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In-Vivo Safety - Pre Ind Drug Development
The document discusses the drug development process from pre-clinical research through Investigational New Drug (IND) application. It outlines the typical studies required to evaluate safety and toxicity, identify target organs of toxicity, determine appropriate dosing for clinical trials, and communicate risks. These include pharmacology, pharmacokinetics, safety pharmacology, acute and repeat-dose toxicology studies in two animal species along with genetic toxicology assays. The goals are to estimate initial safe doses for clinical trials and identify parameters that can monitor toxicity. The process seeks to identify potentially safe compounds for human testing while eliminating those that may be unsafe.
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In-Vivo Safety - Pre Ind Drug Development
- 1. IN-VIVO SAFETY –PRE IND DRUG DEVELOPMENT EVERY STEP OF THE WAY EVERY STEP OF THE WAY Drug Development Boot Camp Brian M. Roche, PhD, DSP, DABT Executive Director of Global Safety Pharmacology Charles River - Ashland
- 2. General Principals • TwoObjectives: • Pharmacologically active • Safe for humans • Goal of preclinical studies is to evaluate toxicity with respect to: • Target organs • Dose dependence • Relationship to exposure • Potential reversibility • Off-target effects • Evaluate toxic effects • Outcomes are to estimate dose levels for IND toxicology and safety pharmacology studies.
- 3. Goals for INDprogram For biopharmaceuticals and small molecules: • Identify an initial safe dose and appropriate dose escalation scheme in humans • Identify potential target organs of toxicity and determine whether such toxicity is reversible • Identify appropriate species for toxicology assessment • Identify parameters that are predictive of toxicity and can be clinically monitored • Communicate risk
- 4. TYPICAL DRUG DEVELOPMENTFUNNEL Discovery Exploratory Development Idea Drug Years Full Development Phase I Phase II Phase III 0 155 10 Preclinical Pharmacology 250 compounds Preclinical Tox & Safety Drug Discovery 5,000 to 10,000 compounds Clinical Pharmacology & Safety, 5 compounds 1 compound
- 5. Discovery Lead OPTox Safety Pharm Phase I IND •Clinical•High Throughput PK IND Enabling Studies: •Safety Pharmacology •CV •CNS •Respiratory •GI •Renal •Dose Formulation Support •Bioanalytical Support IN-VIVO SAFETY – DRUG DEVELOPMENT PROCESS •PK •Dose range finder •Tolerability studies •Biodistribution •Lead op tox •Pharmacology •Anesthetized preps •Langendorff Assay •Small animal Telemetry •2nd species 1000 250 1-6 IND Enabling Studies: •Toxicology •DFR •14-28 Day •Route of administration •2 species •Recovery •Genetic Toxicology •Dose Formulation Support •Bioanalytical Support GLP
- 6. PRIMARY PHARMACOLOGY • Invitro studies • binding assays • Receptor binding affinity • Lead or safety panels • In vivo studies • Single dose/activity in rodent/large animal • Multiple dose effects in large animal • Tolerability studies with safety endpoints • Mechanism of action • Dose selection • Non-GLP
- 7. PHARMACOKINETICS AND TOXICOKINETICS •ADME/DMPK • Metabolic and plasma protein binding studies • CYP inhibition/induction • Systemic exposure in the species used for repeat dose toxicology • PK in test species and in-vitro biochemical data for potential drug interactions before Phase 3. • Nonclinical testing of human metabolites only if exposures are greater than 10% of total drug exposure. Support Phase 3 clinical studies. • Data integration • Interspecies scaling of in vitro and in vivo data to predict IND and clinical performance
- 8. STATISTICAL FACTORS TOCONSIDER False Positives False Negatives
- 9. Discovery Lead OPTox Safety Pharm Phase I IND •Clinical•High Throughput PK IND Enabling Studies: •Safety Pharmacology •CV •CNS •Respiratory •GI •Renal •Dose Formulation Support •Bioanalytical Support IN-VIVO SAFETY – DRUG DEVELOPMENT PROCESS •PK •Dose range finder •Tolerability studies •Biodistribution •Lead op tox •Pharmacology •Anesthetized preps •Langendorff Assay •Small animal Telemetry •2nd species 1000 250 1-6 IND Enabling Studies: •Toxicology •DFR •14-28 Day •Route of administration •2 species •Recovery •Genetic Toxicology •Dose Formulation Support •Bioanalytical Support GLP
- 10. SCENARIOS FOR SMALLAND LARGE MOLECULES Study New Chemical Entity BioPharmaceutical Follow-on Biologics Vaccines Pharmacology Yes Yes Yes Yes PK Yes Limited Mixed limited Acute/DRF Yes (2 species) Yes (1 or 2 relevant species) Yes (1 species) Yes (1 species; rabbit) Repeat dose tox w/TK Yes (2 species; 1 nonrodent) 2 weeks to 9 months Recovery Period Yes (1 or 2 relevant species) 2 weeks to 6 months Recovery period Immunogenicity Local tolerance study Yes (1 species) Yes (1 species) Local tolerance immunogenicity Genotoxicity Yes No No No Safety Pharmacology Yes Yes* No No *Preferred method is standalone assessment of safety pharmacology endpoints but may be considered for incorporation of SP endpoints in toxicology study design.
- 11. SCENARIOS FOR ANTI-CANCERPHARMACEUTICALS Study Type NCE Advanced NCE w/Increased Life Expectancy NBE Advanced NBE w/Increased Life Expectancy Pharmacology Yes Yes Yes Yes PK Limited Limited Limited limited Acute/DRF Yes (2 species) Yes (2 species) Yes (1 or 2 species) Yes (1 or 2 species) Repeat dose tox Yes limited TK Recovery period Yes TK Recovery period Yes limited TK Recovery period Yes TK Recovery period Immunogenicity Genotoxicity No No No No Safety Pharmacology Yes* – could be included in toxicity studies Yes Yes* – could be included in toxicity studies Yes* – could be included in toxicity studies *Preferred method is standalone assessment of safety pharmacology endpoints but may be considered for incorporation of SP endpoints in toxicology study design.
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- 14. EXAMPLE IND PACKAGE– NCE Studies GLP Preclinical Pharmacology: In vitro Studies • Cloned Human Receptor Binding Affinity • PanLab (Cerep) Screen No No Preclinical Pharmacology: In vivo Studies • Activity in Rats • Single Dose Effects in Dogs • Single-Dose Effects in Pigs No No No Preclinical Pharmacokinetics: In vitro Studies • Plasma Protein Binding • Comparative Microsomal Metabolism • Effects on Human Cytochrome P450 • Efflux Transporter Substrate Study Yes Yes Yes No Preclinical Pharmacokinetics/Toxicokinetics: In vivo Studies in Rats • 7 Day Oral Gavage • 28 Day Oral Gavage • Freebase Toxicokinetics • ADME No Yes No Yes
- 15. EXAMPLE IND PACKAGE– NCE Studies continued GLP Preclinical Pharmacokinetics/Toxicokinetics: In vivo Studies in Dogs • TK Oral Study • TK IV Study • Single-Dose PK Study Oral and IV • Oral MTD • 28-Day TK • Freebase Toxicokinetics • ADME No No Yes No Yes No Yes Safety Pharmacology: In vitro Studies • hERG • Langendorff isolated heart (guinea pig) Yes Yes Safety Pharmacology: In vivo Studies • Modified Irwin (rat) • Locomotor Activity (rat) • Intestinal Motility (rat) • Renal Function (rat) • Cardiovascular Range-Finding (dog) • Cardiovascular and Pulmonary Function (dog) Yes Yes Yes Yes No Yes
- 16. EXAMPLE IND PACKAGE– NCE Studies continued GLP Single-Dose Toxicity in Mice and Rats • Acute IV Toxicity in Mice • Acute IV Toxicity in Rats • Acute Oral Toxicity in Mice • Acute oral Toxicity in Rats Yes Yes Yes Yes Repeat-Dose Toxicity in Rats and Dogs • 7-Day Dose Range Finding in Rats • 28-Day Toxicity in Rats • MTD in Dogs • 28-Day Toxicity in Dogs No Yes No Yes Genotoxicity • Ames Test • Chromosomal Aberration Assay (HPBL) • Mouse Micronucleus Assay Yes Yes Yes
- 17. 17 EVERY STEPOF THE WAY17 EVERY STEP OF THE WAY CASE STUDY DISCOVERY/LEAD OP/CANDIDATE SELECTION TO IND