Pharmacokinetics of two 6‐mercaptopurine liquid formulations in children with acute lymphoblastic leukemia. Issue 8 (10th March 2017)

• Record Type: Journal Article
• Authors: Tolbert, Jaszianne A.; Bai, Shasha; Abdel‐Rahman, Susan M.; August, Keith J.; Weir, Scott J.; Kearns, Gregory L.; Neville, Kathleen A.
• Is Part Of: Pediatric blood & cancer. Volume 64:Issue 8(2017)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2017-03-10
• Subjects: ALL -- pediatric oncology -- pharmacokinetics; Tumors in children -- Periodicals; Blood -- Diseases -- Periodicals; Cancer in children -- Periodicals; 618.92
• DOI: 10.1002/pbc.26465
• Languages: English
• ISSNs: 1545-5009

Abstract

Abstract: Background: A liquid formulation of 6‐mercaptopurine (6‐MP) was recently approved by the Food and Drug Administration (Purixan®) based on bioavailability (BA) data from healthy adults. We examined the pharmacokinetics (PK) and BA of 6‐MP in children with acute lymphoblastic leukemia (ALL) comparing a marketed tablet, two extemporaneously prepared liquid formulations, and data from the approved liquid formulation. Methods: Twenty‐two children (6–17 years) participated in a randomized two‐way, crossover study of two cohorts. Group 1 (n = 11; five males) received a 5 mg/ml liquid formulation and the marketed 50 mg 6‐MP tablet on separate occasions, and Group 2 (n = 11; five males) received a 50 mg/ml liquid formulation and the marketed tablet. The usual prescribed 6‐MP dose (25–115 mg/m 2 ) was given after an 8‐hr fast. Serial blood samples were collected over 8 hr postdose. Plasma 6‐MP concentrations were determined using a good laboratory practice (GLP)‐validated liquid chromatography–tandem mass spectrometry method. PK parameters were calculated using noncompartmental analysis and compared within and between cohorts, and thiopurine methyltransferase (TPMT) genotype was analyzed. Results: No patient had a TPMT genotype reflective of a poor metabolizer phenotype. Comparison of PK parameters between 5 and 50 mg/ml treatments revealed significant differences ( P <0.05) in AUCN (where AUC is area under the curve), CmaxN, and Tmax . Comparisons within each group revealed significant differences in AUC0‐∞ and Tmax in the 5 mg/ml group. Conclusions: Pharmacokinetic profiles of 6‐MP established in healthy adults with the approved liquid formulation may not reflect the PK profile in children with ALL. Formulation‐specific differences in PK may significantly impact the dose–exposure profile in these children and must be considered.