P68 Early human in vivo pharmacokinetic predictions in drug discovery

Marie Ahlqvist , AstraZeneca IMED Biotech Unit, Gothenburg, Sweden
Bo Lindmark , AstraZeneca IMED Biotech Unit, Gothenburg, Sweden
Martin A. Hayes , Innovative Medicines CVMD DMPK, AstraZeneca IMED Biotech Unit, Gothenburg, Sweden
Ulrik Jurva , Dx DMPK &BAC, AstraZeneca IMED Biotech Unit, Gothenburg, Sweden
Marcus Olivecrona , AstraZeneca IMED Biotech Unit, Gothenburg, Sweden
Eva Lundborg , AstraZeneca IMED Biotech Unit, Gothenburg, Sweden
Carola Wassvik , AstraZeneca IMED Biotech Unit, Gothenburg, Sweden
Rasmus Jansson Löfmark , AstraZeneca IMED Biotech Unit, Gothenburg, Sweden
Shalini Andersson , AstraZeneca IMED Biotech Unit, Gothenburg, Sweden
Early human in vivo pharmacokinetic predictions in drug discovery

Marie Ahlqvist, Bo Lindmark, Martin Hayes, Ulrik Jurva, Marcus Olivecrona, Eva Lundborg, Carola Wassvik, Rasmus Jansson-Löfmark, Shalini Andersson

Predicting human in vivo pharmacokinetic parameters e.g. clearance (CL), volume of distribution (Vss), bioavailability (F%) and half life (t1/2) from in vitro data is crucial in the drug-development process. These parameters are a central part of human dose predictions which are of significant value for assessing the distance to the candidate drug target profile and the overall potential of new chemical entities. As PKPD understanding evolves during project progression, the confidence in the human dose prediction increases.

An easy to use database query, with columns including predicted human dose in addition to human pharmacokinetic parameters (human CL, Vss, t1/2 and F%) is applied in all AstraZeneca drug projects. There are two versions of the human dose prediction, based either on mean steady state concentration at target level or duration of concentration above target level. Clearance is calculated from either Clint measured in human liver microsomes (HLM) or human hepatocytes, which assumes that the compounds are cleared only by hepatic metabolism. A human dose prediction is performed as soon as Wave 1 data are available i.e. in vitro potency, HLM Clint and human plasma protein binding. Predicted values for fraction unbound in the incubation (fuinc), blood/plasma ratio and Vss are also used in the calculations. When additional data such as Clint in human hepatocytes, measured fuinc, B/P ratio and rat in vivo PK parameters are available, the calculations are automatically updated. There is flexibility at compound level which allows input on fold times IC50 (based on current PKPD knowledge), fraction absorbed (Fabs), absorption constant (Ka), dosing interval (t) and time over IC50.

The predicted human in vivo pharmacokinetic parameters CL/F, Vss/F, t1/2 have been compared with clinical data on 35 in house compounds. The results from this comparison indicate that the compounds are ranked well, 50% of the compounds are predicted within 2-fold and 80% of the compounds are predicted within 5-fold for CL/F, Vss/F and t1/2.