Examining the Basis of Drug-Drug Interaction (DDI) Labeling Recommendations for Antiviral Approvals from 1998 to 2015

Transcription

1 Examining the Basis of Drug-Drug Interaction (DDI) Labeling Recommendations for Antiviral Approvals from 1998 to 2015 Tyler Shugg, PharmD PhD Candidate Department of Pharmacy Practice Purdue University

2 Prevalence of DDIs in Antiviral Pharmacotherapy DDIs remain a leading cause of adverse drug events (ADEs) Many antivirals possess a high potential for serious DDIs involving major drug metabolizing enzymes and drug transporters Clinically significant DDIs (i.e. those necessitating clinical management) have been identified in as many as 41% of HIV patients To mitigate their clinical burden, the potential for DDIs needs to be assessed Miller CD, El-Kholi R, Faragon JJ, et al. Pharmacotherapy Oct:27(10):

3 FDA Guidance to Mitigate DDIs The FDA has issued guidance to industry recommending that the potential for DDIs be established during drug development to serve as part of an adequate assessment of a drug s safety and effectiveness. Objectives of DDI studies during drug development: 1. Determine existence of DDI 2. Assess DDI severity 3. Establish appropriate mitigation strategy (including drug label recommendation) It is essential that DDI studies inform effective clinical managements strategies Center for Drug Research and Evaluation. Food and Drug Administration. Department of Health and Human Services. Guidance for Industry: Drug Interaction Studies, Study Design, Data Analysis, Implications for Dosing, and Label Recommendations Available at:

4 Research Objective Assess the basis for DDI recommendations from all antiviral new molecular entity (NME) approvals from 1998 to 2015 Identify factors that influence DDI label recommendations, including: 1. DDI Information Source 2. Drug Exposure Data 3. Trial Design Elements a. Study Population b. Study Type c. Dosing Regimen 4. Major CYP Isoenzymes & Major Drug Transporters 5. Common Perpetrator and Victim Drugs

5 Methods: Database

6 Results

7 Frequency of DDI Labeling Recommendations By Therapeutic Area Label NME Approvals Recommendations Therapeutic Area Recommendations ( 98-15) Per Approval Antiviral Reproduction Urology Analgesia Endocrinology Cardiovascular Psychiatry Neurology Anti-Infective Gastroenterology

8 Types of Antiviral Labeling Recommendations & Sources Informing Recommendations Distribution of Labeling Recommendations Sources Informing Labeling Recommendations Label Recommendation Frequency Percentage Contraindication % Not Recommended % Dose Adjustment % Use With Caution % No Dose Adjustment % % 59.3% D D I-P K C E P r e d -M e t 0.9% T o ta l= 9 2 2

9 Distributions of Trial Design Elements in DDI Studies Study Subjects 11.7% Study Design 8.7% Medication Dosing (Victim/Perp) 6.7% P a tie n ts C r o s s o v e r H e a lth y V o lu n te e rs P a ra lle l A rm 45.6% 45.6% 69.9% F ix e d S e q u e n tia l 19.7% 3.8% S in g le /S in g S in g le /M u lti M u ltip le /S in M u ltip le /M u 88.3%

10 Frequency of Antiviral DDI Studies Involving Drugs Known to Affect Major CYP Isoenzymes or Drug Transporters

11 P e r c e n ta g e (% ) CYP Isoenzymes Most Commonly Affected By Interacting Drugs in Antiviral DDI Studies CYP Isoenzyme Effect Frequency Percentage 3A Substrate % 5 0 Weak 2D6 Inhibitor % 4 0 Strong 3A Inhibitor % Weak 3A Inhibitor % 3 0 Weak 2C19 Inhibitor % 2 0 Moderate 3A Inhibitor % 1 0 Moderate 1A2 Inhibitor % Strong 3A Inducer % Moderate 2B6 Inducer % 0 1 A 2 2 B 6 2 C 8 2 C 9 2 C A 2 D 6 Moderate 2C9 Inducer % C Y P Is o e n z y m e

12 P e r c e n ta g e (% ) Drug Transporters Most Commonly Affected By Interacting Drugs in Antiviral DDI Studies Drug Transporter Effect Frequency Percentage 5 0 OATP1B1 Inhibitor % OATP1B3 Inhibitor % 4 0 P-gp Inhibitor % 3 0 P-gp Inducer % 2 0 OATP1B1 Substrate % OAT1 Substrate % 1 0 OAT3 Substrate % 0 OATP1B3 Substrate % P-gp Substrate % B C R P O A T 1 O A T P 1 B 1 O A T P 1 B 3 O A T 3 O C T 2 P -g p BCRP Inhibitor % D r u g T r a n s p o r te r

13 F r e q u e n c y F r e q u e n c y Geometric Mean Ratios for C Max and AUC in Antiviral DDI Studies Percent ( ) < > < > 2.0 C Max Antiviral Approvals 53.6% * Other Approvals 71.4% AUC Antiviral Approvals 48.6% * Other Approvals 66.6% C M a x G M R R a tio A U C G M R R a tio

14 Label Recommendations Based on Magnitude of GMR Changes in DDI Studies Change In Drug Exposure Label Recommendation Frequency Percentage Moderate GMR Ratios: ( , ) Severe GMR Ratios: (<0.5, >2.0) All Positive GMR Ratios: (<0.8, >1.25) Contraindication % Not Recommended % Dose Adjustment % Use With Caution % No Dose Adjustment % Contraindication % Not Recommended % Dose Adjustment % Use With Caution % No Dose Adjustment % Contraindication % Not Recommended % Dose Adjustment % Use With Caution % No Dose Adjustment %

15 Label Recommendations & GMR Changes for Most Common Perpetrator & Victim Drugs in DDI Studies Interacting Drug Perpetrators Label Recs Percent Actionable PK DDI Studies Percent Δ GMR Rifampin % % Omeprazole % % Ketoconazole % 15 80% Carbamazepine % 7 100% Victims Ritonavir % % Methadone % % Ethinyl Estradiol 15 20% 15 60% Digoxin 6 0% 5 80%

16 Conclusions PK DDI studies are the most common source informing antiviral DDI labeling recommendations Antiviral DDIs are most commonly mediated by interaction within CYP3A, P-gp, OATP1B1, and OATP1B3 Antiviral DDI studies were more likely to have GMR changes in C Max and AUC outside of the 20% no effect boundary ( ) than approvals in all other therapeutic classes PK DDI studies with >20% GMR changes in C Max and/or AUC informed actionable label recommendations in 49.6% of cases

17 Acknowledgements Office of Clinical Pharmacology, Center for Drug Research and Evaluation, U.S. Food and Drug Administration Primary Mentor: Islam Younis, PhD Department of Pharmacy Practice, College of Pharmacy, Purdue University Indiana Institute for Personalized Medicine, Indiana University School of Medicine Primary Mentor: Brian R. Overholser, PharmD, FCCP