction with other observational datasets or clinical trials, and in limited circumstances may be the best data available for regulatory review. In doing so, we may also support and encourage patient-centered care and a personalized medicine approach to drug development

Intravenous digoxin as a bioavailability standard

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/116960/1/cpt1975171117.pd

Adverse performance effects of acute lorazepam administration in elderly long-term users: pharmacokinetic and clinical predictors.

BACKGROUND: The benzodiazepine lorazepam is widely utilized in the treatment of elderly individuals with anxiety disorders and related conditions. Negative effects of acute lorazepam administration on cognitive performance, especially memory, have been reported in both previously untreated elderly and in individuals who have received short term (up to three weeks) treatment with therapeutic doses. However, it remains unclear if these adverse cognitive effects also persist after long-term use, which is frequently found in clinical practice. METHODS: Cognitively intact elderly individuals (n=37) on long-term (at least three months) daily treatment with lorazepam were studied using a double-blind placebo-controlled cross-over study design. Subjects were administered their highest daily unit dose of lorazepam (0.25-3.00 mg) or placebo on different days, approximately 1 week apart in a random order, and were assessed on memory, psychomotor speed, and subjective mood states. RESULTS: Subjects had significantly poorer recall and slowed psychomotor performance following acute lorazepam administration. There were no significant effects on self-ratings of mood, sedation, or anxiety in the whole group, but secondary analyses suggested a differential response in subjects with Generalized Anxiety Disorder. CONCLUSIONS: The reduced recall and psychomotor slowing that we observed, along with an absence of significant therapeutic benefits, following acute lorazepam administration in elderly long-term users reinforces the importance of cognitive toxicity as a clinical factor in benzodiazepine use, especially in this population

Design and Initial Results of a Multi-Phase Randomized Trial of Ceftriaxone in Amyotrophic Lateral Sclerosis

Objectives: Ceftriaxone increases expression of the astrocytic glutamate transporter, EAAT2, which might protect from glutamate-mediated excitotoxicity. A trial using a novel three stage nonstop design, incorporating Phases I-III, tested ceftriaxone in ALS. Stage 1 determined the cerebrospinal fluid pharmacokinetics of ceftriaxone in subjects with ALS. Stage 2 evaluated safety and tolerability for 20-weeks. Analysis of the pharmacokinetics, tolerability, and safety was used to determine the ceftriaxone dosage for Stage 3 efficacy testing. Methods: In Stage 1, 66 subjects at ten clinical sites were enrolled and randomized equally into three study groups receiving intravenous placebo, ceftriaxone 2 grams daily or ceftriaxone 4 grams daily divided BID. Participants provided serum and cerebrospinal fluid for pharmacokinetic analysis on study day 7. Participants continued their assigned treatment in Stage 2. The Data and Safety Monitoring Board (DSMB) reviewed the data after the last participants completed 20 weeks on study drug. Results: Stage 1 analysis revealed linear pharmacokinetics, and CSF trough levels for both dosage levels exceeding the pre-specified target trough level of 1 µM (0.55 µg/mL). Tolerability (Stages 1 and 2) results showed that ceftriaxone at dosages up to 4 grams/day was well tolerated at 20 weeks. Biliary adverse events were more common with ceftriaxone but not dose-dependent and improved with ursodeoxycholic (ursodiol) therapy. Conclusions: The goals of Stages 1 and 2 of the ceftriaxone trial were successfully achieved. Based on the pre-specified decision rules, the DSMB recommended the use of ceftriaxone 4 g/d (divided BID) for Stage 3, which recently closed. Trial Registration ClinicalTrials.gov NCT00349622

Limited Sampling Strategy to Predict AUC of the CYP3A Phenotyping Probe Midazolam in Adults: Application to Various Assay Techniques

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/97211/1/00912700222011418.pd

Comparison between cytochrome P450 (CYP) content and relative activity approaches to scaling from cDNA-expressed CYPs to human liver microsomes: ratios of accessory proteins as sources of discrepancies between approaches. Drug Metab

This paper is available online at http://www.dmd.org ABSTRACT: Relative activity factors (RAFs) and immunoquantified levels of cytochrome P450 (CYP) isoforms both have been proposed as scaling factors for the prediction of hepatic drug metabolism from studies using cDNA-expressed CYPs. However, a systematic comparison of the two approaches, including possible mechanisms underlying differences, is not available. In this study, RAFs determined for CYPs 1A2, 2B6, 2C19, 2D6, and 3A4 in 12 human livers using lymphoblast-expressed enzymes were compared to immunoquantified protein levels. 2C19, 2D6, and 3A4 RAFs were similar to immunoquantified enzyme levels. In contrast, 1A2 RAFs were 5-to 20-fold higher than CYP1A2 content, and the RAF:content ratio was positively correlated with the molar ratio of NADPH:CYP oxidoreductase (OR) to CYP1A2. The OR:CYP1A2 ratio in lymphoblast microsomes was 92-fold lower than in human liver microsomes. Reconstitution experiments demonstrated a 10-to 20-fold lower activity at OR:CYP1A2 ratios similar to those in lymphoblasts, compared with those in human livers. CYP2B6-containing lymphoblast microsomes had 29-and 13-fold lower OR:CYP and cytochrome b 5 :CYP ratios, respectively, than did liver microsomes and yielded RAFs that were 6-fold higher than CYP2B6 content. Use of metabolic rates from cDNA-expressed CYPs containing nonphysiologic concentrations of electron-transfer proteins (relative to human liver microsomes) in conjunction with hepatic CYP contents may lead to incorrect predictions of liver microsomal rates and relative contributions of individual isoforms. Scaling factors used in bridging the gap between expression systems and liver microsomes should not only incorporate relative hepatic abundance of individual CYPs but also account for differences in activity per unit enzyme in the two systems. The cloning and heterologous expression of the drug-metabolizing human CYPs 1 has resulted in the commercial availability of cDNAexpressed CYPs for use as reagents for in vitro quantitative phenotyping, and bridging the gap between cDNA-expressed cytochromes and human liver microsomes has been the subject of several recent reviews The turnover number of CYPs in human liver microsomes is affected by several factors that are biochemically distinct from the CYP enzyme itself. Examples include the accessory electron-transfer proteins NADPH cytochrome P450-oxidoreductase (OR) and cytochrome b 5 , membrane lipid composition, and ionic strength of the in vitro incubation matrix The relative contribution of each isoform can then be determined as follows: Enzyme kinetic studies using cDNA-expressed human CYPs are being increasingly used to define the functions v i (s) for whatever individual CYPs biotransform a drug. Such analyses indicate the relative affinities and capacities of the CYPs contributing to a biotransformation. However, the relative contribution of each enzyme cannot be estimated unless the results incorporate the scaling factors (A i ). Although immunoquantified levels of CYP isoforms in human liver microsomes RAFs are determined for specific CYPs by comparing the rate of an isoform-specific index reaction at saturating substrate concentrations in human liver microsomes (V max for liver microsomes) to the rate of the same reaction catalyzed by the specific cDNA-expressed CYP under identical conditions (V max for cDNA-expressed enzyme): Mean V max for isoform-specific reaction in human liver microsomes V max for isoform-specific reaction by cDNA expressed isoform When the numerator is expressed in picomoles metabolite per milligram of protein per minute and the denominator as picomoles of metabolite per picomole of CYP per minute, the units of RAF are picomoles of CYP per milligram of protein, which can be compared with the immunoquantified CYP contents. RAFs have been used as estimates of A i in reaction phenotyping Materials and Methods Human Liver Microsomes and Heterologously Expressed CYP Isoforms. Liver samples, obtained from the International Institute for the Advancement of Medicine (Exton, PA) or the Liver Tissue Procurement and Distribution Service (University of Minnesota), were from 12 different transplant donors (L1-L12) with no known liver disease. The donor population (median age 27 years, range 3-50 years; 5 females and 7 males) was balanced with respect to age, sex, race, smoking habits, and alcohol consumption. The tissue was partitioned and kept at Ϫ80°C until the time of microsome preparation as described previously Microsomes from cDNA-transfected human lymphoblastoid cells expressing CYP 1A2, 2B6, 2C19, 2D6, or 3A4 (Crespi, 1995) were purchased from Gentest Corporation (Woburn, MA), aliquoted and stored at Ϫ80°C, and thawed on ice before use. Lymphoblast-expressed CYPs 3A4 and 2D6 used in the study were coexpressed with OR, whereas the activities of lymphoblast- expressed CYPs 1A2, 2B6, and 2C19 were supported by endogenous levels of reductase native to the host cell line. Microsomal protein concentrations and CYP content were provided by the manufacturer. Antibodies and Quantitative Western Blotting. Concentrations of CYP1A2, 2B6, 2C19, 2D6, and 3A4/5 in human liver microsomal preparations from livers L1 to L12 were determined by quantitative Western blotting In Vitro Metabolic Incubations and Metabolite Analysis. Incubations of index substrates with human liver microsomes and lymphoblas

A semiparametric modeling framework for potential biomarker discovery and the development of metabonomic profiles

<p>Abstract</p> <p>Background</p> <p>The discovery of biomarkers is an important step towards the development of criteria for early diagnosis of disease status. Recently electrospray ionization (ESI) and matrix assisted laser desorption (MALDI) time-of-flight (TOF) mass spectrometry have been used to identify biomarkers both in proteomics and metabonomics studies. Data sets generated from such studies are generally very large in size and thus require the use of sophisticated statistical techniques to glean useful information. Most recent attempts to process these types of data model each compound's intensity either discretely by positional (mass to charge ratio) clustering or through each compounds' own intensity distribution. Traditionally data processing steps such as noise removal, background elimination and m/z alignment, are generally carried out separately resulting in unsatisfactory propagation of signals in the final model.</p> <p>Results</p> <p>In the present study a novel semi-parametric approach has been developed to distinguish urinary metabolic profiles in a group of traumatic patients from those of a control group consisting of normal individuals. Data sets obtained from the replicates of a single subject were used to develop a functional profile through Dirichlet mixture of beta distribution. This functional profile is flexible enough to accommodate variability of the instrument and the inherent variability of each individual, thus simultaneously addressing different sources of systematic error. To address instrument variability, all data sets were analyzed in replicate, an important issue ignored by most studies in the past. Different model comparisons were performed to select the best model for each subject. The m/z values in the window of the irregular pattern are then further recommended for possible biomarker discovery.</p> <p>Conclusion</p> <p>To the best of our knowledge this is the very first attempt to model the physical process behind the time-of flight mass spectrometry. Most of the state of the art techniques does not take these physical principles in consideration while modeling such data. The proposed modeling process will apply as long as the basic physical principle presented in this paper is valid. Notably we have confined our present work mostly within the modeling aspect. Nevertheless clinical validation of our recommended list of potential biomarkers will be required. Hence, we have termed our modeling approach as a "framework" for further work.</p

Modest but Variable Effect of Rifampin on Steady-State Plasma Pharmacokinetics of Efavirenz in Healthy African-American and Caucasian Volunteers

ABSTRACT Efavirenz-based antiretroviral regimen is preferred during rifampin-containing tuberculosis therapy. However, current pharmacokinetic data are insufficient to guide optimized concurrent dosing. This study aimed to better characterize the effects of rifampin on efavirenz pharmacokinetics. Subjects were randomized to receive 600 mg efavirenz/day or 600 mg efavirenz with 600 mg rifampin/day for 8 days, with plasma samples collected for pharmacokinetic analysis over 24 h on day 8. Treatments were then crossed over after at least a 2-week washout period, and procedures were repeated. Efavirenz concentrations were determined by high-performance liquid chromatography (HPLC), and pharmacokinetic parameters were estimated by noncompartmental analysis. Efavirenz pharmacokinetic differences between treatment periods were evaluated by paired t test. The coefficients of variation in efavirenz plasma AUC 0-24 (area under the concentration-time curve from 0 to 24 h) were 50% and 56% in the absence and presence of rifampin, respectively. Of the 11 evaluable subjects (6 white, 5 black; 6 women, 5 men), the geometric mean AUC 0-24 ratio on/off rifampin (90% confidence interval) was 0.82 (0.72, 0.92), with individual AUC 0-24 ratios varying from 0.55 to 1.18. Five subjects had a 24-hour efavirenz concentration ( C 24 ) of <1,000 ng/ml on rifampin. They were more likely to have received a lower dose in milligrams/kilogram of body weight and to have lower efavirenz AUC 0-24 values in the basal state. Although rifampin resulted in a modest reduction in efavirenz plasma exposure in subjects as a whole, there was high variability in responses between subjects, suggesting that efavirenz dose adjustment with rifampin may need to be individualized. Body weight and genetic factors will be important covariates in dosing algorithms