Particle Size Distribution Equivalency as Novel Predictors for Bioequivalence
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The use of particle size distribution (PSD) similarity metrics and the development and incorporation of drug release predictions based on PSD properties into PBPK models for various drug administration routes may provide a holistic approach for evaluating the effect of PSD differences on in vitro drug release and bioavailability of disperse systems. The objectives of this study were to provide a rational approach for evaluating the utility of in vitro PSD comparators for predicting bioequivalence for subcutaneously administered test and reference drug emulsions. Two types of in vitro comparators for test and reference emulsion products were evaluated: PSD characterization comparators (overlap metrics, median, and span ratios) and release profile comparators (f2 and various fractional time ratios). A subcutaneous-input PBPK disposition model was developed to simulate blood concentration-time profiles of reference and test emulsion products and pharmacokinetic responses (e.g., AUC, Cmax, and Tmax) were used to determine bioequivalence. A pool of 10,440 pairs of test and reference products was simulated using Monte Carlo experiments. The PSD and release profile comparators were correlated to pass/fail bioequivalence metrics using logistical regression. Based on the use of single in vitro comparators, the f2 method was the best predictor of bioequivalence prediction. The use of combinations of f2 and PSD overlap comparators (e.g., OVL or PROB) improved bioequivalence prediction to about 90%. Simulation procedures used in this study demonstrated a process for developing reliable in vitro BE predictors.
KEY WORDSbioequivalence particle size distribution modeling and simulation emulsion subcutaneous administration PBPK
The authors gratefully acknowledge funding from the US‐FDA and the National Institute of Pharmaceutical Technology and Education through contract #5U01FD004275‐03; NIPTE‐2013‐002.
- 2.U.S. National Archives and Records Administration. Title 21: Food and drugs. Chapter1-Food and Drug Administration. Code of Federal Regulations: part 320-bioavailability and bioequivalence requirements. 2017.Google Scholar
- 3.Food and Drug Administration. Draft guidance on cyclosporine: emulsion form/ophthalmic route. 2013.Google Scholar
- 4.Azzalini A, Capitanio A. The skew-normal and related families: Cambridge University Press; 2014. URL https://www.R-project.org/
- 9.Valentin J. Basic Anatomical and Physiological data for use in radiological protection: reference values. A report of age- and gender-related differences in the anatomical and physiological characteristics of reference individuals. ICRP Publication 89. Ann ICRP. 2002;32(3–4):5–265.Google Scholar
- 12.Hospira. Propofol Injectable Emulsion. https://www.pattersonvet.com/msds/078889390.
- 21.Food and Drug Administration. Guidance for Industry: Bioequivalence Guidance. 2006.Google Scholar
- 23.Gastwirth JL. Statistical measures of earnings differentials. Am Stat. 1975;29(1):32–5.Google Scholar
- 24.Food and Drug Administration. Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products-General Considerations. 2003.Google Scholar
- 25.Food and Drug Administration. Guidance for Industry: immediate-release solid oral dosage forms: scale-up and post-approval changes: chemistry, manufacturing and controls, in vitro dissolution testing, and in vivo bioequivalence documentation. 1995.Google Scholar
- 26.Food and Drug Administration. Guidance for industry: Dissolution testing of immediate release solid oral dosage forms. 1997.Google Scholar
- 27.Food and Drug Administration. Guidance for Industry: SUPAC-MR: modified release solid oral dosage forms. Scale-up and post-approval changes: chemistry, manufacturing, and controls; in vitro dissolution testings and in vivo bioequivalence documentation. 1997.Google Scholar
- 28.Food and Drug Administration. Guidance for Industry: Extended release oral dosage forms: development, evaluation, and application of in vitro/in vivo correlations. 1997.Google Scholar
- 29.Moore JW, Flanner HH. Mathematical comparison of dissolution profiles. Pharm Technol. 1996:64–74.Google Scholar
- 36.Food and Drug Administration. Guidance for Industry: dissolution testing and specification criteria for immediate-release solid oral dosage forms containing biopharmaceutics classification system class 1 and 3 drugs. 2015.Google Scholar
- 37.Food and Drug Administration. Guidance for industry: statistical approaches to establishing bioequivalence. 2001.Google Scholar
- 54.National Center for Biotechnology Information. PubChem compound database. Available from: https://pubchem.ncbi.nlm.nih.gov/.
- 57.Shalizi CR. Logistic Regression. In: Advanced data analysis from an elementary point of view. Carnegie Mellon University; 2017. p. 251–280.Google Scholar