Formulation
IVIVC
Preclinical
The situation
Three prototypes, a preclinical PK study on each, and a decision due before the tox batch is committed.
What we do
- Rank on in vivo exposure, not dissolution alone
- Separate real differences from study noise
- Build and test the dissolution-to-exposure correlation
What you get
- A ranked recommendation, with the reasoning
- Dissolution specifications backed by exposure
- A first correlation to carry into clinical development
Regulatory basis
For extended-release oral products, FDA guidance allows an IVIVC established on human data to support a biowaiver when formulation, process or site change. Ranking prototypes on in vivo exposure early prepares the ground for it.
FDA, Extended Release Oral Dosage Forms: IVIVC
Translational
First-in-human
IND / CTA
The situation
The animal model works and GLP toxicology is done. Now the starting dose has to be defended in an IND or CTA.
What we do
- Predict human PK by allometry and by PBPK, then reconcile
- Find the driver of effect: peak, AUC, or time above threshold
- Translate on exposure, not dose
What you get
- Predicted human profile, assumptions stated
- Starting dose and escalation, with the rationale
- A Phase I sampling schedule that informs the model
Regulatory basis
The starting dose is among the first things a reviewer scrutinises. A rationale tied to the toxicology exposures is far easier to defend than an unexplained scaling factor.
FDA, Estimating the Maximum Safe Starting Dose
Population PK
PK/PD
Phase 2
The situation
First-in-human is complete. The single and multiple ascending dose data are in, and the Phase 2 dose now has to be chosen and justified.
What we do
- Characterise the PK profile across the dose range
- Find the sources of variability that actually matter
- Simulate candidate doses against the exposure target
What you get
- A population PK model, covariates documented
- The recommended Phase 2 dose, with the simulations behind it
- A Phase 2 sampling plan that keeps the model learning
Regulatory basis
FDA's population PK guidance describes using population analyses to identify the factors that explain variability in exposure and to inform dosing. Applied to the first-in-human data, it gives the Phase 2 dose a quantitative basis rather than resting on tolerability alone.
FDA, Population Pharmacokinetics
PBPK
DDI
Special populations
The situation
Co-medications and organ impairment are coming. A dedicated study for each is slow, expensive, and possibly unnecessary.
What we do
- Build the PBPK model from in vitro and clinical data
- Verify it against data it was never fitted to
- Simulate the interactions and the impaired populations
What you get
- A qualified model, calibration documented
- Predicted exposure ratios per scenario
- A ranking of which studies you still need
Regulatory basis
Under ICH M12, PBPK can be used to predict untested interactions and, in some cases, in place of a dedicated clinical study. The model has to be verified against clinical data before it is relied on.
ICH M12, Drug Interaction Studies
Exposure-response
Population PK
Submission
The situation
A dose worked in Phase II. At filing it has to be shown to be the right dose, including for patients at the edges of the distribution.
What we do
- Model exposure and the covariates that genuinely explain it
- Link exposure to efficacy and to safety
- Test the alternatives you did not choose
What you get
- Submission-ready popPK and exposure-response reports
- Dose justification, and the evidence behind the label
- Answers to the dosing questions a reviewer will raise
Regulatory basis
Dose justification is a recurring cause of regulatory questions and post-marketing commitments. Planned prospectively, the analysis answers them before they are asked.
FDA, Exposure-Response Relationships
Paediatric
Extrapolation
Study design
The situation
A paediatric plan is required, but recruiting children is slow, costly and ethically constrained.
What we do
- Judge how far disease, exposure and response extrapolate
- Scale PK to age and size, allowing for maturation
- Simulate doses per age band against the adult target
What you get
- An extrapolation rationale, uncertainty stated
- Doses by age band, with the simulations behind them
- A study design sized to the remaining question
Regulatory basis
ICH E11A sets out how far paediatric extrapolation can go and what must still be collected. E11(R1) asks that the approach be raised with regulators early.
ICH E11A, Pediatric Extrapolation
