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

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Abstract

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.

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Acknowledgements

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

  1. School of Pharmacy, University of Waterloo, Waterloo, ON, Canada

    Alanna McEneny-King, Pierre Chelle & Andrea N. Edginton

  2. Biostatistics Unit, St. Joseph’s Healthcare, Hamilton, ON, Canada

    Gary Foster

  3. Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada

    Arun Keepanasseril & Alfonso Iorio

  4. Department of Medicine, McMaster University, Hamilton, ON, Canada

    Alfonso Iorio

Authors
  1. Alanna McEneny-King
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  2. Pierre Chelle
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  3. Gary Foster
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  4. Arun Keepanasseril
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  5. Alfonso Iorio
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  6. Andrea N. Edginton
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Correspondence to Andrea N. Edginton.

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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,

China

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

States

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

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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). https://doi.org/10.1007/s10928-019-09634-7

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