Pharm Res. 2021 Dec 21; doi: 10.1007/s11095-021-03136-3. Epub 2021 Dec 21.

Untangling Absorption Mechanisms and Variability in Bioequivalence Studies Using Population Analysis.

Pharmaceutical research

Carolina Ameijeiras Rodríguez, Sara Carolina Henriques, Aymara Sancho-Araiz, Iñaki F Trocóniz, Luis Almeida, Nuno Elvas Silva

PMID: 34932170 DOI: 10.1007/s11095-021-03136-3

Abstract

PURPOSE: Both inter-individual (IIV) and inter-occasion (IOV) variabilities are observed in bioequivalence studies. High IOV may be a cause of problems on the demonstration of bioequivalence, despite strict measures are taken to control it. The objective of this study is to investigate further means of controlling IIV by optimizing study design of crossover studies.

METHODS: Data from 18 bioequivalence studies were used to develop population pharmacokinetics (popPK) models to characterize the absorption and disposition processes of 14 drugs, to estimate IOV for each drug substance and to evaluate possible correlations with biopharmaceutical properties of drug substances, classified in accordance to the Biopharmaceutics Drug Disposition Classification System (BDDCS).

RESULTS: Plasma-pharmacokinetics profiles for the 14 drugs analyzed were successfully described using popPK. The pharmacokinetic parameters that showed greater variability were first-order rate constant of absorption, duration of the zero-order absorption process, relative bioavailability and time of latency. ISCV% estimated for C

CONCLUSION: Pharmacokinetic parameters related to drug absorption showed greater variability. Ingestion of the IMP along with 240 mL of water showed to standardize gastric emptying. Given the dependency between C

© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Keywords: BDDCS; bioequivalence; population pharmacokinetics

References

1. Yu A, Sun D, Li BV, Lawrence XY. Bioequivalence history. FDA Bioequivalence standards: Springer; 2014. p. 1-27. - PubMed
2. Amidon GL, Lennernas H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res. 1995;12(3):413–20. - PubMed
3. Wu C-Y, Benet LZ. Predicting Drug Disposition via Application of BCS: Transport/Absorption/ Elimination Interplay and Development of a Biopharmaceutics Drug Disposition Classification System. Pharm Res. 2005;22(1):11–23. - PubMed
4. European Medicines Agency (EMA). Guideline on the Investigation of Bioequivalence, Doc. Ref.: CPMP/EWP/QWP/1401/98 Rev. 1/ Corr., London, 20 January 2010 [Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC500070039.pdf . - PubMed
5. Midha KK, McKay G. Bioequivalence; its history, practice, and future. AAPS J. 2009;11(4):664–70. - PubMed
6. EMA. Guideline for good clinical practice E6 (R2) 2016 [Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/ich-e-6-r2-guideline-good-clinical-practice-step-5_en.pdf . - PubMed
7. Benet LZ, Broccatelli F, Oprea TI. BDDCS applied to over 900 drugs. AAPS J. 2011;13(4):519–47. - PubMed
8. ChemAxon MarvinSketch User’s Guide. [Available from: https://docs.chemaxon.com/display/docs/MarvinSketch_User's_Guide.html . - PubMed
9. Pires DEV, Blundell TL, Ascher DB (2015) pkCSM: Predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures. J Med Chem 58:4066–4072. [Available from: http://biosig.unimelb.edu.au/pkcsm/ . - PubMed
10. Ananchenko G, Novakovic J, Lewis J. Amlodipine besylate. Profiles of Drug Substances, Excipients and Related Methodology. 2012;37:31–77. - PubMed
11. (FDA) USFaDA. PROZAC (fluoxetine) Label 1987 [Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/018936s108lbl.pdf . - PubMed
12. Johnson BM, Chang P-TL. Sertraline hydrochloride. Analytical Profiles of Drug Substances and Excipients. 24: Elsevier; 1996. p. 443-86. - PubMed
13. (FDA) USFDA. SUTENT (sunitinib malate) Label 2006 [Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021938s037lbl.pdf . - PubMed
14. Xeljanz® (Tofacitinib) FDA Clinical Pharmacology and Biopharmaceutics Review [Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000ClinPharmR.pdf . - PubMed
15. ChemAxon - Software Solutions and Services for Chemistry & Biology [Available from: https://chemaxon.com/ . - PubMed
16. (FDA) USFaDA. Imbruvica (Ibrutinib) Label 2018 [Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/205552s033 ,210563s010lbl.pdf. - PubMed
17. Marzo A, Dal Bo L, Mazzucchellia P, Montia NC, Tettamantia RA, Crivellia F, et al. Pharmacokinetics and pharmacodynamics of zofenopril in healthy volunteers. Arzneimittel-Forschung. 1999;49(12):992–6. - PubMed
18. (FDA) USFaDA. Duraclon (clonidine hydrochloride) injection, solution 2010 [Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020615s003lbl.pdf . - PubMed
19. ALOGPS, Virtual Computational Chemistry Laboratory [Available from: http://www.vcclab.org/lab/alogps - PubMed
20. Greenblatt DJ, Wright CE. Clinical pharmacokinetics of alprazolam. Clin Pharmacokinet. 1993;24(6):453–71. - PubMed
21. (FDA) USFaDA. XANAX®(alprazolam) label 2021 [Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/018276s058lbl.pdf . - PubMed
22. Benet LZ, Broccatelli F, Oprea TI. BDDCS applied to over 900 drugs. The AAPS journal. 2011;13(4):519-47. Table IIb.Pharmacokinetic properties Click here to access/download;Table;Table IIb.Pharmacokinetic properties.pdf - PubMed
23. (FDA) USFaDA. Norvasc (Amlodipine besylate) label 2017 [Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/019787s062lbl.pdf . - PubMed
24. Perez-Caballero L, Torres-Sanchez S, Bravo L, Mico JA, Berrocoso E. Fluoxetine: a case history of its discovery and preclinical development. Expert Opin Drug Discovery. 2014;9(5):567–78. - PubMed
25. Altamura AC, Moro AR, Percudani M. Clinical pharmacokinetics of fluoxetine. Clin Pharmacokinet. 1994;26(3):201–14. - PubMed
26. De Vane CL, Liston HL, Markowitz JS. Clinical pharmacokinetics of sertraline. Clin Pharmacokinet. 2002;41(15):1247–66. - PubMed
27. Zoloft (sertraline hydrochloride)_biopharmr. 1998 [Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/99/20990_Zoloft_biopharmr.pdf . - PubMed
28. Haznedar JÖ, Patyna S, Bello CL, Peng GW, Speed W, Yu X, et al. Single-and multiple-dose disposition kinetics of sunitinib malate, a multitargeted receptor tyrosine kinase inhibitor: comparative plasma kinetics in non-clinical species. Cancer Chemother Pharmacol. 2009;64(4):691–706. - PubMed
29. Speed B, Bu H-Z, Pool WF, Peng GW, Wu EY, Patyna S, et al. Pharmacokinetics, distribution, and metabolism of [14C] sunitinib in rats, monkeys, and humans. Drug Metab Dispos. 2012;40(3):539–55. - PubMed
30. Arcoxia 120 mg Film-coated Tablets SmPC, Last revised version, MAY2021 [Available from: https://www.medicines.org.uk/emc/product/10618/smpc . - PubMed
31. Febuxostat_Adenuric SmPC [Available from: https://www.medicines.org.uk/emc/product/1925/smpc#gref . - PubMed
32. Mylan. Zofenopril Mylan film-coated tablet ENG SmPC [Available from: https://mri.ctsmrpeu/human/downloads/PT_H_1446_001_FinalPI_1of4.pdf . - PubMed
33. Catapres®. Prescribing Information. Last revised version, MAY2015 2009 [Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/017407s037lbl.pdf . - PubMed
34. Niemeyer C, Hasenfuss G, Wais U, Knauf H, Schäfer-Korting M, Mutschler E. Pharmacokinetics of hydrochlorothiazide in relation to renal function. Eur J Clin Pharmacol. 1983;24(5):661–5. - PubMed
35. FDA Approved Drug Products: Hydrochlorothiazide Oral Capsules [Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020504s018lbl.pdf . - PubMed
36. Avelox®. Prescribing Information. Last revised version, JUL2016 [Available from: https://www.merck.com/product/usa/pi_circulars/a/avelox/avelox_pi.pdf . - PubMed
37. (FDA) USFaDA. AVELOX (moxifloxacin hydrochloride) Label 1999 [Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021085s063lbl.pdf . - PubMed
38. Hylaton 50mg Tablets - Summary of Product Characteristics (SmPC) - PubMed
39. Collste P, Garle M, Rawlins M, Sjöqvist F. Interindividual differences in chlorthalidone concentration in plasma and red cells of man after single and multiple doses. Eur J Clin Pharmacol. 1976;9(4):319–25. - PubMed
40. Mould DR, Upton RN. Basic concepts in population modeling, simulation, and model-based drug development-part 2: introduction to pharmacokinetic modeling methods. CPT Pharmacometrics Syst Pharmacol. 2013;2:e38. - PubMed
41. Upton RN, Mould DR. Basic concepts in population modeling, simulation, and model-based drug development: part 3-introduction to pharmacodynamic modeling methods. CPT Pharmacometrics Syst Pharmacol. 2014;3:e88. - PubMed
42. FDA. FDA Guidance for Industry: Population Pharmacokinetics. U.S. Department of Health and Human Services Food and Drug Administration 1999 [Available from: https://www.fda.gov/downloads/drugs/guidances/UCM072137.pdf . - PubMed
43. Faulkner J, McGibney D, Chasseaud L, Perry J, Taylor I. The pharmacokinetics of amlodipine in healthy volunteers after single intravenous and oral doses and after 14 repeated oral doses given once daily. Br J Clin Pharmacol. 1986;22(1):21–5. - PubMed
44. Meredith PA, Elliott HL. Clinical pharmacokinetics of amlodipine. Clin Pharmacokinet. 1992;22(1):22–31. - PubMed
45. (FDA) USFaDA. XELJANZ (tofacitinib) Label 2012 [Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000ClinPharmR.pdf . - PubMed
46. Agrawal NG, Porras AG, Matthews CZ, Rose MJ, Woolf EJ, Musser BJ, et al. Single-and multiple-dose pharmacokinetics of etoricoxib, a selective inhibitor of cyclooxygenase-2, in man. J Clin Pharmacol. 2003;43(3):268–76. - PubMed
47. (FDA) USFaDA. Uloric (febuxostat) tablet for oral use 2009 [Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/021856s000_ClinPharmR_P2.pdf . s037lbl.pdf. - PubMed
48. Dressman J, Amidon G, Fleisher D. Absorption potential: estimating the fraction absorbed for orally administered compounds. J Pharm Sci. 1985;74(5):588–9. - PubMed
49. Shum B, Duffull S, Taylor P, Tett S. Population pharmacokinetic analysis of mycophenolic acid in renal transplant recipients following oral administration of mycophenolate mofetil. Br J Clin Pharmacol. 2003;56(2):188–97. - PubMed
50. Chryssafidis P, Tsekouras AA, Macheras P. Revising Pharmacokinetics of Oral Drug Absorption: II Bioavailability-Bioequivalence Considerations. Pharm Res. 2021:1–12. - PubMed
51. Macheras P, Chryssafidis P. Revising Pharmacokinetics of Oral Drug Absorption: I Models Based on Biopharmaceutical/Physiological and Finite Absorption Time Concepts. Pharm Res. 2020;37(10):1–13. - PubMed
52. Rinaki E, Valsami G, Macheras P. Quantitative biopharmaceutics classification system: The central role of dose/solubility ratio. Pharm Res. 2003;20(12):1917–25. - PubMed
53. Rinaki E, Dokoumetzidis A, Macheras P. The mean dissolution time depends on the dose/solubility ratio. Pharm Res. 2003;20(3):406–8. - PubMed
54. Charkoftaki G, Dokoumetzidis A, Valsami G, Macheras P. Elucidating the role of dose in the biopharmaceutics classification of drugs: the concepts of critical dose, effective in vivo solubility, and dose-dependent BCS. Pharm Res. 2012;29(11):3188–98. - PubMed
55. Charalabidis A, Sfouni M, Bergström C, Macheras P. The biopharmaceutics classification system (BCS) and the biopharmaceutics drug disposition classification system (BDDCS): beyond guidelines. Int J Pharm. 2019;566:264–81. - PubMed
56. Macheras PE, Symillides MY. Toward a quantitative approach for the prediction of the fraction of dose absorbed using the absorption potential concept. Biopharm Drug Dispos. 1989;10(1):43–53. - PubMed
57. Romanski KW. Importance of the enteric nervous system in the control of the migrating motility complex. Physiol Int. 2017;104(2):97–129. - PubMed
58. Deloose E, Janssen P, Depoortere I, Tack J. The migrating motor complex: control mechanisms and its role in health and disease. Nat Rev Gastroenterol Hepatol. 2012;9(5):271. - PubMed
59. Code CF, Marlett JA. The interdigestive myo-electric complex of the stomach and small bowel of dogs. J Physiol. 1975;246(2):289–309. - PubMed
60. Administration F-USDoHaHSFaD, (CDER) CfDEaR. Bioequivalence Studies with Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA-Guidance for Industry 2013 [Available from: https://www.fda.gov/downloads/drugs/guidances/ucm377465.pdf . - PubMed
61. Kim KA, Park PW, Park JY. Effect of ABCB1 (MDR1) haplotypes derived from G2677T/C3435T on the pharmacokinetics of amlodipine in healthy subjects. Br J Clin Pharmacol. 2007;63(1):53–8. - PubMed
62. Katoh M, Nakajima M, Yamazaki H, Yokoi T. Inhibitory potencies of 1, 4-dihydropyridine calcium antagonists to P-glycoprotein-mediated transport: comparison with the effects on CYP3A4. Pharm Res. 2000;17(10):1189–97. - PubMed
63. O'Brien FE, Dinan TG, Griffin BT, Cryan JF. Interactions between antidepressants and P-glycoprotein at the blood–brain barrier: clinical significance of in vitro and in vivo findings. Br J Pharmacol. 2012;165(2):289–312. - PubMed
64. Weiss J, Dormann S-MG, Martin-Facklam M, Kerpen CJ, Ketabi-Kiyanvash N, Haefeli WE. Inhibition of P-glycoprotein by newer antidepressants. J Pharmacol Exp Ther. 2003;305(1):197–204. - PubMed
65. Boxberger KH, Hagenbuch B, Lampe JN. Ligand-dependent modulation of hOCT1 transport reveals discrete ligand binding sites within the substrate translocation channel. Biochem Pharmacol. 2018;156:371–84. - PubMed
66. Finch A, Pillans P. P-glycoprotein and its role in drug-drug interactions. Aust Prescr. 2014;37(4):137–9. - PubMed
67. Kapoor A, Iqbal M, Petropoulos S, Ho HL, Gibb W, Matthews SG. Effects of sertraline and fluoxetine on p-glycoprotein at barrier sites: in vivo and in vitro approaches. PLoS One. 2013;8(2):e56525. - PubMed
68. Feng S, Zheng L, Tang S, Gu J, Jiang X, Wang L. In-vitro and in situ assessment of the efflux of five antidepressants by breast cancer resistance protein. J Pharm Pharmacol. 2019;71(7):1133–41. - PubMed
69. Tang SC, Lagas JS, Lankheet NA, Poller B, Hillebrand MJ, Rosing H, et al. Brain accumulation of sunitinib is restricted by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) and can be enhanced by oral elacridar and sunitinib coadministration. Int J Cancer. 2012;130(1):223–33. - PubMed
70. Shukla S, Robey RW, Bates SE, Ambudkar SV. Sunitinib (Sutent, SU11248), a small-molecule receptor tyrosine kinase inhibitor, blocks function of the ATP-binding cassette (ABC) transporters P-glycoprotein (ABCB1) and ABCG2. Drug Metab Dispos. 2009;37(2):359–65. - PubMed
71. Hu S, Chen Z, Franke R, Orwick S, Zhao M, Rudek MA, et al. Interaction of the multikinase inhibitors sorafenib and sunitinib with solute carriers and ATP-binding cassette transporters. Clin Cancer Res. 2009;15(19):6062–9. - PubMed
72. Gao Y-l, He B. ABCB1 1199G> A Polymorphism Affects the Intracellular Accumulation of Antidepressants in LLC-PK1 Recombinant Cell Lines. DNA Cell Biol. 2018;37(12):1055–60. - PubMed
73. Poller B, Wagenaar E, Tang SC, Schinkel AH. Double-transduced MDCKII cells to study Human P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) interplay in drug transport across the blood− brain barrier. Mol Pharm. 2011;8(2):571–82. - PubMed
74. Benet LZ. The role of BCS (biopharmaceutics classification system) and BDDCS (biopharmaceutics drug disposition classification system) in drug development. J Pharm Sci. 2013;102(1):34–42. - PubMed
75. Wu X, Huang W, Ganapathy ME, Wang H, Kekuda R, Conway SJ, et al. Structure, function, and regional distribution of the organic cation transporter OCT3 in the kidney. American Journal of Physiology-Renal Physiology. 2000;279(3):F449–F58. - PubMed
76. Yabuuchi H, Tamai I, Nezu J-I, Sakamoto K, Oku A, Shimane M, et al. Novel membrane transporter OCTN1 mediates multispecific, bidirectional, and pH-dependent transport of organic cations. J Pharmacol Exp Ther. 1999;289(2):768–73. - PubMed
77. Hasegawa M, Kusuhara H, Adachi M, Schuetz JD, Takeuchi K, Sugiyama Y. Multidrug resistance–associated protein 4 is involved in the urinary excretion of hydrochlorothiazide and furosemide. J Am Soc Nephrol. 2007;18(1):37–45. - PubMed
78. Race JE, Grassl SM, Williams WJ, Holtzman EJ. Molecular cloning and characterization of two novel human renal organic anion transporters (hOAT1 and hOAT3). Biochem Biophys Res Commun. 1999;255(2):508–14. - PubMed
79. EMA. Guideline on the Investigation of Bioequivalence 2010 [Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC500070039.pdf . - PubMed

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