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1.  Challenges and Opportunities in Achieving Bioequivalence for Fixed-Dose Combination Products 
The AAPS Journal  2012;14(3):646-655.
Fixed-dose combination (FDC) products are becoming a popular treatment option because of increased patient compliance and convenience, improved clinical effectiveness, and reduced cost to the patient, among several other reasons. A commonly applied approach for approval of a FDC product is demonstrating bioequivalence between the FDC and co-administration of individual mono-products, provided that there is adequate safety and efficacy data for co-administration of the individual agents. However, achieving bioequivalence between the FDC and individual mono-products can be very challenging, and sometimes not possible since combining multiple active ingredients, especially insoluble molecules, in a single drug product could complicate its biopharmaceutical and pharmacokinetic behavior. In this review, some of the major challenges often encountered while assessing bioequivalence during FDC development will be presented along with discussion of future opportunities to facilitate FDC development and approval.
doi:10.1208/s12248-012-9378-x
PMCID: PMC3385830  PMID: 22684403
bioequivalence; fixed-dose combination; formulation; pharmacokinetics
2.  Model-Based Decision Making in Early Clinical Development: Minimizing the Impact of a Blood Pressure Adverse Event 
The AAPS Journal  2009;11(1):99-108.
We describe how modeling and simulation guided program decisions following a randomized placebo-controlled single-rising oral dose first-in-man trial of compound A where an undesired transient blood pressure (BP) elevation occurred in fasted healthy young adult males. We proposed a lumped-parameter pharmacokinetic–pharmacodynamic (PK/PD) model that captured important aspects of the BP homeostasis mechanism. Four conceptual units characterized the feedback PD model: a sinusoidal BP set point, an effect compartment, a linear effect model, and a system response. To explore approaches for minimizing the BP increase, we coupled the PD model to a modified PK model to guide oral controlled-release (CR) development. The proposed PK/PD model captured the central tendency of the observed data. The simulated BP response obtained with theoretical release rate profiles suggested some amelioration of the peak BP response with CR. This triggered subsequent CR formulation development; we used actual dissolution data from these candidate CR formulations in the PK/PD model to confirm a potential benefit in the peak BP response. Though this paradigm has yet to be tested in the clinic, our model-based approach provided a common rational framework to more fully utilize the limited available information for advancing the program.
doi:10.1208/s12248-009-9083-6
PMCID: PMC2664884  PMID: 19199043
drug development; PK/PD model; phase I clinical trial
4.  Understanding the Effect of API Properties on Bioavailability Through Absorption Modeling 
The AAPS Journal  2008;10(4):516-525.
Selection of API phase is one of the first decision points in the formulation development process. Subsequent to phase selection, the focus shifts to the API physical properties such as particle size. Oftentimes, such properties are closely monitored throughout the drug development, as they can have a direct impact on the formulation bioperformance. The purpose of this mini-review was to describe the potential for application of absorption modeling in understanding the effect of API properties on bioavailability. Examples are provided to demonstrate how absorption modeling can be applied both early on to set the formulation strategy as well as during the development process to help with setting of specifications around the API. Limitations of the existing models and areas of possible expansion of such tools are also discussed.
doi:10.1208/s12248-008-9061-4
PMCID: PMC2628211  PMID: 19002590
absorption modeling; API properties; bioavailability; formulation; oral absorption
5.  Summary Workshop Report: Bioequivalence, Biopharmaceutics Classification System, and Beyond 
The AAPS Journal  2008;10(2):373-379.
The workshop “Bioequivalence, Biopharmaceutics Classification System, and Beyond” was held May 21–23, 2007 in North Bethesda, MD, USA. This workshop provided an opportunity for pharmaceutical scientists to discuss the FDA guidance on the Biopharmaceutics Classification System (BCS), bioequivalence of oral products, and related FDA initiatives such as the FDA Critical Path Initiative. The objective of this Summary Workshop Report is to document the main points from this workshop. Key highlights of the workshop were (a) the described granting of over a dozen BCS-based biowaivers by the FDA for Class I drugs whose formulations exhibit rapid dissolution, (b) continued scientific support for biowaivers for Class III compounds whose formulations exhibit very rapid dissolution, (c) scientific support for a number of permeability methodologies to assess BCS permeability class, (d) utilization of BCS in pharmaceutical research and development, and (e) scientific progress in in vitro dissolution methods to predict dosage form performance.
doi:10.1208/s12248-008-9040-9
PMCID: PMC2751390  PMID: 18679807
bioavailability; bioequivalence; biopharmaceutics classification system (BCS); oral absorption; permeability; regulatory science; solubility

Results 1-5 (5)