Poster No: 171

The application of blood spot technology to determinepharmacokinetic parameters for safety pharmacology studiesSonia Roberts, Oladipupo Adeyemi, Mark Dewhurst, Jolie Harris,Jade Barker, Nick Edmunds, Graeme T. Clark

Pfizer Inc, Sandwich, UK

Pharmacokinetic (PK) analysis of NCE's is an integral part of SafetyPharmacology studies. Adequate definition of time dependentchanges in free blood concentrations increases the accuracy ofexposure estimates and the application of PK/PD modeling forpredicting concentration-dependent changes in physiological para-meters. UK Home Office restrictions recommend that total bloodcollections in a 24 hour period are <10% of the total blood volumeper animal (mouse, 25 g=0.14 mL; rat, 400 g=2.56 mL); thereforemultiple animals are required to perform a thorough PK study. Theintroduction of blood spot technology has significantly reduced thevolume of blood required/time point to only 20 μL of whole bloodwhich can be collected with minimal restraint via a saphenous veinpuncture. A full PK profile (for 24 h) can now be defined in eachanimal using a total blood collection volume of only 120 μL. Thistechnique is now applied extensively within our laboratories tosupport PK studies. It reduces the need for satellite animals, allowingPK parameters to be determined in individual animals along with PDendpoints. Thus improving PK/PD data and minimizing stress due torestraint and intravenous sampling. Hence all 3 components of the3Rs are addressed. The suitability of blood spot technology to supportSafety Pharmacology telemetry studies in mouse, rat and marmoset isdemonstrated and its application to PK/PD modeling further supportsthe use of this technique.

doi:10.1016/j.vascn.2011.03.176

Poster No: 172

Study of pharmacodynamic and pharmacokinetic interactions ofselected protease inhibitors with gliclazide in animal modelsShaik Mastan a, Kilari Eswar Kumar b

a Jawaharlal Nehru Technological University, Hyderabad-500072,Andhra Pradesh, Indiab Pharmacology Division, AU College of Pharmaceutical Sciences,Visakhapatnam-530003, Andhra Pradesh, India

The objective of this study was to investigate the safety andeffectiveness of the selected protease inhibitors (PIs) with gliclazideby conducting pharmacodynamic (PD) interaction studies in rats(normal and diabetic) and rabbits, and pharmacokinetic (PK) interac-tion studies in rabbits. These studies were conducted with an oral doseof gliclazide, interacting drug (indinavir/ritonavir/atazanavir) and theircombination with adequate washout periods in between treatments(single dose followed by multiple dose study). The blood samples wereanalyzed for blood glucose by GOD/POD method and insulin wasmeasured by Radio ImmunoAssaymethod. The insulin resistance indexand β-cell function were determined by HOMA. The serum gliclazidelevels were estimated by HPLC method and PK analysis was conductedby non-compartmental analysis using WinNonlin software. The datawas subjected to Student's paired ‘t’ test (n=6). Among PIs, indinavirand ritonavir were associated with significant glucose disorders inanimal models. When given in combination indinavir shows significant(p<0.05) PD interaction with gliclazide. In combination, ritonavir andatazanavir significantly (p<0.05) enhanced the pharmacodynamics of

gliclazide and confirmed PK interaction at hepatic metabolism withreduced gliclazide metabolism (CYP3A4 and/or CYP2C9). Since theseinteractionswere seen in rodent and non-rodent, they are likely to occurin humans also leading to decreased or increased activity of gliclazide,which may need dosage adjustment. Hence care should be taken whenthese combinations are prescribed for their clinical benefit to diabeticpatients.

doi:10.1016/j.vascn.2011.03.177

Poster No: 173

Multi-compartmental PK-PD modeling of baclofenHarriet W. Kamendi a, Khanh Bui b, David J. Lengel a, Russell Bialecki a

a Safety Assessment US, AstraZeneca Pharmaceuticals, Wilmington DE,United Statesb Drug Metabolism and Pharmacokinetics, AstraZeneca Pharmaceuticals,Wilmington DE, United States

Pharmacokinetic and pharmacodynamic (PK-PD) modeling is atool that allows for a predictive and descriptive relationship betweentime course and effect of a drug in the body. PK-PD modeling can beused to determine the potential consequences of drugs in the body.Baclofen, a GABA-A agonist, is indicated for muscle relaxation and asan antispastic agent. It is contraindicated in individuals who havesyncope, seizures and in people with a history of cardiovascularcomplications. This study determines the effects of baclofen on thecardiovascular and thermo-regulatory systems in the rat. Rats werehoused in the novel automated blood sampling and telemetry system(ABST). They were dosed with baclofen (10 mg/kg p.o.). Bloodpressure, heart rate and body temperature were recorded for 24 h.Blood was also sampled in the same animals for PK analysis. Availabledata was used to perform multiple PK-PD analysis using three effectcompartments—BP, heart rate and body temperature. Baclofen dosedependantly increased (p<.05) blood pressure and heart rate whiledecreasing (p<.05) body temperature. PK-PD modeling indicatesthat baclofen differentially affects the effectors. Blood pressure andheart rate responses fit into a simple Emax model where bloodpressure increases up to a maximum. Temperature fit into turnovermodel. Body temperature decreased before returning to normal.Multi-compartment approach to PK-PD analysis using the ABST is apowerful approach to predictive science with high statistical power.Evaluation of multiple compartments in one rat presents a statisti-cally powerful way of characterizing drug effects, their outcomes andelucidating possible causal relationships between organ systems.

doi:10.1016/j.vascn.2011.03.178

Poster No: 174

Can a drug induce cardiovascular changes that affect thekinetic profile?Brian M. Roche, S. Peter Hong, Tom Vinci, Jeremy Smith, Craig Hassler

Battelle Memorial Institute, Columbus, OH, USA

To achieve toxic effects in a Toxicology study and to assess safetyin a safety pharmacology study, doses need to be administered thatexceed anticipated therapeutic doses for humans. Such high dosescan deviate from the linear pharmacokinetic profile typicallyobtained from lower doses of a compound and result in non-linearkinetics. Kinetic profiles characteristic of non-linear kinetics (e.g.,

Abstracts e51