PURPOSE: The purpose of this study were firstly to characterize the population pharmacokinetics of artesunate (ARS) and its active metabolite dihydroartemisinin (DHA) in patients with metastatic breast cancer during long-term (>3 weeks) daily oral ARS administration and secondly to study the relationship between salivary and plasma concentrations of DHA. METHODS: Drug concentration-time data from 23 patients, receiving oral ARS (100, 150, or 200 mg OD), was analyzed using nonlinear mixed effects modeling. A combined drug-metabolite population pharmacokinetic model was developed to describe the plasma pharmacokinetics of ARS and DHA in plasma. Saliva drug concentrations were incorporated as being directly proportional to plasma concentrations. RESULTS: A first-order absorption model for ARS linked to a combined two-compartment disposition model for ARS and one-compartment disposition model for DHA provided the best fit to the data. No covariates were identified that could explain between-subject variability. A time-dependent increase in apparent elimination clearance of DHA was observed. Salivary DHA concentrations were proportionally correlated with total DHA plasma concentrations, with an estimated slope factor of 0.116. CONCLUSIONS: Population pharmacokinetics of ARS and DHA in patients with breast cancer was well described by a combined drug-metabolite model without any covariates and with an increase in apparent elimination clearance of DHA over time. The estimated DHA saliva/plasma ratio was in good agreement with the reported DHA unbound fraction in human plasma. Saliva ARS concentrations correlated poorly with plasma concentrations. This suggests the use of saliva sampling for therapeutic drug monitoring of DHA. However, further studies are warranted to investigate the robustness of this approach.
PURPOSE: The purpose of this study were firstly to characterize the population pharmacokinetics of artesunate (ARS) and its active metabolite dihydroartemisinin (DHA) in patients with metastatic breast cancer during long-term (>3 weeks) daily oral ARS administration and secondly to study the relationship between salivary and plasma concentrations of DHA. METHODS: Drug concentration-time data from 23 patients, receiving oral ARS (100, 150, or 200 mg OD), was analyzed using nonlinear mixed effects modeling. A combined drug-metabolite population pharmacokinetic model was developed to describe the plasma pharmacokinetics of ARS and DHA in plasma. Saliva drug concentrations were incorporated as being directly proportional to plasma concentrations. RESULTS: A first-order absorption model for ARS linked to a combined two-compartment disposition model for ARS and one-compartment disposition model for DHA provided the best fit to the data. No covariates were identified that could explain between-subject variability. A time-dependent increase in apparent elimination clearance of DHA was observed. Salivary DHA concentrations were proportionally correlated with total DHA plasma concentrations, with an estimated slope factor of 0.116. CONCLUSIONS: Population pharmacokinetics of ARS and DHA in patients with breast cancer was well described by a combined drug-metabolite model without any covariates and with an increase in apparent elimination clearance of DHA over time. The estimated DHA saliva/plasma ratio was in good agreement with the reported DHA unbound fraction in human plasma. Saliva ARS concentrations correlated poorly with plasma concentrations. This suggests the use of saliva sampling for therapeutic drug monitoring of DHA. However, further studies are warranted to investigate the robustness of this approach.
Authors: P Newton; Y Suputtamongkol; P Teja-Isavadharm; S Pukrittayakamee; V Navaratnam; I Bates; N White Journal: Antimicrob Agents Chemother Date: 2000-04 Impact factor: 5.191
Authors: Doaa A Elsherbiny; Sara A Asimus; Mats O Karlsson; Michael Ashton; Ulrika S H Simonsson Journal: J Pharmacokinet Pharmacodyn Date: 2008-03-19 Impact factor: 2.745
Authors: Jin Li; Tamara Casteels; Thomas Frogne; Camilla Ingvorsen; Christian Honoré; Monica Courtney; Kilian V M Huber; Nicole Schmitner; Robin A Kimmel; Roman A Romanov; Caterina Sturtzel; Charles-Hugues Lardeau; Johanna Klughammer; Matthias Farlik; Sara Sdelci; Andhira Vieira; Fabio Avolio; François Briand; Igor Baburin; Peter Májek; Florian M Pauler; Thomas Penz; Alexey Stukalov; Manuela Gridling; Katja Parapatics; Charlotte Barbieux; Ekaterine Berishvili; Andreas Spittler; Jacques Colinge; Keiryn L Bennett; Steffen Hering; Thierry Sulpice; Christoph Bock; Martin Distel; Tibor Harkany; Dirk Meyer; Giulio Superti-Furga; Patrick Collombat; Jacob Hecksher-Sørensen; Stefan Kubicek Journal: Cell Date: 2016-12-01 Impact factor: 41.582
Authors: Dieter Lemke; Hans-Werner Pledl; Markus Zorn; Manfred Jugold; Ed Green; Jonas Blaes; Sarah Löw; Anne Hertenstein; Martina Ott; Felix Sahm; Ann-Catherine Steffen; Markus Weiler; Frank Winkler; Michael Platten; Zhen Dong; Wolfgang Wick Journal: Oncotarget Date: 2016-08-30