Biopharmaceutics Applications of Physiologically Based Pharmacokinetic Absorption Modeling and Simulation in Regulatory Submissions to the U.S. Food and Drug Administration for New Drugs.

Physiologically based pharmacokinetic (PBPK) absorption modeling and simulation is increasingly used as a tool in drug product development, not only in support of clinical pharmacology applications (e.g., drug-drug interaction, dose selection) but also from quality perspective, enhancing drug product understanding.

A Biopharmetrics Approach for Drug Product Quality Control with Clinical Relevance.

To exemplify a systematic and quantitative approach (Biopharmetrics approach) for product quality control with clinical relevance, the study utilized multivariate models to connect raw material attributes of a product to its dissolution obtained in a DOE (design of experiment) and further extended the connection to the in vivo exposures (AUC and Cmax) of the product using an available IVIVC (in vitro/in vivo correlation). Thus, a model for the relationship between in vivo exposure and raw material attributes of the product was established. Based on the model, the exposure ratios between future batches (with various raw material attributes) and the pivotal clinical batches (with confirmed clinical efficacy and safety) were predicted resulting in a set of contour lines in a graphical representation.

Dissolution Edge Charts for Immediate Release Products and Their Applications: a Simulation Study to Aid the Setting of Specifications.

One of the most commonly used methods to establish the clinical relevance of dissolution is to align the dissolution specifications with pivotal clinical batches. The objective of the study was to create edge charts for the dissolution of immediate release (IR) drug products to quantitatively establish the bases for setting clinically relevant and discriminating dissolution specifications and to clarify which stage in the US Pharmacopoeia (USP) <711> acceptance tables should be targeted. The simulations of dissolution data were performed on a batch of IR products with 1,000,000 units.

Scientific and Regulatory Considerations in Solid Oral Modified Release Drug Product Development.

This review presents scientific and regulatory considerations for the development of solid oral modified release (MR) drug products. It includes a rationale for patient-focused development based on Quality-by-Design (QbD) principles. Product and process understanding of MR products includes identification and risk-based evaluation of critical material attributes (CMAs), critical process parameters (CPPs), and their impact on critical quality attributes (CQAs) that affect the clinical performance.

Regulatory Experience with In Vivo In Vitro Correlations (IVIVC) in New Drug Applications.

In the past two decades, in vitro in vivo correlation (IVIVC) has been considered an important tool for supporting biowaivers, setting dissolution acceptance criteria, and more recently in the Quality by Design (QbD) framework promoting the establishment of clinically meaningful drug product specifications using dissolution as the endpoint. Based on our review experience at the FDA, for the purposes of this article, we analyzed the current state of regulatory submissions containing IVIVC approaches and discussed the successes and failures from the perspectives of study design to methodology. In the past decade, the overall acceptance rate of the IVIVC submissions is about 40%.

Application of Physiologically Based Absorption Modeling to Characterize the Pharmacokinetic Profiles of Oral Extended Release Methylphenidate Products in Adults.

A previously presented physiologically-based pharmacokinetic model for immediate release (IR) methylphenidate (MPH) was extended to characterize the pharmacokinetic behaviors of oral extended release (ER) MPH formulations in adults for the first time. Information on the anatomy and physiology of the gastrointestinal (GI) tract, together with the biopharmaceutical properties of MPH, was integrated into the original model, with model parameters representing hepatic metabolism and intestinal non-specific loss recalibrated against in vitro and in vivo kinetic data sets with IR MPH. A Weibull function was implemented to describe the dissolution of different ER formulations.

Regulatory Perspectives on Strength-Dependent Dissolution Profiles and Biowaiver Approaches for Immediate Release (IR) Oral Tablets in New Drug Applications.

Dissolution profile comparisons are used by the pharmaceutical industry to assess the similarity in the dissolution characteristics of two formulations to decide whether the implemented changes, usually minor/moderate in nature, will have an impact on the in vitro/in vivo performance of the drug product. When similarity testing is applied to support the approval of lower strengths of the same formulation, the traditional approach for dissolution profile comparison is not always applicable for drug products exhibiting strength-dependent dissolution and may lead to incorrect conclusions about product performance. The objective of this article is to describe reasonable biopharmaceutic approaches for developing a biowaiver strategy for low solubility, proportionally similar/non-proportionally similar in composition immediate release drug products that exhibit strength-dependent dissolution profiles.

Applications of In Vitro-In Vivo Correlations in Generic Drug Development: Case Studies.

In vitro-in vivo correlation (IVIVC) is a predictive mathematical model describing the relationship between an in vitro property and a relevant in vivo response. The main objective of an IVIVC is to serve as a surrogate for human bioequivalence (BE) studies, which may reduce the number of BE studies performed during the initial approval process as well as with certain scale-up and postapproval changes. The US Food and Drug Administration (FDA) published a regulatory guidance related to development, evaluation, and applications of IVIVC for extended-release (ER) oral dosage forms in September 1997.

Influence of drug property and product design on in vitro-in vivo correlation of complex modified-release dosage forms.

The present study examines how drug's inherent properties and product design influence the evaluation and applications of in vitro-in vivo correlation (IVIVC) for modified-release (MR) dosage forms consisting of extended-release (ER) and immediate-release (IR) components with bimodal drug release. Three analgesic drugs were used as model compounds, and simulations of in vivo pharmacokinetic profiles were conducted using different release rates of the ER component and various IR percentages. Plasma concentration-time profiles exhibiting a wide range of tmax and maximum observed plasma concentration (Cmax) were obtained from superposition of the simulated IR and ER profiles based on a linear IVIVC.

Vandetanib for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease: U.S. Food and Drug Administration drug approval summary.

On April 6, 2011, the U.S. Food and Drug Administration approved vandetanib (Caprelsa tablets; AstraZeneca Pharmaceuticals LP) for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable, locally advanced, or metastatic disease.

In vivo bioequivalence and in vitro similarity factor (f2) for dissolution profile comparisons of extended release formulations: how and when do they match?

Purpose: To investigate how likely two extended release formulations are to be bioequivalent when they demonstrate f2 similarity.

Method: Dissolution 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.

Bioavailability considerations in evaluating drug-drug interactions using the population pharmacokinetic approach.

Applying a comedication (COMD) covariate to apparent clearance (CL(app) = CL/F) is a common practice when using population pharmacokinetics (PopPK) to study metabolism-based drug-drug interactions (DDI). This study evaluates the importance of independently applying COMD to F and CL to account for DDI at the level of first-pass metabolism. A known DDI between single oral doses of the CYP3A substrate midazolam (5 mg) and the inhibitor ketoconazole (400 mg) was simulated using a physiologically based pharmacokinetic simulator SimCyp in virtual subjects.

Drug-drug interaction pattern recognition.

Background And Objective: Drug-drug interaction (DDI) is an important aspect of drug development, especially for safety. When a drug is used concomitantly with other drug(s), one of the major concerns is the change of exposures, including the rate and extent of drug absorption, distribution, metabolism and elimination. To address the concerns, a common practice is to measure and report the differences between the exposure in the presence and in the absence of concomitant medication (COMED).

Two commonly used methods for exposure-adverse events analysis: comparisons and evaluations.

The purpose of this study is to compare and evaluate logistic regression and time-to-event analysis, 2 commonly used methods for exposure-adverse event (AE) analyses. An AE data set selected from clinical trials is analyzed by both methods and the results are compared. The parameter estimates, odds ratios for logistic regression, and hazard ratios for time-to-event analysis for each AE are compared and further analyzed.

Population pharmacokinetics with a very small sample size.

The objective of this study was to evaluate whether pharmacokinetic parameters (clearance and volume of distribution of the central compartment) from a sparse sampling population pharmacokinetic study can be obtained with a very small sample size. For this study, three drugs were selected from the literature. The pharmacokinetics of all three drugs were studied in healthy adult subjects and plasma concentrations versus time data for individual subjects from extensive blood sampling were available.

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.

Approval summary for erlotinib for treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen.

Purpose: To describe the Food and Drug Administration (FDA) review and approval of erlotinib (Tarceva, OSI Pharmaceuticals, Melville, NY) for treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one prior chemotherapy regimen.

Experimental Design: The FDA reviewed raw data in electronic format from a randomized controlled clinical trial comparing erlotinib with placebo in patients with locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen.

Results: Patients were randomized in a 2:1 ratio (erlotinib, n = 488 and placebo, n = 243).

Approval summary for imatinib mesylate capsules in the treatment of chronic myelogenous leukemia.

Purpose: Chronic myelogenous leukemia (CML) results from the breakpoint cluster region-Abl fusion gene product, a tyrosine kinase involved in cell division and apoptosis. Imatinib, an orally administered inhibitor of the breakpoint cluster region-Abl tyrosine kinase, is capable of blocking proliferation and inducing apoptosis in CML cell lines. In this report, we describe the preclinical profile of imatinib and the data submitted in the New Drug Application that led to its marketing approval.