Rikke Hebo Larsen1, Lisa Lyngsie Hjalgrim1, Kathrine Grell1,2, Kim Kristensen3, Line Gerner Pedersen1, Emilie Damgaard Brünner1, Bodil Als-Nielsen1, Kjeld Schmiegelow1,4, Jacob Nersting5. 1. Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark. 2. Section of Biostatistics, Department of Public Health, University of Copenhagen, Copenhagen, Denmark. 3. Discovery and Development PKPD, Novo Nordisk, Copenhagen, Denmark. 4. Institute of Clinical Medicine, Faculty of Medicine, University of Copenhagen, Copenhagen, Denmark. 5. Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark. jacob.nersting@regionh.dk.
Abstract
PURPOSE: Mercaptopurine (6MP) is essential to cure childhood acute lymphoblastic leukemia (ALL). A liquid 6MP formulation was recently introduced to facilitate oral 6MP administration, especially to children. Its approval and bioequivalence with 6MP tablet were based on comparative pharmacokinetics in 60 healthy adults. Due to potential pharmacokinetic differences between healthy adults and children with ALL, we compared pharmacokinetics of tablet and liquid 6MP formulations in children with ALL. METHODS: Pharmacokinetics of 50 mg 6MP tablet (Puri-Nethol®) and 20 mg/ml 6MP liquid suspension (Xaluprine®) were compared in a non-blinded, random order, single-dose, cross-over study in 16 children with ALL (eight males). 6MP was administered after a 12 h fast, and 6MP plasma concentrations measured consecutively over seven hours post-dose. Pharmacokinetic outcomes were as follows: Area under the curve (AUC), maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), and terminal half-life (T½). RESULTS: Liquid 6MP formulation resulted in a 26% lower AUC (p = 0.02) compared with tablet (median 1215 vs. 1805 h × nmol/l). No significant differences were observed for Cmax,Tmax and T½ (p = 0.28, p = 0.09, p = 0.41, respectively). Based on criteria declared by the World Health Organization the results did not establish non-inferiority of liquid 6MP formulation compared with 6MP tablet. CONCLUSION: Non-inferiority of liquid 6MP formulation compared with 6MP tablet was not demonstrated. Yet, maintenance therapy doses are adjusted by degree of myelosuppression and not by 6MP dose. Thus, in spite of a lower bioavailability, a liquid 6MP formulation is still desirable in a clinical setting, especially for children. However, if shifting between 6MP formulation is indicated, dose adjustments should be anticipated to maintain equivalent treatment intensity in children with ALL. The study is registered on clinicaltrials.gov (NCT01906671). Date of registration: 24.07.13.
PURPOSE: Mercaptopurine (6MP) is essential to cure childhood acute lymphoblastic leukemia (ALL). A liquid 6MP formulation was recently introduced to facilitate oral 6MP administration, especially to children. Its approval and bioequivalence with 6MP tablet were based on comparative pharmacokinetics in 60 healthy adults. Due to potential pharmacokinetic differences between healthy adults and children with ALL, we compared pharmacokinetics of tablet and liquid 6MP formulations in children with ALL. METHODS: Pharmacokinetics of 50 mg 6MP tablet (Puri-Nethol®) and 20 mg/ml 6MP liquid suspension (Xaluprine®) were compared in a non-blinded, random order, single-dose, cross-over study in 16 children with ALL (eight males). 6MP was administered after a 12 h fast, and 6MP plasma concentrations measured consecutively over seven hours post-dose. Pharmacokinetic outcomes were as follows: Area under the curve (AUC), maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), and terminal half-life (T½). RESULTS: Liquid 6MP formulation resulted in a 26% lower AUC (p = 0.02) compared with tablet (median 1215 vs. 1805 h × nmol/l). No significant differences were observed for Cmax,Tmax and T½ (p = 0.28, p = 0.09, p = 0.41, respectively). Based on criteria declared by the World Health Organization the results did not establish non-inferiority of liquid 6MP formulation compared with 6MP tablet. CONCLUSION: Non-inferiority of liquid 6MP formulation compared with 6MP tablet was not demonstrated. Yet, maintenance therapy doses are adjusted by degree of myelosuppression and not by 6MP dose. Thus, in spite of a lower bioavailability, a liquid 6MP formulation is still desirable in a clinical setting, especially for children. However, if shifting between 6MP formulation is indicated, dose adjustments should be anticipated to maintain equivalent treatment intensity in children with ALL. The study is registered on clinicaltrials.gov (NCT01906671). Date of registration: 24.07.13.
Authors: Y Toyoda; A Manabe; M Tsuchida; R Hanada; K Ikuta; Y Okimoto; A Ohara; Y Ohkawa; T Mori; K Ishimoto; T Sato; T Kaneko; M Maeda; K i Koike; T Shitara; Y Hoshi; R Hosoya; Y Tsunematsu; F Bessho; S Nakazawa; T Saito Journal: J Clin Oncol Date: 2000-04 Impact factor: 44.544
Authors: N Toft; H Birgens; J Abrahamsson; L Griškevičius; H Hallböök; M Heyman; T W Klausen; Ó G Jónsson; K Palk; K Pruunsild; P Quist-Paulsen; G Vaitkeviciene; K Vettenranta; A Åsberg; T L Frandsen; H V Marquart; H O Madsen; U Norén-Nyström; K Schmiegelow Journal: Leukemia Date: 2017-08-18 Impact factor: 11.528
Authors: M Kato; S Ishimaru; M Seki; K Yoshida; Y Shiraishi; K Chiba; N Kakiuchi; Y Sato; H Ueno; H Tanaka; T Inukai; D Tomizawa; D Hasegawa; T Osumi; Y Arakawa; T Aoki; M Okuya; K Kaizu; K Kato; Y Taneyama; H Goto; T Taki; M Takagi; M Sanada; K Koh; J Takita; S Miyano; S Ogawa; A Ohara; M Tsuchida; A Manabe Journal: Leukemia Date: 2016-10-04 Impact factor: 11.528
Authors: Rob Pieters; Hester de Groot-Kruseman; Vincent Van der Velden; Marta Fiocco; Henk van den Berg; Evelien de Bont; R Maarten Egeler; Peter Hoogerbrugge; Gertjan Kaspers; Ellen Van der Schoot; Valerie De Haas; Jacques Van Dongen Journal: J Clin Oncol Date: 2016-06-06 Impact factor: 44.544
Authors: Smita Bhatia; Wendy Landier; Muyun Shangguan; Lindsey Hageman; Alexandra N Schaible; Andrea R Carter; Cara L Hanby; Wendy Leisenring; Yutaka Yasui; Nancy M Kornegay; Leo Mascarenhas; A Kim Ritchey; Jacqueline N Casillas; David S Dickens; Jane Meza; William L Carroll; Mary V Relling; F Lennie Wong Journal: J Clin Oncol Date: 2012-05-07 Impact factor: 44.544
Authors: Ahmed B Bayoumy; Femke Crouwel; Nripen Chanda; Timothy H J Florin; Hans J C Buiter; Chris J J Mulder; Nanne K H de Boer Journal: Eur J Drug Metab Pharmacokinet Date: 2021-09-06 Impact factor: 2.441