KEY FINDINGS FROM PRECLINICAL AND CLINICAL DRUG INTERACTION STUDIES
PRESENTED IN NEW DRUG AND BIOLOGICAL LICENSE APPLICATIONS APPROVED BY
THE FDA IN 2014
Jingjing Yu, Tasha K. Ritchie, Zhu Zhou, and Isabelle Ragueneau-Majlessi
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA, USA (J.Y.,
T.K.R., Z.Z., I.R-M.)
Drug Metabolism and Disposition
Supplemental Data
Contents: - Supplemental Table 1 - Supplemental Table 2 Supplemental Table 1. Chemical structures of compounds within the NDA/BLAs approved in 2014
(ordered by approval date)
NDA Compound
(Approval (CAS Registry Structure
Date) Number)
202293 Dapagliflozin
(01/08) (461432-26-8)
205677 Tasimelteon
(01/31) (609799-22-6)
203202 Droxidopa
(08/18) (23651-95-8)
204684 Miltefosine
(03/19) (58066-85-6)
205437 Apremilast
(03/21) (608141-41-9)
205755 Ceritinib
(04/29) (1032900-25-6)
204886 Vorapaxar
(05/08) (618385-01-6)
021883 Dalbavancin
(05/23) (171500-79-1)
203567 Efinaconazole
(06/06) (164650-44-6)
205435 Tedizolid phosphate
(06/20) (856867-55-5)
206256 Belinostat
(07/03) (414864-00-9)
204427 Tavaborole
(07/07) (174671-46-6)
206545 Idelalisib
(07/23) (870281-82-6)
203108 Olodaterol
(07/31) (868049-49-4)
204629 Empagliflozin
(08/01) (864070-44-0)
206334 Oritavancin
(08/06) (171099-57-3)
204569 Suvorexant
(08/13) (1030377-33-3)
205494 Eliglustat
(08/19) (491833-29-5)
204760 Naloxegol
(09/06) (854601-70-0)
Ledipasvir
(1256388-51-8) 205834
(10/10)
Sofosbuvir*
(1190307-88-0)
Netupitant
(290297-26-6) 205718
(10/10) Palonosetron*
(135729-56-5)
203684 Sulfur hexafluoride
(10/10) (2551-62-4)
205832 Nintedanib
(10/15) (656247-17-5)
022535 Pirfenidone
(10/15) (53179-13-8)
206307 Finafloxacin
(12/17) (209342-40-5)
Ceftolozane
206829 (689293-68-3)
(12/19)
Tazobactam
(89786-04-9)
206162 Olaparib
(12/19) (763113-22-0)
Ombitasvir
(1258226-87-7)
Paritaprevir 206619 (1216941-48-8) (12/19)
Ritonavir*
(155213-67-5)
Dasabuvir
(1132935-63-7)
206426 Peramivir
(12/19) (330600-85-6)
*drugs approved prior to 2014
Supplemental Table 2. Clinical inhibitions (1.25 ≤ AUC < 2) and inductions (0.5 < AUC ≤ 0.8) with labeling impact, NMEs as victims or perpetrators
Enzymes / Max Max Transporters Victim Perpetrator AUC Cmax Labeling Impact Reference Possibly Ratio Ratio Involved
Monitor for tenofovir-associated adverse Tenofovir (with reactions in patients receiving efavirenz and Ledipasvir and P-gp 1.94 1.72 HARVONI concomitantly with the (FDA, 2014k) emtricitabine as Sofosbuvir combination of efavirenz, emtricitabine ATRIPLA) and tenofovir DF.
Ombitasvir, When VIEKIRA PAK is co-administered Paritaprevir, OATPs (FDA, Pravastatin 1.82 1.36 with pravastatin, the dose of pravastatin Dasabuvir, (CYP3A) 2014ai) should not exceed 40 mg per day. and Ritonavir
Moderate (e.g., ciprofloxacin) inhibitors
of CYP1A2 increase systemic exposure
of ESBRIET and may alter the adverse Pirfenidone Ciprofloxacin CYP1A2 1.80 1.22 (FDA, 2014i) reaction profile of ESBRIET. Consider
dosage reduction with use of
ciprofloxacin.
Patients taking concomitant CYP3A (FDA, Idelalisib Ketoconazole CYP3A 1.79 1.25 inhibitors should be monitored for signs 2014an) of Zydelig toxicity.
Patients should be monitored closely for
tolerability of OFEV. Management of CYP3A, P- Nintedanib Ketoconazole 1.61 1.79 adverse reactions may require (FDA, 2014x) gp interruption, dose reduction, or
discontinuation of therapy with OFEV.
Digoxin Eliglustat P-gp 1.49 1.71 Co-administration with drugs that are (FDA, 2014e) substrates for P-gp may result in
increased concentrations of the other
drug.
No dose adjustment is needed for CYP3A
substrates, however patients on sensitive
CYP3A substrates with narrow
Midazolam Suvorexant CYP3A 1.47 1.23 therapeutic range (e.g., alfentanil, (FDA, 2014c)
cyclosporine, ergotamine, fentanyl,
pimozide, quinidine, sirolimus,
tacrolimus) should be closely monitored.
Caution and monitoring for
chemotherapeutic related adverse
Docetaxel Netupitant CYP3A 1.42 1.49 reactions are advised in patients receiving (FDA, 2014a)
chemotherapy agents metabolized
primarily by CYP3A4.
Patients should especially tell the Ritonavir (with Ledipasvir P-gp 1.35 1.27 healthcare provider if they take darunavir (FDA, 2014k) Darunavir) (PREZISTA) and ritonavir (NORVIR).
Ombitasvir, Clinical monitoring of patients is
Paritaprevir, recommended. A decrease in alprazolam (FDA, Alprazolam CYP3A 1.34 1.09 Dasabuvir, dose can be considered based on clinical 2014ai)
and Ritonavir response.
Use ORBACTIV in patients on chronic
warfarin therapy only when the benefits Warfarin Oritavancin CYP2C9 1.32 N/A (FDA, 2014z) can be expected to outweigh the risk of
bleeding.
No dose adjustment of naloxone is Ombitasvir, required upon co-administration with Paritaprevir, (FDA, Naloxone UGTs 1.30 1.24 VIEKIRA PAK. Patients should be Dasabuvir, 2014ai) closely monitored for sedation and and Ritonavir cognitive effects. Digoxin concentrations should be
Digoxin Suvorexant P-gp 1.27 1.21 monitored when co-administering (FDA, 2014c)
BELSOMRA with digoxin.
Ombitasvir, Darunavir Co-administration of VIEKIRA PAK Paritaprevir, (FDA, (with CYP3A 0.74 0.78 with darunavir/ritonavir is not Dasabuvir, 2014ai) Ritonavir) recommended. and Ritonavir
Monitor patients for decreased efficacy of
Ombitasvir, omeprazole. Consider increasing the
Paritaprevir, omeprazole dose in patients whose (FDA, Omeprazole CYP2C19 0.62 0.62 Dasabuvir, symptoms are not well controlled; avoid 2014ai)
and Ritonavir use of more than 40 mg per day of
omeprazole.
Cigarette
smoking
(minimum of The efficacy of HETLIOZ may be Tasimelteon CYP1A2 0.53 0.57 (FDA, 2014l) 10 tobacco reduced in smokers.
cigarettes/day
6 months)
2014 NMEs are underlined