eprintid: 10085747 rev_number: 38 eprint_status: archive userid: 608 dir: disk0/10/08/57/47 datestamp: 2019-11-13 17:14:03 lastmod: 2021-12-16 01:47:15 status_changed: 2020-04-20 09:58:15 type: article metadata_visibility: show creators_name: Chiesa, R creators_name: Standing, JF creators_name: Winter, R creators_name: Nademi, Z creators_name: Chu, J creators_name: Pinner, D creators_name: Kloprogge, F creators_name: McLellen, S creators_name: Amrolia, PJ creators_name: Rao, K creators_name: Lucchini, G creators_name: Silva, J creators_name: Ciocarlie, O creators_name: Lazareva, A creators_name: Gennery, AR creators_name: Doncheva, B creators_name: Cant, AJ creators_name: Hambleton, S creators_name: Flood, T creators_name: Rogerson, E creators_name: Devine, K creators_name: Prunty, H creators_name: Heales, S creators_name: Veys, P creators_name: Slatter, M title: Proposed therapeutic range of treosulfan in reduced toxicity pediatric allogeneic hematopoietic stem cell transplant conditioning: results from a prospective trial ispublished: inpress divisions: UCL divisions: B02 divisions: D01 divisions: D13 divisions: G23 divisions: G24 note: © 2019 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract: Treosulfan is given off‐label in pediatric allogeneic hematopoietic stem cell transplant. This study investigated treosulfan's pharmacokinetics (PKs), efficacy, and safety in a prospective trial. Pediatric patients (n = 87) receiving treosulfan‐fludarabine conditioning were followed for at least 1 year posttransplant. PKs were described with a two‐compartment model. During follow‐up, 11 of 87 patients died and 12 of 87 patients had low engraftment (≤ 20% myeloid chimerism). For each increase in treosulfan area under the curve from zero to infinity (AUC(0‐∞)) of 1,000 mg hour/L the hazard ratio (95% confidence interval) for mortality increase was 1.46 (1.23–1.74), and the hazard ratio for low engraftment was 0.61 (0.36–1.04). A cumulative AUC(0‐∞) of 4,800 mg hour/L maximized the probability of success (> 20% engraftment and no mortality) at 82%. Probability of success with AUC(0‐∞) between 80% and 125% of this target were 78% and 79%. Measuring PK at the first dose and individualizing the third dose may be required in nonmalignant disease. date: 2019 date_type: published official_url: https://doi.org/10.1002/cpt.1715 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green article_type_text: Journal Article verified: verified_manual elements_id: 1717420 doi: 10.1002/cpt.1715 lyricists_name: Amrolia, Persis lyricists_name: Heales, Simon lyricists_name: Kloprogge, Frank lyricists_name: Standing, Joseph lyricists_name: Veys, Paul lyricists_id: PJAMR87 lyricists_id: SJRHE78 lyricists_id: FLKKL46 lyricists_id: STAND26 lyricists_id: PAVEY50 actors_name: Flynn, Bernadette actors_id: BFFLY94 actors_role: owner full_text_status: public publication: Clinical Pharmacology & Therapeutics event_location: United States citation: Chiesa, R; Standing, JF; Winter, R; Nademi, Z; Chu, J; Pinner, D; Kloprogge, F; ... Slatter, M; + view all <#> Chiesa, R; Standing, JF; Winter, R; Nademi, Z; Chu, J; Pinner, D; Kloprogge, F; McLellen, S; Amrolia, PJ; Rao, K; Lucchini, G; Silva, J; Ciocarlie, O; Lazareva, A; Gennery, AR; Doncheva, B; Cant, AJ; Hambleton, S; Flood, T; Rogerson, E; Devine, K; Prunty, H; Heales, S; Veys, P; Slatter, M; - view fewer <#> (2019) Proposed therapeutic range of treosulfan in reduced toxicity pediatric allogeneic hematopoietic stem cell transplant conditioning: results from a prospective trial. Clinical Pharmacology & Therapeutics 10.1002/cpt.1715 <https://doi.org/10.1002/cpt.1715>. (In press). Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10085747/1/Amrolia_cpt.1715.pdf