PMID- 34698901
OWN - NLM
STAT- MEDLINE
DCOM- 20220222
LR  - 20220402
IS  - 1432-0843 (Electronic)
IS  - 0344-5704 (Print)
IS  - 0344-5704 (Linking)
VI  - 89
IP  - 1
DP  - 2022 Jan
TI  - Evaluation of the absolute oral bioavailability of the anaplastic lymphoma 
      kinase/c-ROS oncogene 1 kinase inhibitor lorlatinib in healthy participants.
PG  - 71-81
LID - 10.1007/s00280-021-04368-1 [doi]
AB  - PURPOSE: Lorlatinib is a third-generation tyrosine kinase inhibitor currently 
      approved for the treatment of anaplastic lymphoma kinase (ALK)-positive 
      metastatic non-small cell lung cancer. This open-label, phase 1, randomized 
      two-sequence, two-treatment, two-period, crossover study investigated the 
      absolute oral bioavailability of lorlatinib in healthy participants. METHODS: 
      Eligible participants were randomized to receive two treatments in one of two 
      sequences: lorlatinib 100 mg single oral dose followed by lorlatinib 50 mg 
      intravenous (IV) dose, or lorlatinib IV dose followed by lorlatinib oral dose, 
      each with at least a 10-day washout between successive lorlatinib doses. Blood 
      samples for pharmacokinetics were collected for up to 144 hours (h) after dosing. 
      Validated liquid chromatographic-tandem mass spectrometry was used to determine 
      plasma concentrations of lorlatinib and its benzoic acid metabolite PF-06895751. 
      RESULTS: In total, 11 participants were enrolled (mean age 37.6 years, all male). 
      The adjusted geometric mean (90% confidence interval) for the absolute oral 
      bioavailability was 80.78% (75.73-86.16%). Using non-compartmental analysis, the 
      estimated arithmetic mean elimination plasma half-life of lorlatinib was 25.5 and 
      27.0 h after the oral and IV doses, respectively. No deaths, serious adverse 
      events (AEs), or severe AEs were reported, and most treatment-emergent AEs were 
      mild in severity, with two events of transaminase increase of moderate severity. 
      All treatment-emergent AEs were resolved by the end of the study. CONCLUSION: 
      Both oral and IV lorlatinib were well-tolerated in healthy participants and oral 
      lorlatinib is highly bioavailable after oral administration.
CI  - (c) 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, 
      part of Springer Nature.
FAU - Hibma, Jennifer E
AU  - Hibma JE
AUID- ORCID: 0000-0002-6547-2186
AD  - Pfizer (Clinical Pharmacology Oncology), La Jolla, 10555 Science Center Drive, 
      CB10-2727, San Diego, CA, 92121, USA. Jennifer.e.hibma@pfizer.com.
FAU - O'Gorman, Melissa
AU  - O'Gorman M
AD  - Pfizer (Pharmacometrics Oncology), Groton, CT, USA.
FAU - Nepal, Sunil
AU  - Nepal S
AD  - Pfizer (Statistics Oncology), Groton, CT, USA.
AD  - Independent Statistical Consultant, Schwenksville, PA, USA.
FAU - Pawlak, Sylvester
AU  - Pawlak S
AD  - Pfizer (Clinical Development and Operations), New Haven, CT, USA.
FAU - Ginman, Katherine
AU  - Ginman K
AD  - Pfizer (Clinical Development and Operations), South Lyon, MI, USA.
FAU - Pithavala, Yazdi K
AU  - Pithavala YK
AD  - Pfizer (Clinical Pharmacology Oncology), La Jolla, 10555 Science Center Drive, 
      CB10-2727, San Diego, CA, 92121, USA.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20211026
PL  - Germany
TA  - Cancer Chemother Pharmacol
JT  - Cancer chemotherapy and pharmacology
JID - 7806519
RN  - 0 (Aminopyridines)
RN  - 0 (Lactams)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Pyrazoles)
RN  - EC 2.7.10.1 (ALK protein, human)
RN  - EC 2.7.10.1 (Anaplastic Lymphoma Kinase)
RN  - OSP71S83EU (lorlatinib)
SB  - IM
EIN - Cancer Chemother Pharmacol. 2022 Jun;89(6):839. PMID: 35303141
MH  - Administration, Oral
MH  - Adult
MH  - Aminopyridines/*administration & dosage/*adverse effects/blood/*pharmacokinetics
MH  - Anaplastic Lymphoma Kinase/*antagonists & inhibitors
MH  - Biological Availability
MH  - Healthy Volunteers
MH  - Humans
MH  - Injections, Intravenous
MH  - Lactams/*administration & dosage/*adverse effects/blood/*pharmacokinetics
MH  - Male
MH  - Middle Aged
MH  - Protein Kinase Inhibitors/administration & dosage/adverse 
      effects/blood/pharmacokinetics
MH  - Pyrazoles/*administration & dosage/*adverse effects/blood/*pharmacokinetics
PMC - PMC8933379
OTO - NOTNLM
OT  - Absolute bioavailability
OT  - Absorption
OT  - Lorlatinib
OT  - Pharmacokinetics
COIS- JEH, MG, SP, KG, and YKP are employees of Pfizer Inc and own stock or stock 
      options in Pfizer. SN is a former employee of Pfizer Inc and owns stock or stock 
      options in Pfizer.
EDAT- 2021/10/27 06:00
MHDA- 2022/02/23 06:00
PMCR- 2021/10/26
CRDT- 2021/10/26 12:30
PHST- 2021/07/28 00:00 [received]
PHST- 2021/10/14 00:00 [accepted]
PHST- 2021/10/27 06:00 [pubmed]
PHST- 2022/02/23 06:00 [medline]
PHST- 2021/10/26 12:30 [entrez]
PHST- 2021/10/26 00:00 [pmc-release]
AID - 10.1007/s00280-021-04368-1 [pii]
AID - 4368 [pii]
AID - 10.1007/s00280-021-04368-1 [doi]
PST - ppublish
SO  - Cancer Chemother Pharmacol. 2022 Jan;89(1):71-81. doi: 
      10.1007/s00280-021-04368-1. Epub 2021 Oct 26.