PMID- 31173885
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20200122
IS  - 1873-488X (Electronic)
IS  - 1056-8719 (Linking)
VI  - 99
DP  - 2019 Sep-Oct
TI  - Translatability of the S7A core battery respiratory safety pharmacology studies: 
      Preclinical respiratory and related clinical adverse events.
PG  - 106596
LID - S1056-8719(19)30098-X [pii]
LID - 10.1016/j.vascn.2019.106596 [doi]
AB  - INTRODUCTION: Before entering into first-in-human studies, most new chemical 
      entities must undergo a series of preclinical evaluations. ICH S7A safety 
      pharmacology (SP) guidelines, adopted in 2001, include respiratory assessments as 
      part of the core battery. Despite these safety measures being in place for nearly 
      two decades, studies examining the relationship between preclinical findings 
      captured in respiratory SP studies and clinical respiratory adverse events (AEs) 
      are sparse. Therefore, the aim of this study is to evaluate the predictive value 
      of preclinical respiratory observations to identify clinical respiratory AEs for 
      both investigational products in early drug development and approved drugs. 
      METHOD: Three independent databases were interrogated to evaluate the concordance 
      between preclinical and clinical respiratory AEs. Two databases stem from early 
      clinical phase studies, evaluating 52 and 128 investigational products 
      respectively. The third database was derived from a large repository of nearly 
      4000 FDA and EMA drug approval documents. RESULTS: Analysis of early phase 
      clinical studies revealed little to no predictive risk for clinical respiratory 
      adverse events when respiratory findings were observed in preclinical studies, 
      with a positive predictive value (PPV) of 27% and 36% for each dataset 
      respectively. In addition, the likelihood ratio, which reflects the shift in 
      predictability of human risk, was 1.02 and 0.76 respectively, indicating no 
      change in liability. Evaluation of approved drugs revealed a small shift in 
      predictability for preclinical respiratory findings to translate into respiratory 
      clinical AE, with likelihood ratios ranging from 2.5-3.4 and PPV of 18-29% for 
      severe AEs such as lung disorder, respiratory depression and respiratory failure. 
      DISCUSSION: Altogether the translatability of preclinical respiratory findings 
      into clinical AEs is low. Mandating dedicated respiratory SP studies as part of 
      the core battery should be reconsidered in light of the low translatability of 
      respiratory risk clinically and can be effectively incorporated into toxicology 
      investigations.
CI  - Copyright (c) 2019 Elsevier Inc. All rights reserved.
FAU - Paglialunga, Sabina
AU  - Paglialunga S
AD  - Celerion, Tempe, AZ, United States of America.
FAU - Morimoto, Bruce H
AU  - Morimoto BH
AD  - Alkahest, Inc., San Carlos, CA, United States of America.
FAU - Clark, Matthew
AU  - Clark M
AD  - Elsevier, Philadelphia, PA, United States of America.
FAU - Friedrichs, Gregory S
AU  - Friedrichs GS
AD  - Novartis Institue of Biomedical Research, East Hanover, NJ, United States of 
      America. Electronic address: greg.friedrichs@novartis.com.
LA  - eng
PT  - Journal Article
DEP - 20190605
PL  - United States
TA  - J Pharmacol Toxicol Methods
JT  - Journal of pharmacological and toxicological methods
JID - 9206091
SB  - IM
OTO - NOTNLM
OT  - Adverse drug reactions
OT  - Concordance
OT  - ICH S7A
OT  - Likelihood ratio
OT  - Methods
OT  - Nonclinical predictive value
OT  - Pulmonary
EDAT- 2019/06/08 06:00
MHDA- 2019/06/08 06:01
CRDT- 2019/06/08 06:00
PHST- 2019/05/17 00:00 [received]
PHST- 2019/06/03 00:00 [accepted]
PHST- 2019/06/08 06:00 [pubmed]
PHST- 2019/06/08 06:01 [medline]
PHST- 2019/06/08 06:00 [entrez]
AID - S1056-8719(19)30098-X [pii]
AID - 10.1016/j.vascn.2019.106596 [doi]
PST - ppublish
SO  - J Pharmacol Toxicol Methods. 2019 Sep-Oct;99:106596. doi: 
      10.1016/j.vascn.2019.106596. Epub 2019 Jun 5.