Table 3.

Examples of non‐DDI PBPK analyses and their impact on drug development and regulatory decisions

Drug	Key theme (impact level) and question(s)	Brief description	Internal impact	Qualification dataset	FDA/EMA response
Lesinurad (marketed) Pepin et al., 201667	Absorption: specifications for dissolution and particle size (high) Using an validated in silico model to support proposed specifications for dissolution and particle size without having to do a in vivo relative BA or bioequivalence study	In silico PBPK model (GastroPlus) using 3 compartment PK model based on IV and PO clinical data with a mechanistic absorption model based on in vitro dissolution data fitting particle size distribution.	Waiver granted for a clinical relative bioequivelance study	IV and PO clinical data. Validated using clinical data from a batch that was bioinequivalent. Several methods to input in vitro dissolution data into the model were evaluated.	FDA: Accepted. PBPK model accepted in support of proposed control strategy without the need for a relative BA study. EMA: Not submitted by the sponsor.
Canagliflozin (marketed) Tistaert et al., 2015) 68	Absorption (high) Differences in particle size between different API batches manufactured in a different will not lead to differences in oral bioavailability and no relative bioavailability study is needed	During formulation development the granulation and milling processes were slightly changed. Non‐particle‐engineered to particle‐engineered. Bottom‐up approach predicted physchem and measured solubilities; particle size distribution combined with compartmental PK based on clinical data.	PBPK modeling was used to assess particle size sensitivity of canaglifozin bioavailability, without the need to perform a relative BA study	PK of canagliflozin across 3 dose levels of the non‐particle size engineered tablets. And a nonclinical bioavailability study in beagle dogs.	FDA: Accepted. Requested additional information upon reviewing the data package: (1) Physchem property data; including intrinsic dissolution profile comparison; (2) GastroPlus model and simulation details, including description, assumption and validation for the model. Also include the scenarios, parameters and interpretations for the simulation; (3) the data for each trial used in the cross‐study comparison. EMA: Not submitted by the sponsor.
Ribociclib (marketed) Samant et al., 201757	Absorption (high) Impact of PPIs on ribociclib absorption	No change in absorption was predicted when changing stomach pH to simulate the impact of PPIs, which was confirmed by clinical data that were evaluated using PopPK and NCA approaches.	No PPI study was performed.	SAD/MAD, ritonavir DDI, midazolam DDI	FDA: Accepted. (using PopPK and PBPK approach) EMA: Not accepted. Agency accepted approach based on PopPK and NCA but not PBPK.
Eribulin (NDA submission) Not published	Pediatric (Low–moderate) What is the starting dose of eribulin in children	A PBPK model was developed for eribulin and used to perform simulations with the Simcyp pediatric population. Model predicted that the starting dose in 6 – 12 year old patients should be half of the therapeutic doses in adults. CL characteristic CYP3A metabolism, but mainly biliary excretion (which was converted into HLM CLint with the retrograde calculator)	PBPK confirmed results from traditional population‐based scaling approaches to set the starting dose for the pediatric program	Clinical PK data. Results of the first pediatric trial showed that the model predicted the clearance of 12 – 18 year old patients very well. Clearance of 6 – 12 year old was slightly over predicted, but within acceptable range.	FDA: No comment. Starting dose was accepted. EMA: No comment. Starting dose was accepted.
Blinatumomab (NDA submission) Xu et al., 201556	PD of drug‐mediated drug interaction (high) Is transient cytokine elevation resulting from the immunotherapy Blinatumomab likely to result in clinically meaningful DDIs?	Blinatumomab immunotherapy mediates transient cytokine elevation. Cytokine elevations may affect CYP activities. A PBPK model was established to evaluate the effect of transient cytokine elevation on CYP activities. Transient cytokine elevation observed during blinatumomab treatment has a low DDI potential.	No DDI study was planned or performed.	The predictability of the PBPK model was first verified by predicting transient CYP suppression in human hepatocytes after incubation with cytokine cocktail for 2 days. Additional model verification was applied to chronic CYP suppression observed in rheumatoid arthritis patients (published data).	FDA: Applicant's PBPK predictions are not recommended to be included in the drug label. However, a DDI study was not required. EMA: Agency supported the same drug label language with regards to drug interactions as in the USPI.
Quetiapine (late development) Johnson et al., 201469	Pediatrics (medium) Bridging formulations. Quetiapine XR and Quetiapine formulations and extrapolating from adult to pediatric	Could we set a dose for the XR formulation in children without performing a trial based on existing preclinical and clinical exposure data?	Inform dose selection in children	Internal compound file	FDA: Accepted. EMA: Not submitted by the sponsor.
Deflazacort (late development) US FDA Clinical Pharmacology Review 44	Pediatrics (medium) Effect of CYP3A4 perpetrators in pediatric population	PBPK model built in adult population with DDIs CYP3A4 verified with clinical data. Pediatric PK data showed no change in PK compared to adults	Dose adjustments with CYP3A4 perpetrators in line with adult adjustments	DDI CYP3A4 in adult population. A case could be made to support same dose adjustments in pediatrics as in adults.	FDA: Accepted. EMA: No response.