Drug Development (Block 1) Flashcards

Question

Types of DMPK studies -Metabolism

Answer 1

In vitro cross-species metabolism Metabolite identification CYP450 metabolism Transporter assays

Answer 2

Mass balance Transporter assays

Answer 3

Shows whether anything is happening in other (non-target) organs Multiple doses in 2 animal species - rodent and non-rodent Doses must exceed intended human exposure Prior to FTiH generally conduct a 28 day study Recovery group included to see if toxicology is reversible Study is under GLP conditions, ideally with drug manufactured to GMP

Answer 4

Study designed to explore ascending does groups and establish a dose response curve

Answer 5

Critical to understand exposures associated NOAEL and MTD Will be used in the calculation of starting dose for human clinical trials Do not want to exceed exposures associated effect levels in humans Interspecies differences in protein binding are taken into account

Answer 6

Good Laboratory Practice is a set of guidelines to ensure quality and integrity of non-clinical lab studies

Answer 7

1st time new investigational medicinal product is tested in humans Usually healthy volunteers Sometimes patients with advanced disease (eg. cancer) Small numbers of subjects (20-80) Aim is to evaluate safety, tolerability and pharmacokinetics Clinical Pharmacology studies to explore ADME These are called Phase I studies, but can span clinical development

Answer 8

Providing scientific basis for rational safe and effective prescribing

Answer 9

The relationship between dose & therapeutic effect The relationship between dose & toxicity Exploring the causes of interindividual variability

Answer 10

Peak clinical conc in plasma

Answer 11

First Time in Human Study (FTiH) is generally a single ascending dose study (SAD) Cohort 6-8 active drug; 2-4 placebo Double- blind Emerging data is continually reviewed by a safety monitoring committee Doses can be either escalated or de-escalated

Answer 12

Cohort design, placebo controlled Aim is to dose long enough to achieve steady state i.e. concentrations remain constant – reached equilibrium Generally achieved in 4-5 half-lives Main endpoint is safety, tolerability and pharmacokinetics Will determine what dose(s) can be studied in Phase 2

Answer 13

Not all of a drug that gets administered will enter the systemic circulation; during disintegration, dissolution, and transport some of the active compound may be lost.

Answer 14

Fabs – fraction absorbed FG – fraction escaping gut metabolism FH – fraction escaping hepatic metabolism

Answer 15

The fraction of drug that reached then circulation

Answer 16

assessment of systemic drug availability of extravascular dose compared with IV dose

Answer 17

compares bioavailability of one formulation with another

Answer 18

Two or more formulations of the same drug are compared, are usually designed as crossover studies. Each patient acts as his or her own control. This allows for the direct comparison of treatments.

Answer 19

Initial studies are done in the fasted state and then food effect studies follow. Study design: Statistically sized cross-over design PK of drug assessed following drug administration under fasted and fed conditions

Answer 20

studying whether the drug actually reaches target site in sufficient concentration; clinical studies to understand relationship between plasma concentrations and concentrations at site of action may be required

Answer 21

Most early healthy volunteer studies exclude co-medications CYP450 enzymes are the main metabolising enzyme system If drug is a substrate, inhibitor or inducer of a common pathway (eg. CYP3A4), the impact on exposure when dosed with other agents may need to be considered

Answer 22

CYP450 liability is assessed non-clinically as part of DMPK package However understanding this doesn’t predict the impact on clinical exposure Clinical DDI study is conducted: New Drug is dosed alone or in combination with a known inhibitor Cross-over design Endpoint is PK Compare AUC and Cmax following drug administered alone or in combinatation Dosing recommendations will be based on whether impact is clinically relevant

Answer 23

Mass balance study

Answer 24

understand full clearance mechanisms of drug and metabolites

Answer 25

Single dose of radio-labelled (C14) drug: plasma, urine and faeces collected Radiolabelled drug and concentrations of parent and metabolite(s) measured Assesses the major routes of clearance: may influence whether a renal and hepatic impairment study is required Proportion of parent drug converted to metabolite(s) Metabolite identification (eg. detection of unique human metabolites, active metabolites)

Answer 26

liver and kidney are major routes of elimination -> impairment = significant change in exposure Assessment of influence renal and hepatic impairment on exposure can lead to dosage adjustment warnings on the label Until these studies are done, patient population will need to be restricted Requirement for studies will depend on major route(s) of elimination

Answer 27

Elderly Risk of altered exposure Obese Ethnic groups – if the main programme is conducted in the West, specific PK study may be required to justify dose in certain ethnic groups (eg. Chinese, Japanese)

Answer 28

PK variability due to alterations in Vd and Clearance. Vd could be overestimated for hydrophilic drugs due to poor penetration into adipose tissue. Obese patients have increased organ mass which may lead to increased renal blood flow thus increasing renal clearance. Those with gastric bypass have loss of surface area for drug absorption.

Answer 29

physiologic alterations include reduced gastric acid secretions affecting absorption, reduced renal and hepatic blood flow which slows the rate of clearance, and reduced serum protein concentrations which increases free drug concentrations.

Answer 30

Most clinical pharmacology studies are conducted in healthy volunteers, however, it is important to understand PK in target patient population bc weight/body surface area, renal or hepatic function, illness severity, clinical indication, age, concomitant medications, and ethnicity can have an impact

Answer 31

Intensive PK samples can be taken in Phase 1 Easy to calculate Cmax, AUC, clearance, volume of distribution etc. PK parameters calculated for each individual

Answer 32

Generally only sparse PK samples collected Impossible to calculate PK parameters if individual data used in isolation; used in combination with phase 1 information

Answer 33

all data is analysed together allows exploration of mean exposure and variability sources use simulations to predict appropriate dosing regimen for majority of individuals

Answer 34

Main aim is proof of concept– some form of clinical efficacy Endpoint may be different to that explored in Phase 3 Generally in patients with condition under study (or related condition) Further safety and PK evaluation Can be comparator studies or single arm May explore dose range May be open label or blinded

Answer 35

Review of data and agreement for design of Phase III study Sponsor looks for regulatory agreement for: Endpoints and timing of endpoints of trial (eg. mortality, clinical cure) Size Patient population Comparator and blinding Dose Duration Paediatric plan

Answer 36

Clinical trial application; includes protocol, investigators brochure, IMPD, scientific advice, informed consent and patient information leaflet, investigational product labelling and GMP-related documents, and ethics

Answer 37

Pivotal studies designed and executed to provide statistically significant evidence of efficacy and safety Generally randomised controlled trial (RCT) against standard of care or placebo Parallel study design Sometimes adaptive design can be used Often two identical independent studies required Nearly always double blind

Answer 38

Superiority Non-inferiority Equivalence

Answer 39

To determine a clinically relevant difference between two treatments. i.e. want to show new treatment is statistically significantly better than existing therapy or placebo

Answer 40

To determine whether new treatment is not inferior to another established treatment

Answer 41

To determine whether a new treatment is neither worse nor better than another established treatment More often used for approval of generics, or formulation changes

Answer 42

Submission documents reviewed by team of technical experts EU – centralised procedure Regulatory defence Additional analysis may be required Regulatory inspections Process could take up to 2 years (longer in some countries)

Answer 43

Core information is included in the summary of product characteristics (SPC) or label Patient information leaflet are also produced written in clear, easy-to-understand language for general public and patients

Answer 44

Post-marketing commitments Pharmacovigilance Paediatic investigation plan

Answer 45

studies required by regulatory authorities but not included in original package May remove some restrictions on the label

Answer 46

science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other medicine-related problem Up to approval, evidence of safety and efficacy is limited to data from clinical trials, where patients are selected carefully and followed up under controlled conditions Safety of medicines is monitored throughout their use in healthcare practice

Answer 47

drugs are first approved for adults and aren't always tested for children so there is a government push to bring in a focus on it; in the EU it's mandatory unless there's a specific waiver for conditions that don't exist in paediatric patients

Answer 48

children aren't just small adults; process are different and must be accounted for