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Role of Pharmacokinetics and Pharmacodynamics in Drug Development

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32 views15 pages

Role of Pharmacokinetics and Pharmacodynamics in Drug Development

Uploaded by

s13064
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© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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Role of pharmacokinetics and

pharmacodynamics in Drug
Development
PHAR2220 Biopharmaceutics and Pharmacokinetics
Xiaoyu Yan, [email protected]
Telegram group PHAR2220_2024

2
X
Drug Development Process

• Dose finding

https://www.linguamatics.com/solutions/drug-development-safety-and-pharmacovigilance

3
Role of pharmacokinetics in the drug
development

4
Exposure metrics

5
Therapeutic monitoring of warfarin
 An anticoagulant, or blood thinner
 Treat blood clots
 Deep vein thrombosis
 Pulmonary embolism
 Atrial fibrillation
 Bleeding risk
 Narrow therapeutic window
 Drug-drug interaction
 Polymorphism
 PK CYP2C9
 PD VKORC1
6
Rivaroxaban, a novel oral anticoagulant
(NOAC)

No therapeutical drug monitoring is needed


7
Clinical pharmacokinetics of rivaroxaban

Mueck W, Stampfuss J, Kubitza D, Becka M (2014) Clinical pharmacokinetics 53 (1):1-16.

8
Rivaroxaban indication and dose
 Deep vein thrombosis (DVT) and pulmonary embolism (PE), including
treatment and prevention
 Nonvalvular atrial fibrillation
 Peripheral artery disease (PAD) and coronary artery disease (CAD)

9
Post marketing exposure-response analysis
support no TDM
 Nonvalvular atrial fibrillation
 Efficacy
 Prevent Stroke, Embolism
 Safety
 Bleeding
 PK is only available in 161 patients
 PK modeling using 1-CMT model
was used to predict PK in ~ 7000
patients in a phase 3 trial
 No clear threshold to support
TDM
10 Zhang Li, et al. J. Thromb. Haemost.(2020) 50:20–29
Dose adjustment in renal impairment (RI)
patient with atrial fibrillation (AF)
 Dose finding study was only conducted for acute symptomatic DVT,
which is 15 mg BID for 21 days followed by 20 mg QD
 Dosing regimen selection in AF
patients is based on DVT
 Assuming same mechanism of
drug action in different patient
populations
 Dose selection is based on PK
matching
 Compared with DVT population
AF population is older with RI
 No dose finding studies were
conducted in AF patients
 One phase 3 study was conducted
confirming the dose
 Save $$$$
Mueck W, et al (2011). Clinical pharmacokinetics 50 (10):675-686

11
Dose regimen in pediatric patients with
venous thromboembolism (VTE)
 Target exposure in adult patients was established in
clinical trials
 Physiologically based
pharmacokinetic
modeling was conducted
to find the equivalent
dose and regimen in
Children
 Phase 1 clinical trial in
children was conducted
to confirm the modeling
results
Willimann S, et al., Thromb J. 2018 4;16:32

12
Rivaroxaban dose in Japanese patients
 Global Phase 3 trial in in AF patients was conducted using
20 mg QD dose
 PK model-based simulation
supports 15 mg QD dose in
Japanese patients
 A small phase 3 clinical trial
in Japanese patients was
conducted and confirmed
the dosing regimen selection

13 Tanigawa T, Drug Metab. Pharmacokinet. (2013) 28 (1):59-70


Rivaroxaban dose in Japanese patients
PT: Thrombin time, a pharmacodynamic marker

14 Kaneko M, et al. Drug Metab. Pharmacokinet. (2013) 28 (4):321-331


Summary
Pharmacokinetics and pharmacodynamics play a very important
role in clinical drug development, and provide guidance on
➢ Therapeutic drug monitoring
➢ Dose selection in
➢ Different diseases
➢ Renal impairment patients
➢ Hepatic impairment patients
➢ Elder patients
➢ Pediatrics
➢ Ethnic group
➢ Food effect
➢ Obesity

15

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