Human PK Projection Qualified Against Phase 1 Clinical Data

Pharmaron poster on a human PK projection strategy, showing the projection workflow, hepatocyte clearance scaling and predicted versus observed Phase 1 clearance.

Poster Authors:

Simon Taylor1, Barry Jones1, Chunyan Han2, Xingjin Jiao2, Yi Wang2

1 Pharmaron UK Ltd., West Hill Innovation Park, Hertford Road, Hoddesdon, Herts. EN11 9FH, UK

2 Pharmaron Beijing, Co. Ltd., No. 6, Taihe Road, BDA, Beijing, 100176, China

Human PK projection is the method drug teams use to estimate human pharmacokinetics before the first clinical dose. A projection is only as useful as its track record, so Pharmaron compared projected human pharmacokinetics (PK) for four small molecule candidates against the values observed in Phase 1 trials. Observed clearance fell within 2-fold of the projections.

Pharmaron’s drug metabolism and pharmacokinetics (DMPK) team presented this work at a Lunch and Learn session in Oxford, UK on 23 June 2026. The poster below walks through the projection strategy, the in vitro systems behind it and how each projection compared to observed clearance. Download it for the full workflow and the molecule-by-molecule data.

What is human PK projection?

Human PK projection estimates how a drug candidate will be cleared, distributed and absorbed in people, using data collected before any human dosing. The estimate guides compound selection and sets the starting dose for a first-in-human study. Pharmaron builds each projection from physicochemical properties, absorption, distribution, metabolism and excretion (ADME) data and preclinical in vivo results. Clearance, volume of distribution at steady state (Vss) and absorption are scaled separately, then combined to simulate human PK using compartmental or physiologically based pharmacokinetic (PBPK) methods.

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How does Pharmaron project human PK?

In vitro intrinsic clearance was measured in human hepatocytes using two formats: standard suspension and a plated low clearance system. In vitro systems tend to under-predict clearance, so Pharmaron applied laboratory specific regression offset equations to correct the scaling for rat and human. An in vitro-in vivo correlation (IVIVC) of metabolic clearance was established in preclinical species, which supported extrapolation to human for compounds cleared mainly by metabolism. Vss was projected from physicochemistry. Oral absorption was projected from Caco-2 permeability data combined with in vivo PK.

How did the projections compare to Phase 1 data?

After Phase 1 data became available, Pharmaron compared each projection to the observed values, with a focus on clearance. Human clearance estimates from the suspension and plated hepatocyte formats agreed with each other. Projected Vss matched the physicochemistry of the molecules. Oral absorption was projected as moderate to high for all four candidates. Observed human PK values stayed within 2-fold of the projections. The poster reports the results for each molecule, along with the assay details and correction factors.

Key takeaways

  • One projection strategy supported four small molecule candidates into Phase 1 evaluation.
  • Suspension and plated human hepatocyte formats gave matching human clearance estimates after regression offset correction.
  • Observed oral clearance in Phase 1 stayed within 2-fold of the Pharmaron projections.
  • Preclinical IVIVC added confidence for compounds cleared mainly by metabolism.

What is in the poster?

The poster includes the projection workflow diagram, the regression offset approach, preclinical data for the molecules and the observed versus projected human PK comparison. It is the supporting evidence behind the summary above.

Frequently asked questions

What is human PK projection in drug development?

It is the estimation of human pharmacokinetics, mainly clearance, volume of distribution and absorption, from preclinical and in vitro data before the first human dose.

How accurate are human PK projections compared to Phase 1 data?

In this Pharmaron dataset, observed human clearance for four candidates stayed within 2-fold of the projections.

How is human clearance predicted from hepatocyte assays?

Intrinsic clearance is measured in suspension or plated human hepatocytes, corrected with a regression offset, then scaled to whole-body clearance.

What is the regression offset approach?

It is a laboratory specific correction that adjusts for the tendency of in vitro systems to under-predict clearance.

Pharmaron scientist in lab coat and gloves loading a sample into an automated analyzer for preclinical PK biologics studies

Download the poster to see how Pharmaron projected human PK for four candidates and how each compared to Phase 1 clinical data.

Download the Poster

References

1. Sohlenius-Sternbeck AK, et al. Evaluation of the human prediction of clearance from hepatocyte and microsome intrinsic clearance for 52 drug compounds. Xenobiotica. 2010;40(9):637-649. PMID 20624033.

2. Sohlenius-Sternbeck AK, et al. Practical use of the regression offset approach for the prediction of in vivo intrinsic clearance from hepatocytes. Xenobiotica. 2012;42(9):841-853. PMID 22509824.

3. Lancett P, et al. Development and Characterization of a Human Hepatocyte Low Intrinsic Clearance Assay for Use in Drug Discovery. Drug Metab Dispos. 2018;46(8):1169-1178. PMID 29880630. DOI 10.1124/dmd.118.081596.

4. FDA. Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers (Guidance for Industry).

5. FDA. Physiologically Based Pharmacokinetic Analyses: Format and Content (Guidance for Industry).