An alternative approach has been developed to estimate the clinical dose of new drug molecules at an early stage in the drug discovery process. This approach has been compared to traditional methods using the clinical dose as indicated on the drug label of 136 marketed drugs. At the early stages of drug discovery only in silico predictions or some initial in vitro screening data are normally available, typically parameters such as affinity/potency (pXC50)from isolated enzymes or receptors, measured albumin and phospholipid binding using biomimetic HPLC measurements, and in vitro clearance using P450 enzymes or liver microsomes. The combination of the biomimetic HPLC phospholipid and protein binding provides a drug efficiency max parameter described previously (HPLC DEmax), and in vitro potency makes it possible to estimate a clinical dose that would result in an efficacious steady state free concentration at the site of action. The influence of the potential discrepancies between the in vitro and a later stage in vivo DEmax, the whole blood potency, volume of distribution and clearance on the dose estimation has been investigated, using data from a GSK programme profiled during lead optimisation. It was found that drug potency had the greatest influence on estimating the clinical dose. When the estimated dose is low, the impact of other parameters such as the volume of distribution and clearance was much less significant and typically did not affect compound ranking.