Skip to main content


Log in

Development and evaluation of a generic population pharmacokinetic model for standard half-life factor VIII for use in dose individualization

  • Original Paper
  • Published:
Journal of Pharmacokinetics and Pharmacodynamics Aims and scope Submit manuscript


Hemophilia A is a rare bleeding disorder resulting from a lack of functional factor VIII (FVIII). Therapy consists of replacement with exogenous FVIII, but is complicated by high inter-patient variability. A population pharmacokinetics (PopPK) approach can facilitate the uptake of an individualized approach to hemophilia therapy. We developed a PopPK model using data from seven brands of standard half-life FVIII products. The final model consists of a 2-compartment structure, with a proportional residual error model and between-subject variability on clearance and central volume. Fat-free mass, age, and brand were found to significantly affect pharmacokinetic (PK) parameters. Internal and external evaluations found that the model is fit for Bayesian forecasting and capable of predicting PK for brands not included in the modelling dataset, and useful for determining individualized prophylaxis regimens for hemophilia A patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others


  1. Stonebraker JS, Bolton-Maggs PHB, MichaelSoucie J, Walker I, Brooker M (2010) A study of variations in the reported haemophilia A prevalence around the world. Haemophilia 16(1):20–32

    Article  CAS  Google Scholar 

  2. Ahlberg Å (1965) Incidence, treatment and prophylaxis of arthropathy and other musculo-skeletal manifestations of haemophilia A and B. Acta Orthop Scand 36(sup77):3–132

    Article  Google Scholar 

  3. Collins PW et al (2009) Break-through bleeding in relation to predicted factor VIII levels in patients receiving prophylactic treatment for severe hemophilia A. J Thromb Haemost 7:413–420

    Article  CAS  Google Scholar 

  4. Oldenburg J (2011) Prophylaxis in bleeding disorders. Thromb Res 127:S14–S17

    Article  CAS  Google Scholar 

  5. Berntorp E, Spotts G, Patrone L, Ewenstein B (2014) Advancing personalized care in hemophilia A: ten years’ experience with an advanced category antihemophilic factor prepared using a plasma/albumin-free method. Biol Targets Ther 8:115

    Article  Google Scholar 

  6. Fischer K, Collins PW, Ozelo MC, Srivastava A, Young G, Blanchette VS (2016) When and how to start prophylaxis in boys with severe hemophilia without inhibitors: communication from the SSC of the ISTH. J Thromb Haemost 14(5):1105–1109

    Article  CAS  Google Scholar 

  7. Björkman S, Folkesson A, Jönsson S (2009) Pharmacokinetics and dose requirements of factor VIII over the age range 3–74 years. Eur J Clin Pharmacol 65(10):989–998

    Article  Google Scholar 

  8. McEneny-King A, Iorio A, Foster G, Edginton AN (2016) The use of pharmacokinetics in dose individualization of factor VIII in the treatment of hemophilia A. Expert Opin Drug Metab Toxicol 12(11):1313–1321

    Article  CAS  Google Scholar 

  9. Iorio A, Blanchette V, Blatny J, Collins P, Fischer K, Neufeld E (2017) Estimating and interpreting the pharmacokinetic profiles of individual patients with hemophilia A or B using a population pharmacokinetic approach: communication from the SSC of the ISTH. J Thrombs Haemost 15(12):2461–2465

    Article  CAS  Google Scholar 

  10. Iorio A et al (2018) Performing and interpreting individual pharmacokinetic profiles in patients with Hemophilia A or B: rationale and general considerations. Res Pract Thromb Haemost 2(3):535–548

    Article  Google Scholar 

  11. Samor B, Michalski C, Brandin M-P, Andre M-H, Chtourou S, Tellier Z (2012) A qualitative and quantitative analysis of von Willebrand factor contained in a very high-purity plasma-derived FVIII concentrate. Vox Sang 103(1):35–41

    Article  CAS  Google Scholar 

  12. Morfini M, Marchesini E, Paladino E, Santoro C, Zanon E, Iorio A (2015) Pharmacokinetics of plasma-derived vs. recombinant FVIII concentrates: a comparative study. Haemophilia 21(2):204–209

    Article  CAS  Google Scholar 

  13. Cafuir LA, Kempton CL (2017) Current and emerging factor VIII replacement products for hemophilia A. Ther Adv Hematol 8(10):303–313

    Article  CAS  Google Scholar 

  14. Di Paola J et al (2007) ReFacto®1and Advate®2: a single-dose, randomized, two-period crossover pharmacokinetics study in subjects with haemophilia A. Haemophilia 13(2):124–130

    Article  Google Scholar 

  15. Recht M et al (2009) Clinical evaluation of moroctocog alfa (AF-CC), a new generation of B-domain deleted recombinant factor VIII (BDDrFVIII) for treatment of haemophilia A: demonstration of safety, efficacy, and pharmacokinetic equivalence to full-length recombinant factor V. Haemophilia 15(4):869–880

    Article  CAS  Google Scholar 

  16. Kessler CM et al (2005) B-domain deleted recombinant factor VIII preparations are bioequivalent to a monoclonal antibody purified plasma-derived factor VIII concentrate: a randomized, three-way crossover study. Haemophilia 11(2):84–91

    Article  CAS  Google Scholar 

  17. Gruppo RA, Brown D, Wilkes MM, Navickis RJ (2003) Comparative effectiveness of full-length and B-domain deleted factor VIII for prophylaxis–a meta-analysis. Haemophilia 9(3):251–260

    Article  CAS  Google Scholar 

  18. Johnston A (2012) The relevance of factor VIII (FVIII) pharmacokinetics to TDM and hemophilia a treatment: is B domain-deleted FVIII equivalent to full-length FVIII? Ther Drug Monit 34(1):110–117

    Article  CAS  Google Scholar 

  19. Pipe SW (2009) Functional roles of the factor VIII B domain. Haemophilia 15(6):1187–1196

    Article  CAS  Google Scholar 

  20. Abrantes J, Nielsen E, Korth-Bradley J, Harnisch L, Jönsson S (2017) Elucidation of factor VIII activity pharmacokinetics: a pooled population analysis in patients with hemophilia a treated with moroctocog alfa. Clin Pharmacol Ther 102(6):977–988

    Article  CAS  Google Scholar 

  21. Björkman S (2012) Population pharmacokinetics of recombinant factor VIII: the relationships of pharmacokinetics To Age and Body Weight. Blood 119(2):612–618

    Article  Google Scholar 

  22. Nestorov I, Neelakantan S, Ludden TM, Li S, Jiang H, Rogge M (2015) Population pharmacokinetics of recombinant factor VIII Fc fusion protein. Clin Pharmacol Drug Dev 4(3):163–174

    Article  CAS  Google Scholar 

  23. Garmann D, McLeay S, Shah A, Vis P, MaasEnriquez M, Ploeger BA (2017) Population pharmacokinetic characterization of BAY 81-8973, a full-length recombinant factor VIII: lessons learned—importance of including samples with factor VIII levels below the quantitation limit. Haemophilia 23(4):528–537

    Article  CAS  Google Scholar 

  24. Jiménez-Yuste V et al (2015) The pharmacokinetics of a B-domain truncated recombinant factor VIII, turoctocog alfa (NovoEight®), in patients with hemophilia A. J Thromb Haemost 13(3):370–379

    Article  Google Scholar 

  25. Bolon-Larger M, Bressolle F, Chevalier Y, Chamouard V, Gomeni R, Boulieu R (2015) Population pharmacokinetics of continuous infusion of factor VIII in hemophilia-a patients undergoing orthopedic surgery. IJPPS 7(2):109–114

    CAS  Google Scholar 

  26. Karafoulidou A et al (2009) Population pharmacokinetics of recombinant factor VIII: C (ReFacto) in adult HIV-negative and HIV-positive haemophilia patients. Eur J Clin Pharmacol 65(11):1121–1130

    Article  CAS  Google Scholar 

  27. Hazendonk H et al (2016) A population pharmacokinetic model for perioperative dosing of factor VIII in hemophilia A patients. Haematologica 101(10):1159–1169

    Article  Google Scholar 

  28. Beal SL (2001) Ways to fit a PK model with some data below the quantification limit. J Pharmacokinet Pharmacodyn 28(5):481–504

    Article  CAS  Google Scholar 

  29. Al-Sallami HS, Goulding A, Grant A, Taylor R, Holford N, Duffull SB (2015) Prediction of fat-free mass in children. Clin Pharmacokinet 54(11):1169–1178

    Article  CAS  Google Scholar 

  30. Brekkan A, Berntorp E, Jensen K, Nielsen EI, Jönsson S (2016) Population pharmacokinetics of plasma-derived factor IX: procedures for dose individualization. J Thromb Haemost 14(4):724–732

    Article  CAS  Google Scholar 

  31. Konkle B (2014) von Willebrand factor and aging. Semin Thromb Hemost 40(06):640–644

    Article  CAS  Google Scholar 

  32. Lenting PJ, Van Schooten CJM, Denis CV (2007) Clearance mechanisms of von Willebrand factor and factor VIII. J Thromb Haemost 4(7):1353–1360

    Article  Google Scholar 

  33. Lalezari S et al (2014) Correlation between endogenous VWF: Ag and PK parameters and bleeding frequency in severe haemophilia A subjects during three-times-weekly prophylaxis with rFVIII-FS. Haemophilia 20(1):e15–e22

    Article  CAS  Google Scholar 

  34. Turecek PL et al (2016) A world-wide survey and field study in clinical haemostasis laboratories to evaluate FVIII: C activity assay variability of ADYNOVATE and OBIZUR in comparison with ADVATE. Haemophilia 22(6):957–965

    Article  CAS  Google Scholar 

  35. Barrowcliffe TW (2003) Standardization of FVIII & FIX assays. Haemophilia 9(4):397–402

    Article  CAS  Google Scholar 

  36. Sommer JM et al (2014) Comparative field study evaluating the activity of recombinant factor VIII Fc fusion protein in plasma samples at clinical haemostasis laboratories. Haemophilia 20(2):294–300

    Article  CAS  Google Scholar 

  37. Viuff D, Barrowcliffe TW, Saugstrup T, Ezban M, Lillicrap D (2011) International comparative field study of N8 evaluating factor VIII assay performance. Haemophilia 17(4):695–702

    Article  CAS  Google Scholar 

  38. Chelle P et al (2014) Routine clinical care data for population pharmacokinetic modeling: the case for Fanhdi/Alphanate in hemophilia A patients. J Pharmacokinet Pharmacodyn.

    Article  PubMed  Google Scholar 

Download references


We would like to thank the centres in the WAPPS-Hemo network for contributing data used for the external validation of the presented model. The full list of centres is found in Appendix.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Andrea N. Edginton.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 337 kb)

Appendix: List of WAPPS-Hemo centres

Appendix: List of WAPPS-Hemo centres

Alberta Children’s Hospital, Calgary, Canada

Amrita Hospital, Kochi, India

Antwerp University Hospital, Edegem, Belgium

AOU Città della Salute e della Scienza di Torino, Turin, Italy

Arthur Bloom Haemophilia centre, Cardiff, United Kingdom

Azienda Ospedaliera Pugliese-Ciaccio, Catanzaro, Italy

Azienda Ospedaliero Universitaria di Parma, Parma, Italy

BC Children’s Hospital, Vancouver, Canada

Beijing Children’s Hospital, Beijing, China

Belarusian Centre for Paediatric Oncology and Haematology, Minsk, Belarus

Bern University Hospital, Bern, Switzerland

Bloodworks Northwest, Seattle, United States

Calvary Mater Hospital/John Hunter Children’s Hospital, Newcastle, Australia

Center for Bleeding and Clotting, Minneapolis, United States

Center for Hemorrhagic and Thrombotic Diseases, University Hospital of Udine, Udine, Italy

Center for Inherited Blood Disorders, Orange County, United States

Centre de traitement des Hémophiles Eaubonne-Montmorency, Montmorency, France

Centre de traitement des Hémophiles Hôpital, Mignot, France

Centre Hospitalier Le Mans, Le Mans, France

Centro Asistencial Regional de Hemoterapia (CARDHE), Bahia Blanca, Argentina

Centro de Hemoterapia e Hematologia do Espirito Santo, Victoria, Brazil

Centro Emofilia di Padova, Padova, Italy

Centro Emofilia e Trombosi, Bari, Italy

Centro Hospitalar de Lisboa Central, Lisbon, Portugal

Centro Médico Imbanaco, Cali, Colombia

Centro. Nacional de Hemofilia, Caracas, Venezuela

CHEO Research Institute, Ottawa, Canada

Children’s Hospital Colorado Anschutz Medical Campus, Aurora, United States

Children’s Hospital of Michigan, Detroit, United States

Children’s Hospital, Boston, United States

Children’s Hospital, Los Angeles, United States

Children’s Medical University Hospital, Riga, Latvia

Children’s of Minnesota, Minneapolis, United States

CHR de la Citadelle, Liège, Belgium

Christchurch Hemophilia Treatment Centre, Christchurch, New Zealand

CHRU de Besançon, Besançon, France

CHU Caen, Caen, France

CHU de Rouen, Rouen, France

CHU Sainte Justine, Montreal, Canada

CHU, University Hospital of Nancy, Nancy, France

Clinique Vasculaire et Coagulation, Angers, France

Complejo Asistencial Dr. Sótero del Río, Santiago, Chile

Complejo Hospitalario de Navarra, Pamplona, Spain

Congenital Coagulopathies Unit, Balearic Islands, Spain

CTH-Cordoba, Cordoba, Argentina

Dr. von Haunersches Kinderspital, Munich, Germany

Ege University Hospital, Izmir, Turkey

Emory University, Atlanta, United States

Erasmus MC, Sophia Children’s Hospital, Rotterdam, Netherlands

Exeter and Barnstaple Haemophilia Centre, Barnstaple, United Kingdom

Farwaniya General Hospital, Al Farwaniyah, Kuwait

Fondazione IRCCS Policlinico San Matteo, Pavia, Italy

Fondazione Policlinico universitario “Agostino Gemelli”, Rome, Italy

Foothills Medical Centre, Calgary, Canada

Fundación de Hemofilia de Salta, Salta, Argentina

Fundacion de la Hemofilia Rosario, Rosario, Argentina

Fundacion de la Hemofilia, Buenos Aires, Argentina

Gent University Hospital, Gent, Belgium

Gulf States Hemophilia, Houston, United States

Haematology and Haemophilia Centre Catelfranco Veneto, Catelfranco Veneto, Italy

Haemophilia Centre Copenhagen, Copenhagen, Denmark

Haemophilia Centre of Perugia, Perugia, Italy

Haemophilia Comprehensive Care Ljubljana, Ljubljana, Slovenia

Hamilton Health Sciences, Hamilton, Canada

Hämophilie-Zentrum Rhein Main GmbH, Frankfurt, Germany

Heim Pál Gyermekkórház, Budapest, Hungary

Helsinki University Hospital, Helsinki, Finland

Hematologia y oncologia del oriente SAS, Bogota, Colombia

Hematology and Oncology Department, CHU Nord, St. Etienne, France

Hemocentro Unicamp, São Paulo, Brazil

Hemofiliecentrum, UZ Leuven, Leuven, Belgium

Hemophilia Center of Western New York, Buffalo, United States

Hemophilia Center of Western Pennsylvania, Pittsburgh, United States

Hemophilia Comprehensive Care Team, Jakarta, Indonesia

Hemophilia Treatment Center of Central PA, Hershey, United States

Hemostasis and Thrombosis Center of Nevada, Las Vegas, United States

Hemostasis and Thrombosis Center Rhode Island, Rhode Island, United States

Hôpital de l’Enfant-Jésus, Quebec City, Canada

Hôpital Trousseau, CHRU de Tours, Tours, France

Hôpital Universitaire des Enfants Reine Fabiola, Huderf, Belgium

Hôpitaux Universitaires de Genève, Geneva, Switzerland

Hospital Alvaro Cunqueiro, Vigo, Spain

Hospital Clinico Universitario de Santiago, Santiago, Spain

Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

Hospital de Santa Maria, Lisbon, Portugal

Hospital General Universitario de Alicante, Alicante, Spain

Hospital Humberto Notti, Mendoza, Argentina

Hospital Miguel Servet, Zaragoza, Spain

Hospital Posadas, Buenos Aires, Argentina

Hospital Regional Universitario de Málaga, Málaga, Spain

Hospital Roberto del Río, Santiago, Chile

Hospital Sant Joan de Déu, Barcelona, Spain

Hospital Teresa Herrera Materno Infantil, Coruna, Spain

Hospital Universitario Dr José Eleuterio Gonzalez, Monterrey, Mexico

Hospital Universitario La Paz, Madrid, Spain

Hospital Universitario Virgen de la Arrixaca, Murcia, Spain

Hospital University and Politechnic La Fe, Valencia, Spain

Hospital Vall d’Hebron, Barcelona, Spain

Hospital Virgen de las Nieves, Granada, Spain

Hull and East Yorkshire Hospitals NHS Trust, Hull, United Kingdom

Indiana Hemophilia and Thrombosis Center, Indianapolis, United States

Institute of Hematology and Blood Diseases Hospital Chinese Academy of Medical Science, Tianjin,


Instituto Guatemalteco de Seguridad Social, Guatemala City, Guatemala

Intergral Solutions SD S.A.S, Bogota, Colombia

IPS Especializada, Bogota, Colombia

IWK Health Centre, Halifax, Canada

Johns Hopkins All Children’s Hospital, St. Petersburg, United States

Kaohsiung Medical University Hospital, Kaohsiung, Taiwan

King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

Kingston General Hospital, Kingston, Canada

Klinik für Kinder- und JugendmedizinUniversitätsklinikum Jena, Jena, Germany

Korea Hemophilia Foundation Seoul Clinic, Seoul, South Korea

Kuopio University Hospital, Kuopio, Finland

Kyung Hee University Hospital at Gangdong, Seoul, South Korea

Laiko General Hospital of Athens, Athens, Greece

L’hemostase de Strasbourg, Strasbourg, France

London Health Sciences Center, London, Canada

Luzerner Kantonsspital, Lucerne, Switzerland

Manitoba Health Sciences Centre, Winnipeg, Canada

Massachusetts General Hospital, Boston, United States

Maxima Medisch Centrum, Veldhoven, Netherlands

Mohács Hospital, Mohács, Hungary

Montreal Children’s Hospital, Montreal, Canada

Nagoya University Hospital, Nagoya, Japan

Nanfang Hospital, Guangzhou, China

National Haemophilia Center Budapest, Budapest, Hungary

Nationwide Children’s Hospital, Columbus, United States

Nemours Children’s Specialty Care, Jacksonville, United States

North Dakota Hemostasis and Thrombosis Treatment Center, Fargo, United States

North Estonia Medical Center, Tallinn, Estonia

Northern Alberta Bleeding and Rare Blood Disorders Clinic - Kaye Edmonton Clinic, Edmonton, Canada

Northwest Ohio Hemophilia Treatment Center, Toledo, United States

Ogikubo Hospital, Tokyo, Japan

Oklahoma Center for Bleeding and Clotting Disorders, Oklahoma City, United States

ONCOORIENTE SAS, Villavicencio, Colombia

Oregon Health and Science University, Portland, United States

Orthopaedic Hemophilia Treatment Center, Los Angeles, United States

Ospedale S. Bortolo, Vicenza, Italy

Oulu University Hospital, Oulu, Finland

Palmetto Health Richland, Columbia, United States

Pediatric Hemophilia Center of Turin, Italy

Peking Union Medical College Hospital, Beijing, China

Phoenix Children’s Hospital, Phoenix, Unites States

Policlinico di Palermo, Palermo, Italy

Policlinico Umberto I - “Sapienza” Università di Roma, Rome, Italy

Pontificia Universidad Católica de Chile, Santiago, Chile

Rady Children’s Hospital, San Diego, United States

Riley Children’s Health, Indianapolis, United States

Royal Adelaide Hospital, Adelaide, Australia

Royal Brisbane and Women’s Hospital, Brisbane, Australia

Royal Free Hospital, London, United Kingdom

Royal London, London, United Kingdom

Ruan Rehacer IPS, Bogota, Colombia

Rush University Medical Center, Chicago, United States

Sahlgrenska University Hospital, Gothenburg, Sweden

Saskatchewan Bleeding Disorders Program, Saskatoon, Canada

Sheffield Children’s Hospital, Sheffield, United Kingdom

SickKids Hospital, Toronto, Canada

Skåne University Hospital, Malmö, Sweden

South Texas Hemophilia Treatment Center, San Antonio, United States

St. George’s University Hospital, London, United Kingdom

St. Joseph’s Hospital - Center for Bleeding and Clotting Disorders, Tampa, United States

St. Jude Affiliate Clinic at NH Hemby Children’s Hospital, Charlotte, United States

St. Jude Children’s Research Hospital, Memphis, United States

St. Michael’s Hospital, Toronto, Canada

St. Paul’s Hospital, Vancouver, Canada

St-Luc University Hospital, Brussels, Belgium

Stollery Children’s Hospital, Edmonton, Canada

Taichung Veterans General Hospital, Taichung, Taiwan

Taipei Medical University Hospital Hemophilia Center, Taipei, Taiwan

Tampere University Hospital, Tampere, Finland

The Alfred Hospital, Melbourne, Australia

The Bleeding and Clotting Disorders Institute, Peoria, United States

The Children’s Hospital at Montefiore, New York, United States

The Children’s Hospital of Philadelphia, Philadelphia, United States

The Children’s Hospital, Zhengjiang University School of Medicine, Hangzhou, China

The Maine Hemophilia and Thrombosis Center, Scarborough, United States

The Royal Children’s Hospital, Melbourne, Australia

The Women’s and Childrens Hospital, Adelaide, Australia

Turku University Hospital, Turku, Finland

U.O. Pediatria Generale e Specialistica “B. Trambusti”, Bari, Italy

UHHS Cleveland. University Hospitals Health System, Cleveland, United States

Universitaets - Kinderklinik Wien, Vienna, Austria

Universitätsklinikum Bonn, Bonn, Germany

University Children’s Hospital Berne, Berne, Switzerland

University Children’s Hospital Zurich, Zurich, Switzerland

University Hospital Bristol, Bristol, United Kingdom

University Hospital Brno, Brno, Czech Republic

University Hospital Coventry and Warwickshire, Coventry, United Kingdom

University Hospital Magdeburg, Magdeburg, Germany

University Hospital Southampton, Southampton, United Kingdom

University Hospitals of Leicester, Leicester, United Kingdom

University Medical Center Utrecht, Utrecht, Netherlands

University Medical Centre Ljubljana, Ljubljana, Slovenia

University of California San Francisco Pediatric Hemophilia Treatment Center, San Francisco, United


University of Debrecen, Debrecen, Hungary

University of Florida Hemophilia Treatment Cente, Gainsville, United States

University of Helsinki and Children’s Hospital, Helsinki, Finland

University of Iowa Children’s Hospital, Iowa City, United States

University of Kentucky Hemophilia Treatment Center, Lexington, United States

University of Louisville, Louisville, United States

University of Miami Hemophilia Treatment Center, Miami, United States

University of North Carolina, Chapel Hill, United States

University of Szeged, Szeged, Hungary

University of Virginia Health System, Charlottesville, United States

University of Wisconsin Comprehensive Program for Bleeding Disorders, Madison, United States

Valley Children’s Healthcare, Madera, United States

Vanderbilt University Medical Center, Nashville, United States

Vivantes Clinic in Friedrichshain, Berlin, Germany

Wake Forest University, Winston-Salem, United States

Weill Cornell Medical College, New York, United States

Zurich University Hospital, Zurich, Switzerland

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

McEneny-King, A., Chelle, P., Foster, G. et al. Development and evaluation of a generic population pharmacokinetic model for standard half-life factor VIII for use in dose individualization. J Pharmacokinet Pharmacodyn 46, 411–426 (2019).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: