Impact of the pharmaceutical sciences on health care: a reflection over the past 50 years.

During the last century, particularly the latter half, spectacular progress has been made in improving the health and longevity of people. The reasons are many, but the development of medicines has played a critical role. This report documents and reflects on the impressive contribution that those working in the pharmaceutical sciences have made to healthcare over the past 50 years. It is divided into six sections (drug discovery; absorption, distribution, metabolism, and excretion; pharmacokinetics and pharmacodynamics; drug formulation; drug regulation; and drug utilization), each describing key contributions that have been made in the progression of medicines, from conception to use. A common thread throughout is the application of translational science to the improvement of drug discovery, development, and therapeutic application. Each section has been coordinated by a leading scientist who was asked, after consulting widely with many colleagues across the globe, to identify "The five most influential ideas/concepts/developments introduced by 'pharmaceutical scientists' (in their field) over the past 50 years?" Although one cannot predict where the important breakthroughs will come in the future to meet the unmet medical needs, the evidence presented in this report should leave no doubt that those engaged in the pharmaceutical sciences will continue to make their contributions heavily felt.

2011 White paper on recent issues in bioanalysis and regulatory findings from audits and inspections.

The 5th Workshop on Recent Issues in Bioanalysis (WRIB) was organized by the Calibration and Validation Group as a 2-day full immersion workshop for pharmaceutical companies, CROs and regulatory agencies to discuss, review, share perspectives, provide potential solutions and agree upon a consistent approach to recent issues in the bioanalysis of both small and large molecules. High quality, better compliance to regulations and scientific excellence are the foundation of this workshop. As in the previous editions of this significant event, recommendations were made and a consensus was reached among panelists and attendees, including industry leaders and regulatory experts representing the global bioanalytical community, on many 'hot' topics in bioanalysis. This 2011 White Paper is based on the conclusions from this workshop, and aims to provide a practical reference guide on those topics.

Investigation and resolution of incurred sample reanalysis failures: two case studies.

The reanalysis of incurred bioanalytical samples (incurred sample reanalysis) provides additional data that help us to ensure that a 'validated bioanalytical method' is reproducible. While the guidelines for the conduct of incurred sample reanalysis evaluations have been well described, published information pertaining to the occurrence of failures and the manner in which they are resolved has not received the same amount of attention. The purpose of this manuscript is to describe two case studies where incurred sample reanalysis failures were encountered for small molecules, the approaches that were taken to elucidate the root cause of the failures, and the remedial actions that were implemented to prevent such failures from recurring.

2010 white paper on recent issues in regulated bioanalysis & global harmonization of bioanalytical guidance.

The 4th Calibration and Validation Group Workshop on Recent Issues in Regulated Bioanalysis, a 2-day full immersion workshop, was organized by the Calibration and Validation Group. Contract research organizations, pharmaceutical companies and regulatory agencies came together to discuss several 'hot' topics concerning bioanalytical issues and regulatory challenges and to reach a consensus among panelists and attendees on many points regarding method validation of small and large molecules.

2009 White Paper on recent issues in regulated bioanalysis from the 3rd Calibration and Validation Group Workshop.

The 3rd Calibration and Validation Group Workshop on Recent Issues in Regulated Bioanalysis was organized by the Calibration and Validation Group as a 1.5-day full immersion workshop for contract research organizations, pharmaceutical companies and regulatory agencies to discuss several 'hot' topics concerning bioanalytical issues and regulatory challenges. A consensus was reached among panelists and attendees on many points regarding method validation of small molecules.

Challenges and opportunities in establishing scientific and regulatory standards for assuring therapeutic equivalence of modified release products: workshop summary report.

Modified release products are complex dosage forms designed to release drug in a controlled manner to achieve desired efficacy and safety. Inappropriate control of drug release from such products may result in reduced efficacy or increased toxicity. This workshop provided an opportunity for pharmaceutical scientists from academia, industry, and regulatory agencies to discuss current industry practices and regulatory expectations for demonstrating pharmaceutical equivalence and bioequivalence of MR products, further facilitating the establishment of regulatory standards for ensuring therapeutic equivalence of these products.

Challenges and opportunities in establishing scientific and regulatory standards for assuring therapeutic equivalence of modified-release products: workshop summary report.

Modified-release products are complex dosage forms designed to release drug in a controlled manner to achieve desired efficacy and safety. Inappropriate control of drug release from such products may result in reduced efficacy or increased toxicity. This workshop provided an opportunity for pharmaceutical scientists from academia, industry and regulatory agencies to discuss current regulatory expectations and industry practices for demonstrating pharmaceutical equivalence and bioequivalence of MR products, further facilitating the establishment of regulatory standards for ensuring therapeutic equivalence of these products.

Challenges and opportunities in establishing scientific and regulatory standards for determining therapeutic equivalence of modified-release products: Workshop summary report.

BACKGROUND: Modified-release (MR) products are complex dosage forms designed to release drug in a controlled manner to achieve the desired efficacy and safety profiles. Inappropriate control of drug release from such products may result in reduced efficacy or increased toxicity. OBJECTIVE: This paper is a summary report of the American Association of Pharmaceutical Scientists, International Pharmaceutical Federation, and Product Quality Research Institute workshop titled "Challenges and Opportunities in Establishing Scientific and Regulatory Standards for Assuring Therapeutic Equivalence of Modified Release Products", held October 1-2, 2009, in Baltimore, Maryland. METHODS: The workshop provided an opportunity for pharmaceutical scientists from academia, industry, and regulatory agencies to discuss current regulatory expectations and industry practices for evaluating the pharmaceutical equivalence and bioequivalence of oral MR products. RESULTS: In the case of conventional monophasic MR formulations, the current regulatory approaches and criteria for bioequivalence evaluation were considered adequate for the assessment of therapeutic equivalence and inter-changeability of drug products. Additional measures may occasionally be needed to determine the bioequivalence of multiphasic MR products. The metric of partial AUC proposed by the US Food and Drug Administration received broad support as an additional measure for evaluating bioequivalence of multiphasic MR products designed to have a rapid onset of drug action followed by sustained response. The cutoff for partial AUCs may be based on the pharmacokinetic/pharmacodynamic or pharmacokinetic/ response characteristics of the products under examination. If the new metric is highly variable, the bioequivalence limits may be set based on the known within-subject variability for the reference product. CONCLUSIONS: The current regulatory approaches and criteria for bioequivalence evaluation were considered adequate for the assessment of therapeutic equivalence and interchangeability of conventional monophasic MR products. Additional measures may occasionally be needed to establish the bioequivalence of multiphasic MR products, and development of such measures is an important objective. The metric of partial AUC was proposed for products designed to have a rapid drug action followed by sustained response.

The 2nd Calibration and Validation Group workshop on recent issues in good laboratory practice bioanalysis.

This event was organized by the Calibration and Validation Group (a scientific nonprofit organization based in Toronto, Canada) as a 1.5-day workshop for contract research organizations and pharmaceutical companies involved in providing bioanalytical data for bioavailability, bioequivalence, pharmacokinetic and comparability studies.

Confirmatory reanalysis of incurred bioanalytical samples.

Bioanalytical methods used to support the drug development process are validated to ensure that they function in the manner in which they are intended. "Incurred" or study samples can vary in their composition when compared with the standards and quality control samples used to validate the method and analyze these samples. During the 3rd American Association of Pharmaceutical Scientists(AAPS)/Food and Drug Administration(FDA) Bioanalytical Workshop, it was suggested that the reproducibility in the analysis of incurred samples be evaluated in addition to the usual prestudy validation activities performed. This manuscript provides recommendations concerning the number and types of samples that should be analyzed in such an evaluation, as well as the manner in which the resultant data should be analyzed. Suggestions as to follow-up activities and data reporting are also discussed. This approach is at best a beginning and is offered as a platform for future discussion, comments, and revision.

Poor correlation between 6beta-hydroxycortisol:cortisol molar ratios and midazolam clearance as measure of hepatic CYP3A activity.

AIMS: A non-invasive proposed method for measuring CYP3A activity is the urinary 6beta-hydroxycortisol:cortisol ratio. This ratio has been used as an indicator of CYP3A induction and inhibition, with mixed results. This investigation evaluated the relationship between a validated, biomarker, intravenous midazolam clearance and the urinary cortisol ratio under constitutive conditions and with the influence of a moderate CYP3A inhibitor. METHODS: This was a sequential, cross-over study design. Intravenous midazolam 0.025 mg kg(-1) was administered to 10 male and 10 female subjects once every 14 days for 4 months. Fluvoxamine 150 mg day(-1) was given to all subjects during the last two visits. Total body clearance of midazolam and urinary 6beta-hydroxycortisol:cortisol molar ratio were used as biomarkers of hepatic CYP3A activity. RESULTS: No significant correlations were found between these two markers (r(2) < 0.5, P > 0.05). Larger interindividual and intra-individual variability in CYP3A activity was observed in 6beta-hydroxycortisol:cortisol ratios compared with midazolam clearances. With fluvoxamine therapy, midazolam clearance values decreased approximately 1.5-fold and cortisol ratios decreased approximately 1.9-fold. CONCLUSIONS: The high intra-individual variability of the urinary cortisol ratio, compared with midazolam, makes this a suboptimal CYP3A phenotyping tool.

Over-the-counter progesterone cream produces significant drug exposure compared to a food and drug administration-approved oral progesterone product.

Progesterone products are available in prescription form as well as over-the-counter (OTC) topical preparations sold for "cosmetic" uses. In a randomized study design, the authors compared the drug exposure from an OTC progesterone cream to a Food and Drug Administration-approved oral preparation at the labeled daily doses recommended for each product. Twelve healthy postmenopausal women received 200-mg oral progesterone capsules once daily for 12 days or progesterone cream 40 mg twice daily for 12 days. At steady state (day 12 of each phase), whole-blood samples were collected over 24 hours (oral progesterone) or 12 hours (topical progesterone) and assayed for total progesterone concentration. No significant differences were found in dose-normalized 24-hour progesterone exposure comparing the cream to oral capsules (median AUC(0-24) 12.5 ng x h/mL vs 10.5 ng x h/mL, respectively; P = .81). In light of the potential risks associated with long-term progesterone use, the authors question whether topical progesterone products should be available OTC.

Flumazenil reduces midazolam-induced cognitive impairment without altering pharmacokinetics.

OBJECTIVES: Intravenous midazolam is used as an in vivo biomarker of hepatic cytochrome P450 (CYP) 3A activity. Midazolam is a central nervous system depressant and can produce cognitive impairment. The purpose of this study was 2-fold: (1) to determine whether administration of intravenous flumazenil given before intravenous midazolam minimizes cognitive impairment and (2) to determine whether flumazenil pretreatment has an effect on midazolam pharmacokinetics during hepatic CYP3A phenotyping. METHODS: Eleven healthy subjects (8 men) received intravenous flumazenil (0.005 mg/kg) or placebo followed 7 minutes later by intravenous midazolam (0.025 mg/kg) in a randomized, double-blind crossover study. Plasma midazolam concentrations were obtained before dosing and at 5, 30, 60, 120, 240, 300, and 360 minutes after dosing and were assayed by liquid chromatography-tandem mass spectrometry. Midazolam pharmacokinetics were determined by noncompartmental methods. The two 1-sided tests procedure was used to compare area under the curve (AUC) between study phases. Data were log-transformed before analysis, and bioequivalence criteria were applied. Digit symbol substitution tests, performed before dosing and at 5, 30, 60, 120, 240, 300, and 360 minutes after dosing, were used to measure cognition. General linear modeling was used to compare scores between study phases. RESULTS: Midazolam AUC extrapolated to infinity [AUC(0-infinity)] between phases was bioequivalent. The AUC ratio (flumazenil plus midazolam/midazolam) was 0.99, with a 90% confidence interval of 0.98 to 1.00. Statistically significant differences(P

Single plasma concentrations of 1'-hydroxymidazolam or the ratio of 1'-hydroxymidazolam:midazolam do not predict midazolam clearance in healthy subjects.

The 30-minute ratio of 1'-hydroxymidazolam:midazolam plasma concentrations has been used as a measure of midazolam clearance in liver transplant patients. This study determined if a single concentration of 1'-hydroxymidazolam or the ratio of 1'-hydroxymidazolam:midazolam could be used to predict midazolam clearance in healthy subjects. Plasma midazolam and 1'-hydroxymidazolam concentrations from three previous studies were used for analyses. Data obtained predose and at 5, 30, 60, 120, 240, 300, and 360 minutes following intravenous doses of midazolam in 61 adults were divided and used to derive and validate equations to predict midazolam clearance. Equations were derived using linear regression and then validated by comparing predicted to observed clearance. Only one equation was related to midazolam clearance as afunction of 1'-hydroxymidazolam, but it did not predict midazolam clearance (r = 0.29, p = 0.31). Single sampling of 1'-hydroxymidazolam or 1'-hydroxymidazolam:midazolam plasma concentrations cannot be used to predict midazolam clearance in healthy adults.

Limited sampling strategy to predict AUC of the CYP3A phenotyping probe midazolam in adults: application to various assay techniques.

Midazolam clearance is used to phenotype hepatic CYP3A activity but requires multiple plasma samples following a single intravenous dose. The authors evaluated the use of a limited sampling scheme, using different assay techniques to determine the reproducibility of such a strategy in estimating midazolam AUC. Seventy-three healthy adults received midazolam as a single intravenous bolus dose. At least eight plasma samples were collected from each subject and were assayed using either LC/MS/MS or electron capture gas chromatography. Eleven subjects were randomly selected for the training set using stepwise linear regression to determine relationships between midazolam plasma concentrations and AUC. Validation of the predictive equations was done using the remaining 62 subjects. Mean percent error (MPE), mean absolute error (MAE), and root mean square error (RMSE) were calculated to determine bias and precision. Based on the training set, five models were generated with coefficients of determination ranging from 0.87 to 0.95. Validation showed that MPE, MAE, and RMSE values were acceptable for three of the models. Intrasubject reproducibility was good. In addition, training set datafrom one institution were able to predict data from the other two institutions using other assay techniques. Minimized plasma sampling mayprovide a simpler method for estimating midazolam AUC for CYP3A phenotyping. A limited sampling strategy is more convenient and cost-effective than standard sampling strategies and is applicable to more than one assay technique.