Patrick Marroum

Impact of pharmacometrics on drug approval and labeling decisions: a survey of 42 new drug applications.

The value of quantitative thinking in drug development and regulatory review is increasingly being appreciated. Modeling and simulation of data pertaining to pharmacokinetic, pharmacodynamic, and disease progression is often referred to as the pharmacometrics analyses. The objective of the current report is to assess the role of pharmacometrics at the US Food and Drug Administration (FDA) in making drug approval and labeling decisions. The New Drug Applications (NDAs) submitted between 2000 and 2004 to the Cardio-renal, Oncology, and Neuropharmacology drug products divisions were surveyed. For those NDA reviews that included a pharmacometrics consultation, the clinical pharmacology scientists ranked the impact on the regulatory decision(s). Of about a total of 244 NDAs, 42 included a pharmacometrics component. Review of NDAs involved independent, quantitative evaluation by FDA pharmacometricians, even when such analysis was not conducted by the sponsor. Pharmacometric analyses were pivotal in regulatory decision making in more than half of the 42 NDAs. Of the 14 reviews that were pivotal to approval related decisions, 5 identified the need for additional trials, whereas 6 reduced the burden of conducting additional trials. Collaboration among the FDA clinical pharmacology, medical, and statistical reviewers and effective communication with the sponsors was critical for the impact to occur. The survey and the case studies emphasize the need for early interaction between the FDA and sponsors to plan the development more efficiently by appreciating the regulatory expectations better.

Development and internal validation of an in vitro-in vivo correlation for a hydrophilic metoprolol tartrate extended release tablet formulation

AbstractPurpose. To develop and validate internally an in vitro-in vivo correlation (IVIVC) for a hydrophilic matrix extended release metoprolol tablet. Methods. In vitro dissolution of the metoprolol tablets was examined using the following methods: Apparatus II, pH 1.2 & 6.8 at 50 rpm and Apparatus I, pH 6.8, at 100 and 150 rpm. Seven healthy subjects received three metoprolol formulations (100 mg): slow, moderate, fast releasing and an oral solution (50 mg). Serial blood samples were collected over 48 hours and analyzed by a validated HPLC assay using fluorescence detection. The f2 metric (similarity factor) was used to analyze the dissolution data. Correlation models were developed using pooled fraction dissolved (FRD) and fraction absorbed (FRA) data from various combinations of the formulations. Predicted metoprolol concentrations were obtained by convolution of the in vivo dissolution rates. Prediction errors were estimated for Cmax and AUC to determine the validity of the correlation. Results. Apparatus I operated at 150 rpm, and pH of 6.8 was found to be the most discriminating dissolution method. There was a significant linear relationship between FRD and FRA when using either two or three of the formulations. An average percent prediction error for Cmax and AUC for all formulations of less than 10% was found for all IVIVC models. Conclusions. The relatively low prediction errors for Cmax and AUC observed strongly suggest that the metoprolol IVIVC models are valid. The average percent prediction error of less than 10% indicates that the correlation is predictive and allows the associated dissolution data to be used as a surrogate for bioavailability studies.

Metabolites and bioequivalence: past and present.

Although it is widely recognised that measurement of metabolite concentrations is crucial to understanding the clinical pharmacology characteristics of a new molecular entity, a clear consensus on the role of metabolites in the assessment of bioequivalence has never been achieved within the scientific community. However, a regulatory policy for the role of metabolites in bioavailability and bioequivalence has been established by the US FDA. One school of thought believes that the parent drug alone is sensitive to picking up formulation differences, whereas another school of thought believes that establishing bioequivalence criteria on all the species that contribute to safety and efficacy is the only way to ensure the switchability of two products.In this paper, a brief review of the pharmacokinetics of metabolites under different scenarios is presented and the history of the role of metabolites in the assessment of bioequivalence is summarised. Relevant examples from the literature illustrating conflicting opinions on the need for the measurement of metabolites in bioequivalence studies are given. Cases from the literature in which the parent drug is able to meet the 90% confidence intervals while the metabolite(s) fail to do so, and vice versa, are presented to illustrate the difficulty in choosing the pertinent entity to measure. The relevant current US FDA policy and guidelines related to bioavailability and bioequivalence are discussed and contrasted with the rules and regulations applicable in Canada and Europe.

In Vivo Bioequivalence and In Vitro Similarity Factor (f2) for Dissolution Profile Comparisons of Extended Release Formulations: How and When Do They Match?

ABSTRACTPurposeTo investigate how likely two extended release formulations are to be bioequivalent when they demonstrate f2 similarity.MethodDissolution profiles were simulated using the Weibull model and varying model parameters around those of a reference profile. The f2 values were calculated for the comparisons of each simulation with the reference profile. The in vivo inputs obtained from an in vitro-in vivo correlation model were convolved with a unit impulse response function. The AUC, Cmax, and Tmax from each simulated in vivo concentration profile were compared to the reference profile. The AUCR (AUC ratio) and CmaxR (Cmax ratio) were determined. The consistency between f2 and bioequivalence was investigated.ResultsThe relationships between AUCR, CmaxR, f2 and the Weibull model parameters demonstrate that the bioequivalence regions enclosed by the contour lines of 80% and 125% of AUCR and CmaxR were generally close to the regions enclosed by the f2 = 50 contour line, but did not exactly match, especially when Dmax and B deviated from the reference values.ConclusionsWhen f2 is used for in vitro dissolution profile comparison, the completeness of the dissolution profiles should not differ more than 10%, and the shapes of the dissolution profiles should not be significantly different.

The product label: how pharmacokinetics and pharmacodynamics reach the prescriber.

The product label, or package insert, is the ‘manual’ for the safe and effective use of a drug. Important pharmacokinetic and pharmacodynamic properties of a drug product should appear in the label under specific sections, as required in the Code of Federal Regulations (CFR), using a format and language recommended by the Food and Drug Administration (FDA) in various guidances to the industry. The relevant regulations and guidance documents impacting on how this information is conveyed to the healthcare professional are discussed, with special emphasis on how the new proposed rule will impact upon how information is to be conveyed. With the availability of new clinical pharmacology information not available at the time of approval, package inserts for older drugs should be updated to reflect the new data and recommend the proper dosage regimen, enabling prescribers to optimise drug therapy and minimise possible adverse events.

Draft Guidance for Industry Extended-Release Solid Oral Dosage Forms

This draft guidance provides recommendations to pharmaceutical scientists related to various aspects of in vitro/in vivo correlations (IVIVC) for oral extended-release (ER) drug products particularly as utilized in the NDA/ANDA review process. It presents a comprehensive perspective on methods of developing IVIVC, appropriate means of evaluating the predictability of IVIVC, and relevant applications for IVIVC in the areas of changes (e.g., formulation, equipment, process, and manufacturing site) and setting dissolution specifications. To access the final guidance on the WWW, connect to theFDA home page at http://www.fda.gov/CDER/ and go to the “Regulatory Guidance” section.

History and Evolution of the Dissolution Test

INTRODUCTION The release of the drug substance from a solid dosage form has a major impact on its rate and extent of absorption. In certain instances, as is the case with modified-release formulations, the rate-limiting step in the appearance of the drug in the systemic circulation is its release from the formulation. In the vast majority of cases, in vitro dissolution of an immediate-release product is one of the most important tools in assuring the batch-to-batch quality of the drug product. Establishing appropriate dissolution specifications will assure that the manufacture of the dosage form is consistent and successful throughout the product’s life cycle and that each dosage unit within a batch will have the same pharmaceutical qualities that correspond to those shown to have an adequate safety and efficacy profile. Due to the critical role that dissolution plays in the bioavailability of the drug, in vitro dissolution can serve as a relevant predictor of the in vivo performance of the drug product. This article discusses the history as well as the evolution of dissolution and its role in the drug development and approval process

Industry Perspective on Standardizing Food-Effect Studies for New Drug Development

Investigating the effect of food on bioavailability during the development of an oral drug product is of prime importance because it has major implications on the study design of the clinical trials and dosing and administration recommendations. For modified-release formulations that exhibit dose dumping when administered with food, this may result in clinical concerns around safety and efficacy. In this article, we provide an overview of the various considerations in our opinion that impact the design and conduct of food-effect studies. We summarize the various recommendations from the different regulatory agencies and provide specific suggestions on study conduct in terms of statistical design, timing of studies, subject selection, and type and caloric content of the meal. We also discuss the role of modeling and simulation. Finally, we present an interpretation of the results of food-effect studies in addition to dosing and labeling recommendations in relation to regulatory guidance documents.

Applications of Clinically Relevant Dissolution Testing: Workshop Summary Report

This publication summarizes the proceedings of day 3 of a 3-day workshop on “Dissolution and Translational Modeling Strategies Enabling Patient-Centric Product Development.” Specifically, this publication discusses the current approaches in building clinical relevance into drug product development for solid oral dosage forms, along with challenges that both industry and regulatory agencies are facing in setting clinically relevant drug product specifications (CRDPS) as presented at the workshop. The concept of clinical relevance is a multidisciplinary effort which implies an understanding of the relationship between the critical quality attributes (CQAs) and their impact on predetermined clinical outcomes. Developing this level of understanding, in many cases, requires introducing deliberate but meaningful variations into the critical material attributes (CMAs) and critical process parameters (CPPs) to establish a relationship between the resulting in vitro dissolution/release profiles and in vivo PK performance, a surrogate for clinical outcomes. Alternatively, with the intention of improving the efficiency of the drug product development process by limiting the burden of conducting in vivo studies, this understanding can be either built, or at least enhanced, through in silico efforts, such as IVIVC and physiologically based pharmacokinetic (PBPK) absorption modeling and simulation (M&S). These approaches enable dissolution testing to establish safe boundaries and reject drug product batches falling outside of the established safe range (e.g., due to inadequate in vivo performance) enabling the method to become clinically relevant. Ultimately, these efforts contribute towards patient-centric drug product development and allow regulatory flexibility throughout the lifecycle of the drug product.

Application of Exposure-Response Analyses to Establish the Pharmacodynamic Similarity of a Once-Daily Regimen to an Approved Twice-Daily Dosing Regimen for the Treatment of HCV Infection

The triple direct-acting antiviral (3-DAA) regimen (two co-formulated tablets of ombitasvir/paritaprevir/ritonavir once daily and one tablet of dasabuvir twice daily) for patients with hepatitis C virus (HCV) genotype 1 infection has been reformulated for once-daily administration containing all three active DAAs (3QD regimen). Two bioequivalence studies compared the 3-DAA and 3QD regimens. In study 1, fed, single-, and multiple-dose crossover comparisons revealed exposures for drug components that were slightly outside the bioequivalence criteria, i.e., 21 to 29% lower dasabuvir Ctrough, paritaprevir Cmax, and ritonavir Cmax. In study 2, fed and fasted single-dose crossover comparisons demonstrated a large impact of food on exposures, confirming the product’s labeling requirement for administration only with food, and revealed a lack of bioequivalence under fasting conditions. Exposure-response analyses using efficacy data from phase 2/3 studies of the 3-DAA regimen demonstrated that the lower dasabuvir Ctrough for the 3QD regimen (under fed condition) would have minimal impact on sustained virologic response at week 12 post-treatment (SVR12). Thus, the pharmacodynamic similarity between the regimens was established and the analyses provided the basis for regulatory approval of the 3QD regimen to treat patients with chronic HCV genotype 1 infection.