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A Case Study of In Silico Modelling of Ciprofloxacin Hydrochloride/Metallic Compound Interactions

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Abstract

With the development of physiologically based absorption models, there is an increased scientific and regulatory interest in in silico modelling and simulation of drug–drug and drug–food interactions. Clinically significant interactions between ciprofloxacin and metallic compounds are widely documented. In the current study, a previously developed ciprofloxacin-specific in silico absorption model was employed in order to simulate ciprofloxacin/metallic compound interaction observed in vivo. Commercially available software GastroPlus™ (Simulations Plus Inc., USA) based on the ACAT model was used for gastrointestinal (GI) simulations. The required input parameters, relating to ciprofloxacin hydrochloride physicochemical and pharmacokinetic characteristics, were experimentally determined, taken from the literature or estimated by GastroPlus™. Parameter sensitivity analysis (PSA) was used to assess the importance of selected input parameters (solubility, permeability, stomach and small intestine transit time) in predicting percent drug absorbed. PSA identified solubility and permeability as critical parameters affecting the rate and extent of ciprofloxacin absorption. Using the selected input parameters, it was possible to generate a ciprofloxacin absorption model, without/with metal cation containing preparations co-administration, which matched well the in vivo data available. It was found that reduced ciprofloxacin absorption in the presence of aluminium hydroxide, calcium carbonate or multivitamins/zinc was accounted for by reduced drug solubility. The impact of solubility–permeability interplay on ciprofloxacin absorption can be observed in the ciprofloxacin–aluminium interaction, while in ciprofloxacin–calcium and ciprofloxacin–zinc interactions, effect of solubility was more pronounced. The results obtained indicate that in silico model developed can be successfully used to complement relevant in vitro studies in the simulation of physicochemical ciprofloxacin/metallic compound interactions.

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REFERENCES

  1. 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;12:413–20. doi:10.1023/A:1016212804288.

    Article  PubMed  CAS  Google Scholar 

  2. Agoram B, Woltosz WS, Bolger MB. Predicting the impact of physiological and biochemical processes on oral drug bioavailability. Adv Drug Deliv Rev. 2001;50(Supple 1):S41–67. doi:10.1016/S0169-409X(01)00179-X.

    Article  PubMed  CAS  Google Scholar 

  3. Zhang X, Lionberger RA, Davit BM, Yu LX. Utility of physiologically based absorption modeling in implementing quality by design in drug development. AAPS J. 2011;13:59–71. doi:10.1208/s12248-010-9250-9.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  4. Zhang L, Zhang YD, Zhao P, Huang S. Predicting drug–drug interactions: an FDA perspective. AAPS J. 2009;11:300–6. doi:10.1208/s12248-009-9106-3.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  5. Prueksaritanont T, Chu X, Gibson C, Cui D, Yee KL, Ballard J, et al. Drug–drug interaction studies: regulatory guidance and an industry perspective. AAPS J. 2013;15:629–45. doi:10.1208/s12248-013-9470-x.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  6. Parrott N, Lukacova V, Fraczkiewicz G, Bolger MB. Predicting pharmacokinetics of drugs using physiologically based modeling—application to food effects. AAPS J. 2009;11:45–53. doi:10.1208/s12248-008-9079-7.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  7. Okumu A, Di Maso M, Lobenberg R. Computer simulations using GastroPlus™ to justify a biowaiver for etoricoxib solid oral drug products. Eur J Pharm Biopharm. 2009;72:91–8. doi:10.1016/j.ejpb.2008.10.019.

    Article  PubMed  CAS  Google Scholar 

  8. Lukacova V, Woltosz WS, Bolger MB. Prediction of modified release pharmacokinetics and pharmacodynamics from in vitro, immediate release, and intravenous data. AAPS J. 2009;11:323–34. doi:10.1208/s12248-009-9107-2.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  9. Kuentz M, Nick S, Parrott N, Rothlisberger D. A strategy for preclinical formulation development using GastroPlus as pharmacokinetic simulation tool and a statistical screening design applied to a dog study. Eur J Pharm Sci. 2006;27:91–9. doi:10.1016/j.ejps.2005.08.011.

    Article  PubMed  CAS  Google Scholar 

  10. Harder S, Fuhr U, Beermann D, Staib AH. Ciprofloxacin absorption in different regions of the human gastrointestinal tract. Investigations with hf-capsule. Brit J Clin Pharmacol. 1990;30:35–9. doi:10.1111/j.1365-2125.1990.tb03740.x.

    Article  CAS  Google Scholar 

  11. Lehto P, Kivisto TK, Neuvonen JP. The effect of ferrous sulphate on the absorption of norfloxacin, ciprofloxacin and ofloxacin. Brit J Clin Pharmacol. 1994;37:82–5. doi:10.1111/j.1365-2125.1994.tb04245.x.

    Article  CAS  Google Scholar 

  12. Kara M, Hasinoff BB, McKay WD, Campbell RCN. Clinical and chemical interactions between iron preparations and ciprofloxacin. Brit J Clin Pharmacol. 1991;31:257–61. doi:10.1111/j.1365-2125.1991.tb05526.x.

    Article  CAS  Google Scholar 

  13. Polk RE, Healy DP, Sahai J, Drwal L, Racht E. Effect of ferrous sulfate and multivitamins with zinc on absorption of ciprofloxacin in normal volunteers. Antimicrob Agents Chemother. 1989;33:1841–4. doi:10.1128/AAC.33.11.1841.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  14. Frost RW, Lettieri JT, Noe A, Shamblen EC, Lasseter K. Effect of aluminium hydroxide and calcium carbonate antacids on ciprofloxacin bioavailability. Antimicrob Agents Chemother. 1992;36:830–2. doi:10.1128/AAC.36.4.830.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  15. Lode H. Drug interactions with quinolones. Clin Infect Dis. 1992;10:S136.

    Google Scholar 

  16. Dahan A, Miller JM. The solubility–permeability interplay and its implications in formulation design and development for poorly soluble drugs. AAPS J. 2012;14:244–51. doi:10.1208/s12248-012-9337-6.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  17. Parojčić J, Stojković A, Tajber L, Grbić S, Paluch K, Đurić Z, et al. Biopharmaceutical characterization of ciprofloxacin HCl–ferrous sulfate interaction. J Pharm Sci. 2011;100:5174–84. doi:10.1002/jps.22707.

    Article  PubMed  CAS  Google Scholar 

  18. Ljungberg B, Nilsson-Ehle I. Pharmacokinetics of intravenous ciprofloxacin at three different doses. J Antimicrob Chemother. 1988;22:715–20. doi:10.1093/jac/22.5.715.

    Article  PubMed  CAS  Google Scholar 

  19. Cipro Labeling Revision 04/06/2009 Supplement 073. US Food and Drug Administration. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019537s073,020780s030lbl.pdf. Accessed Sep 2009.

  20. Kasim NA, Whitehouse M, Ramachandran C, Bermejo M, Lennernas H, Hussain AS, et al. Molecular properties of WHO essential drugs and provisional biopharmaceutical classification. Mol Pharm. 2004;1:85–96. doi:10.1021/mp034006h.

    Article  PubMed  CAS  Google Scholar 

  21. pION INC. Molecule of the month—ciprofloxacin HCl. 2003. http://www.pioninc.com/molecules/ciprofloxacin2.pdf. Accessed 1 Oct 2008

  22. Bergan T. Extravascular penetration of ciprofloxacin. Diagn Microbiol Infect Dis. 1990;13:103–4. doi:10.1016/0732-8893(90)90093-B.

    Article  PubMed  CAS  Google Scholar 

  23. Schiller C, Frohlich CP, Giessmann T, Siegmund W, Monnikes H, Hosten N, et al. Intestinal fluid volumes and transit of dosage forms as assessed by magnetic resonance imaging. Aliment Pharmacol Ther. 2005;22:971–9. doi:10.1111/j.1365-2036.2005.02683.x.

    Article  PubMed  CAS  Google Scholar 

  24. Perez de la Cruz Moreno M, Oth M, Deferme S, Lammert F, Tack J, Dressman J, et al. Characterization of fasted-state human intestinal fluids collected from duodenum and jejunum. J Pharm Pharmacol. 2006;58:1079–89. doi:10.1211/jpp.58.8.0009.

    Article  PubMed  CAS  Google Scholar 

  25. Center for Drug Evaluation and Research; Food and Drug Administration. Guidance for Industry. Extended release oral dosage forms: development, evaluation, and application of in vitro/in vivo correlations. 1997. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070239.pdf

  26. Wilson CG. Gastrointestinal transit and drug absorption. In: Dressman JB, Lennernas H, editors. Oral drug absorption. Prediction and assessment. USA: Marcel Dekker; 2000. p. 1–11.

    Google Scholar 

  27. Yu LX, Crison JR, Amidon GL. Compartmental transit and dispersion model analysis of small intestinal transit flow in humans. Int J Pharm. 1996;140:111–8. doi:10.1016/0378-5173(96)04592-9.

    Article  CAS  Google Scholar 

  28. Hoffken G, Lode H, Prinzing C, Borner K, Koeppem P. Pharmacokinetics of ciprofloxacin after oral and parenteral administration. Antimicrob Agents Chemother. 1985;27:375–9. doi:10.1128/AAC.27.3.375.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  29. Bergan T, Thorsteinsson SB, Kolstad IM, Johnsen S. Pharmacokinetics of ciprofloxacin after intravenous and increasing oral doses. Eur J Clin Microbiol. 1986;5:187–92. doi:10.1007/BF02013984.

    Article  PubMed  CAS  Google Scholar 

  30. Borner K, Hoffken G, Lode H, Koeppe P, Prinzing C, Glatzel P, et al. Pharmacokinetics of ciprofloxacin in healthy volunteers after oral and intravenous administration. Eur J Clin Microbiol. 1986;5:179–86. doi:10.1007/BF02013983.

    Article  PubMed  CAS  Google Scholar 

  31. Breda SA, Jimenez-Kairuz AF, Manzo RH, Olivera ME. Solubility behavior and biopharmaceutical classification of novel high-solubility ciprofloxacin and norfloxacin pharmaceutical derivatives. Int J Pharm. 2009;371:106–13. doi:10.1016/j.ijpharm.2008.12.026.

    Article  PubMed  CAS  Google Scholar 

  32. Sanchez BM, Cabarga MM, Navarro AS, Hurle AD. A physico-chemical study of the interaction of ciprofloxacin and ofloxacin with polyvalent cations. Int J Pharm. 1994;106:229–35. doi:10.1016/0378-5173(94)90006-X.

    Article  Google Scholar 

  33. Turel I. The interactions of metal ions with quinolone antibacterial agents. Coord Chem Rev. 2002;232:22–47. doi:10.1016/S0010-8545(02)00027-9.

    Article  Google Scholar 

  34. Tartaglione TA, Raffalovich AC, Poynor WJ, Espinel-Ingroff A, Kerkering TM. Pharmacokinetics and tolerance of ciprofloxacin after sequential increasing oral doses. Antimicrob Agents Chemother. 1986;29:62–6. doi:10.1128/AAC.29.1.62.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  35. Wingender W, Forster D, Beermann D, Rohwedder R, Graefe KH, Schacht P. Effect of gastric emptying time on rate and extent of the systemic availability of ciprofloxacin in humans. In: Ishigami J, editor. Recent advances in chemotherapy, antimicrobial section. Tokyo: University of Tokyo Press; 1985. p. 1585–6.

    Google Scholar 

  36. Alovero FL, Olivera ME, Manzo RH. In vitro pharmacodynamic properties of a fluoroquinolone pharmaceutical derivate: hydrochloride of ciprofloxacin–aluminium complex. Int J Antimicrob Agents. 2003;21:446–51. doi:10.1016/S0924-8579(03)00051-7.

    Article  PubMed  CAS  Google Scholar 

  37. Žakelj S, Berginc K, Uršič D, Veber M, Kristl A. Metal cation-fluoroquinolone complexes do not permeate through the intestinal absorption barrier. J Pharm Biomed Anal. 2010;53:655–9. doi:10.1016/j.jpba.2010.05.021.

    Article  CAS  Google Scholar 

  38. Rodrıguez Cruz S, Gonzalez Alonso I, Sanchez–Navarro A, Sayalero Marinero L. In vitro study of the interaction between quinolones and polyvalent cations. Pharm Acta Helv. 1999; 73:237–45. doi:10.1016/S0031-6865(98)00029-6.

  39. Arayne MS, Sultana N, Hussain F. Interactions between ciprofloxacin and antacids—dissolution and adsorption studies. Drug Metabol Drug Interact. 2005;21:117–29. doi:10.1515/DMDI.2005.21.2.117.

    Article  PubMed  CAS  Google Scholar 

  40. Tanaka M, Kurata T, Fujisawa C, Ohshima Y, Aoki H, Okazaki O, et al. Mechanistic study of inhibition of levofloxacin absorption by aluminum hydroxide. Antimicrob Agents Chemother. 1993;37:2173–8. doi:10.1128/AAC.37.10.2173.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  41. Stojkovic A, Parojcic J, Djuric Z, Corrigan OI. Biopharmaceutical investigation of ciprofloxacin hydrochloride calcium interaction. Proceedings from 8th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology Istanbul, Turkey 2012.

  42. Zupančić M, Turel I, Bukovec P, White AJP, Williams DJ. Synthesis and characterization of two novel zinc (II) complexes with ciprofloxacin crystal structure of [C17H19N3O3F]2 ZnCl4 2H2O. Croat Chem Acta. 2001;74:61–74.

    Google Scholar 

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Acknowledgments

This work was performed under the project TR-34007 supported by the Ministry of Education, Science and Technological Development, Republic of Serbia.

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Authors and Affiliations

  1. Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11000, Belgrade, Serbia

    Aleksandra Stojkovic, Jelena Parojcic & Zorica Djuric

  2. School of Pharmacy, Trinity College, University in Dublin, College Green, Dublin 2, Ireland

    Owen I. Corrigan

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  1. Aleksandra Stojkovic
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  2. Jelena Parojcic
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  3. Zorica Djuric
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  4. Owen I. Corrigan
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Correspondence to Aleksandra Stojkovic.

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Stojkovic, A., Parojcic, J., Djuric, Z. et al. A Case Study of In Silico Modelling of Ciprofloxacin Hydrochloride/Metallic Compound Interactions. AAPS PharmSciTech 15, 270–278 (2014). https://doi.org/10.1208/s12249-013-0055-x

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