PMID- 33903938
OWN - NLM
STAT- MEDLINE
DCOM- 20210917
LR  - 20210917
IS  - 1432-0843 (Electronic)
IS  - 0344-5704 (Linking)
VI  - 88
IP  - 2
DP  - 2021 Aug
TI  - Population pharmacokinetics and exposure-response of selumetinib and its 
      N-desmethyl metabolite in pediatric patients with neurofibromatosis type 1 and 
      inoperable plexiform neurofibromas.
PG  - 189-202
LID - 10.1007/s00280-021-04274-6 [doi]
AB  - PURPOSE: Selumetinib (ARRY-142886) is a potent, selective, MEK1/2 inhibitor 
      approved in the US for the treatment of children (>/= 2 years) with 
      neurofibromatosis type 1 (NF1) and symptomatic, inoperable plexiform 
      neurofibromas (PN). We characterized population pharmacokinetics (PK) of 
      selumetinib and its active N-desmethyl metabolite, evaluated 
      exposure-safety/efficacy relationships, and assessed the proposed therapeutic 
      dose of 25 mg/m(2) bid based on body surface area (BSA) in this patient 
      population. METHODS: Population PK modeling and covariate analysis (demographics, 
      formulation, liver enzymes, BSA, patients/healthy volunteers) were based on 
      pooled PK data from adult healthy volunteers (n = 391), adult oncology patients 
      (n = 83) and pediatric patients with NF1-PN (n = 68). Longitudinal 
      selumetinib/metabolite exposures were predicted with the final model. 
      Exposure-safety/efficacy analyses were applied to pediatric patients (dose 
      levels: 20, 25, 30 mg/m(2) bid). RESULTS: Selumetinib and metabolite 
      concentration-time courses were modeled using a joint compartmental model. 
      Typical selumetinib plasma clearance was 11.6 L/h (95% CI 11.0-12.2 L/ h). Only 
      BSA had a clinically relevant (> 20%) impact on exposure, supporting BSA-based 
      administration in children. Selumetinib and metabolite exposures in responders 
      (>/= 20% PN volume decrease from baseline) and non-responders were largely 
      overlapping, with medians numerically higher in responders. No clear 
      relationships between exposure and safety events were established; exposure was 
      not associated with key adverse events (AEs) including rash acneiform, diarrhea, 
      vomiting, and nausea. CONCLUSION: Findings support continuous selumetinib 
      25 mg/m(2) bid in pediatric patients. Importantly, the updated dosing nomogram 
      ensures that patients will receive a clinically active, yet tolerable, dose 
      regardless of differences in BSA and allows dose reductions, if necessary.
FAU - Schalkwijk, Stein
AU  - Schalkwijk S
AUID- ORCID: 0000-0001-8204-5242
AD  - CPQP, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge, UK. 
      stein.schalkwijk@astrazeneca.com.
AD  - AstraZeneca, da Vinci, Melbourn Science Park, Melbourn, SG8 6HB, Hertfordshire, 
      UK. stein.schalkwijk@astrazeneca.com.
FAU - Zhou, Li
AU  - Zhou L
AD  - CPQP, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Waltham, MA, 
      USA.
FAU - Cohen-Rabbie, Sarit
AU  - Cohen-Rabbie S
AD  - CPQP, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge, UK.
FAU - Jain, Lokesh
AU  - Jain L
AD  - Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & 
      Co., Inc., Quantitative Pharmacology and Pharmacometrics, 2000 Galloping Hill 
      Road, Kenilworth, NJ, USA.
FAU - Freshwater, Tomoko
AU  - Freshwater T
AD  - Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & 
      Co., Inc., Quantitative Pharmacology and Pharmacometrics, 2000 Galloping Hill 
      Road, Kenilworth, NJ, USA.
FAU - So, Karen
AU  - So K
AD  - Oncology R&D, AstraZeneca, Cambridge, UK.
FAU - He, Zhongqing
AU  - He Z
AD  - Data Science and Artificial Intelligence, R&D, AstraZeneca, Waltham, MA, USA.
FAU - Gioni, Ioanna
AU  - Gioni I
AD  - Oncology Biometrics, AstraZeneca, Cambridge, UK.
FAU - Tomkinson, Helen
AU  - Tomkinson H
AD  - CPQP, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge, UK.
FAU - Vishwanathan, Karthick
AU  - Vishwanathan K
AD  - AstraZeneca, da Vinci, Melbourn Science Park, Melbourn, SG8 6HB, Hertfordshire, 
      UK.
FAU - Zhou, Diansong
AU  - Zhou D
AD  - CPQP, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Waltham, MA, 
      USA.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210426
PL  - Germany
TA  - Cancer Chemother Pharmacol
JT  - Cancer chemotherapy and pharmacology
JID - 7806519
RN  - 0 (AZD 6244)
RN  - 0 (Benzimidazoles)
RN  - 0 (Protein Kinase Inhibitors)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Benzimidazoles/*pharmacokinetics/*therapeutic use
MH  - Child
MH  - Child, Preschool
MH  - Female
MH  - Healthy Volunteers
MH  - Humans
MH  - Longitudinal Studies
MH  - Male
MH  - Neurofibroma, Plexiform/*drug therapy/metabolism
MH  - Neurofibromatosis 1/*drug therapy/metabolism
MH  - Protein Kinase Inhibitors/pharmacokinetics/therapeutic use
MH  - Young Adult
OTO - NOTNLM
OT  - Exposure-response
OT  - Neurofibromatosis type 1
OT  - Pediatric dosing
OT  - Population pharmacokinetic modeling
OT  - Selumetinib
EDAT- 2021/04/28 06:00
MHDA- 2021/09/18 06:00
CRDT- 2021/04/27 07:01
PHST- 2020/11/27 00:00 [received]
PHST- 2021/04/03 00:00 [accepted]
PHST- 2021/04/28 06:00 [pubmed]
PHST- 2021/09/18 06:00 [medline]
PHST- 2021/04/27 07:01 [entrez]
AID - 10.1007/s00280-021-04274-6 [pii]
AID - 10.1007/s00280-021-04274-6 [doi]
PST - ppublish
SO  - Cancer Chemother Pharmacol. 2021 Aug;88(2):189-202. doi: 
      10.1007/s00280-021-04274-6. Epub 2021 Apr 26.