Evaluation of an innovative population pharmacokinetic-based design for behavioral pharmacodynamic endpoints.
Pre-clinical behavioral pharmacology studies supporting indications like analgesia typically consist of at least three different studies; dose-finding, duration of effect, and tolerance-development studies. Pharmacokinetic (PK) plasma samples are generally taken from a parallel group of animals to avoid disruption of the behavioral pharmacodynamic (PD) endpoint. Our objective was to investigate if pre-clinical behavioral pharmacology studies in rats could be performed effectively by combining three studies into a single experimental design and using sparse PK sampling in the same animals as for PD. A refined dosing strategy was applied for a muscarinic agonist, AZD6088, using the rat spinal nerve ligation heat hyperalgesia model. PD measurements were performed on day 1, 3, 5 and 8. Two PK samples per day were taken day 2 and 4. In a separate control group, PD measurements were performed on rats without PK sampling. Data was analyzed using a population approach in NONMEM. The animals produced a consistent and reproducible response irrespective of day of testing suggesting that blood sampling on alternate days did not interfere with the PD responses. A direct concentration-effect relationship with good precision was established and no tolerance development was observed. The new design combining three studies into one and eliminating a satellite PK group realized substantial savings compared to the old design; animal use was reduced by 58% and time required to generate results was reduced by 55%. The design described here delivers substantial savings in animal lives, time, and money whilst still delivering a good quality and precise description of the PKPD relationship.
Clinical Pharmacology and Pharmacometrics, AstraZeneca R&D Södertälje, 151 85, Södertälje, Sweden. anders.viberg@astrazeneca.com
Anders
A
Viberg
Giovanni
G
Martino
Etienne
E
Lessard
Jennifer M A
JM
Laird
D000818:Animals; D017046:Cost Savings; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000191:economics / Q000379:methods; D004361:Drug Tolerance; D023381:Endpoint Determination / Q000379:methods*; D006930:Hyperalgesia / Q000188:drug therapy*; D048289:Imidazolidines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D008954:Models, Biological; D018721:Muscarinic Agonists / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D017711:Nonlinear Dynamics; D010880:Piperidines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D013997:Time Factors
C579428:AZD6088; D048289:Imidazolidines; D018721:Muscarinic Agonists; D010880:Piperidines