Not to be confused with apatinib.
Lapatinib
|
| Systematic (IUPAC) name |
N-[3-Chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-
[5-[(2-methylsulfonylethylamino)methyl]-2-furyl]
quinazolin-4-amine
|
| Clinical data |
| Trade names |
Tykerb, Tyverb |
| AHFS/Drugs.com |
Monograph |
| MedlinePlus |
a607055 |
| License data |
- EU EMA: Tyverb
- US FDA: Lapatinib
|
Pregnancy
category |
- AU: D
- US: D (Evidence of risk)
|
Routes of
administration |
By mouth (tablets) |
| Legal status |
| Legal status |
- AU: S4 (Prescription only)
- CA: ℞-only
- UK: POM (Prescription only)
- US: ℞-only
- ℞ (Prescription only)
|
| Pharmacokinetic data |
| Bioavailability |
Variable, increased with food |
| Protein binding |
>99% |
| Metabolism |
Hepatic, mostly CYP3A-mediated (minor 2C19 and 2C8 involvement) |
| Biological half-life |
24 hours (repeated dosing), 14.2 hours (single dose) |
| Excretion |
Mostly fecal |
| Identifiers |
| CAS Number |
231277-92-2 N
388082-78-8 (ditosylate) |
| ATC code |
L01XE07 (WHO) |
| PubChem |
CID 208908 |
| IUPHAR/BPS |
5692 |
| DrugBank |
DB01259 Y |
| ChemSpider |
181006 Y |
| UNII |
0VUA21238F Y |
| KEGG |
D04024 N |
| ChEBI |
CHEBI:49603 Y |
| ChEMBL |
CHEMBL554 Y |
| Chemical data |
| Formula |
C29H26ClFN4O4S |
| Molar mass |
581.058 g/mol |
| 3D model (Jmol) |
Interactive image |
SMILES
-
CS(=O)(=O)CCNCc1ccc(o1)c2ccc3c(c2)c(ncn3)Nc4ccc(c(c4)Cl)OCc5cccc(c5)F
|
InChI
-
InChI=1S/C29H26ClFN4O4S/c1-40(36,37)12-11-32-16-23-7-10-27(39-23)20-5-8-26-24(14-20)29(34-18-33-26)35-22-6-9-28(25(30)15-22)38-17-19-3-2-4-21(31)13-19/h2-10,13-15,18,32H,11-12,16-17H2,1H3,(H,33,34,35) Y
-
Key:BCFGMOOMADDAQU-UHFFFAOYSA-N Y
|
| NY (what is this?) (verify) |
Lapatinib (INN), used in the form of lapatinib ditosylate (USAN) (trade names Tykerb and Tyverb) is an orally active drug for breast cancer and other solid tumours.[1] It is a dual tyrosine kinase inhibitor which interrupts the HER2/neu and epidermal growth factor receptor (EGFR) pathways.[2] It is used in combination therapy for HER2-positive breast cancer. It is used for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 (ErbB2).[3]
Contents
- 1 Status
- 2 Mode of action
- 2.1 Biochemistry
- 2.2 Clinical application
- 3 Adverse effects
- 4 Ongoing trials in gastric cancer
- 5 References
- 6 External links
Status
On March 13, 2007, the U.S. Food and Drug Administration (FDA) approved lapatinib in combination therapy for breast cancer patients already using capecitabine (Xeloda).[2][3] In January 2010, Tykerb received accelerated approval for the treatment of postmenopausal women with hormone receptor positive metastatic breast cancer that overexpresses the HER2 receptor and for whom hormonal therapy is indicated (in combination with letrozole).[3]
Pharmaceutical company GlaxoSmithKline (GSK) markets the drug under the propriety names Tykerb (mostly U.S.) and Tyverb (mostly Europe and Russia).[4] The drug currently has approval for sale and clinical use in the US,[2][4] Australia,[2] Bahrain,[2] Kuwait,[2] Venezuela,[2] Brazil,[5] New Zealand,[5] South Korea,[5] Switzerland,[4] Japan, Jordan, the European Union, Lebanon, India and Pakistan.[4]
On the August 2, 2013, India's Intellectual Property Appellate Board revoked the patent for Glaxo's Tykerb citing its derivative status, while upholding at the same time the original patent granted for lapatinib.[6]
The drug lapatinib ditosylate is classified as S/NM (a synthetic compound showing competitive inhibition of the natural product) that is naturally derived or inspired substrate (Gordon M. Cragg, Paul G. Grothaus, and David J. Newman, Impact of Natural Products on Developing New Anti-Cancer Agents, Chem. Rev. 2009, 109, 3012–3043)
Mode of action
Biochemistry
Lapatinib inhibits the tyrosine kinase activity associated with two oncogenes, EGFR (epidermal growth factor receptor) and HER2/neu (human EGFR type 2).[7] Over expression of HER2/neu can be responsible for certain types of high-risk breast cancers in women.[2]
Like sorafenib, lapatinib is a protein kinase inhibitor shown to decrease tumor-causing breast cancer stem cells.[8]
Lapatinib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFR/HER2 protein kinase domain, preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinase#Signal transduction).[9]
Clinical application
Breast cancer
Lapatinib is used as a treatment for women's breast cancer in treatment-naïve, ER+/EGFR+/HER2+ breast cancer patients and in patients who have HER2-positive advanced breast cancer that has progressed after previous treatment with other chemotherapeutic agents, such as anthracycline, taxane-derived drugs, or trastuzumab (Herceptin).
A 2006 GSK-supported randomized clinical trial on female breast cancer previously being treated with those agents (anthracycline, a taxane and trastuzumab) demonstrated that administrating lapatinib in combination with capecitabine delayed the time of further cancer growth compared to regimens that use capecitabine alone. The study also reported that risk of disease progression was reduced by 51%, and that the combination therapy was not associated with increases in toxic side effects.[10] The outcome of this study resulted in a somewhat complex and rather specific initial indication for lapatinib—use only in combination with capecitabine for HER2-positive breast cancer in women whose cancer have progressed following previous chemotherapy with anthracycline, taxanes and trastuzumab.
Adverse effects
Like many small molecule tyrosine kinase inhibitors, lapatinib is regarded as well tolerated. The most common side effects reported are diarrhea, fatigue, nausea and rashes.[2][11] In clinical studies elevated liver enzymes have been reported. QT prolongation has been observed with the use of lapatinib ditosylate but there are no reports of torsades de pointes. Caution is advised in patients with hypokalaemia, hypomagnesaemia, congenital long QT syndrome, or with coadministration of medicines known to cause QT prolongation. In combination with capecitabine, reversible decreased left ventricular function are common (2%).[12]
Ongoing trials in gastric cancer
Phase III study designed to assess lapatinib in combination with chemotherapy for advanced HER2-positive gastric cancer in 2013 failed to meet the primary endpoint of improved overall survival (OS) against chemotherapy alone. The trial did not discover new safety signals, while the median OS for patients in the lapatinib and chemotherapy group was 12.2 months against 10.5 months for patients in the placebo plus chemotherapy. Secondary endpoints of the randomized, double-blinded study, were progression-free survival (PFS), response rate and duration of response. Median PFS was 6 months, response rate was 53% and the duration of response was 7.3 months in the investigational combination chemotherapy group compared to median PFS of 5.4 months, response rate of 39% and duration of response of 5.6 months for patients in chemotherapy alone group. Diarrhoea, vomiting, anemia, dehydration and nausea were serious adverse events (SAE) reported in over 2% of patients in the investigational combination chemotherapy group, while vomiting was the most common SAE noted in the chemotherapy group.[13]
References
- ^ Burris HA (2004). "Dual kinase inhibition in the treatment of breast cancer: initial experience with the EGFR/ErbB-2 inhibitor lapatinib". Oncologist. 9 Suppl 3: 10–5. doi:10.1634/theoncologist.9-suppl_3-10. PMID 15163842.
- ^ a b c d e f g h i Higa GM, Abraham J (September 2007). "Lapatinib in the treatment of breast cancer". Expert Review of Anticancer Therapy (log in required). Future Drugs. 7 (9): 1183–92. doi:10.1586/14737140.7.9.1183. PMID 17892419.
- ^ a b c Pazdur, Richard (14 January 2011). "FDA Approval for Lapatinib Ditosylate". Womens Health (Lond Engl). Cancer.gov. 6 (2): 173. doi:10.2217/whe.10.11. PMID 20187722.
- ^ a b c d "GlaxoSmithKline receives marketing authorisation in the EU for Tyverb (lapatinib), the first oral targeted therapy for ErbB2-positive breast cancer" (Press release). GlaxoSmithKline. 2008-06-12. Retrieved 2008-06-21.
- ^ a b c "GlaxoSmithKline Reports Positive New Data On Tykerb (lapatinib) At The 2007 American Society Of Clinical Oncology (ASCO) Annual Meeting" (Press release). Medical News Today. June 4, 2007. Retrieved December 2, 2008.
- ^ Kulkarni, Kaustubh (2 August 2013). "India revokes GSK cancer drug patent in latest Big Pharma blow". Reuters. Mumbai, India: Reuters. Retrieved 2 August 2013.
- ^ Wood ER, Truesdale AT, McDonald OB, Yuan D, Hassell A, Dickerson SH, Ellis B, Pennisi C, et al. (2004). "A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells". Cancer Research. 64 (18): 6652–9. doi:10.1158/0008-5472.CAN-04-1168. PMID 15374980.
- ^ Angel Rodriguez (April 2008). New type of drug shrinks primary breast cancer tumors significantly in just six weeks; research provides leads to a new target in cancer treatment – the cancer stem cell.
- ^ Nelson MH, Dolder CR (February 2006). "Lapatinib: a novel dual tyrosine kinase inhibitor with activity in solid tumors". Ann Pharmacother. 40 (2): 261–9. doi:10.1345/aph.1G387. PMID 16418322.
- ^ Geyer CE, Forster J, Lindquist D, et al. (December 2006). "Lapatinib plus capecitabine for HER2-positive advanced breast cancer". N. Engl. J. Med. 355 (26): 2733–43. doi:10.1056/NEJMoa064320. PMID 17192538.
- ^ Burris HA, Hurwitz HI, Dees EC, et al. (August 2005). "Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas". J. Clin. Oncol. 23 (23): 5305–13. doi:10.1200/JCO.2005.16.584. PMID 15955900.
- ^ NCI Cancer Drug Information. FDA Approval for Lapatinib Ditosylate (Tykerb®). Retrieved 27 January 2014.
- ^ |url=http://www.bioportfolio.com/news/article/1492867/GSK-Tykerb-Tyverb-Phase-III-gastric-cancer-study-fails-to-meet-primary.html
External links
- Tykerb (lapatinib) Tablets, for Oral Use. Full Prescribing Information
- Lapatinib Ditosylate — National Cancer Institute
- Canadian drug touted for advanced breast cancer
|
|
|
| CI monoclonal antibodies ("-mab") |
| Receptor tyrosine kinase |
- ErbB: HER1/EGFR (Cetuximab
- Panitumumab)
- HER2/neu (Trastuzumab
- Trastuzumab emtansine)
|
|
| Others for solid tumors |
- EpCAM (Catumaxomab
- Edrecolomab)
- VEGF-A (Bevacizumab)
|
|
| Leukemia/lymphoma |
- lymphoid: CD20 (Ibritumomab
- Ofatumumab
- Rituximab
- Tositumomab), CD30 (Brentuximab), CD52 (Alemtuzumab)
- myeloid: CD33 (Gemtuzumab)
|
|
|
| Tyrosine-kinase inhibitors ("-nib") |
| Receptor tyrosine kinase |
- ErbB: HER1/EGFR (Erlotinib
- Gefitinib
- Osimertinib
- Vandetanib)
- HER1/EGFR and HER2/neu
- Afatinib
- Lapatinib
- Neratinib
- RTK class III: C-kit and PDGFR (Axitinib
- Masitinib
- Pazopanib
- Sunitinib
- Sorafenib
- Toceranib)
- FLT3 (Lestaurtinib)
- VEGFR
- Axitinib
- Cediranib
- Lenvatinib
- Nintedanib
- Pazopanib
- Regorafenib
- Semaxanib
- Sorafenib
- Sunitinib
- Tivozanib
- Toceranib
- Vandetanib
RET inhibitors: Vandetanib (also VEGFR and EGFR). Entrectinib (ALK, ROS1, NTRK). c-MET inhibitor: Cabozantinib (also VEGFR2).
|
|
| Non-receptor |
- bcr-abl
- Imatinib
- Dasatinib
- Nilotinib
- Ponatinib
- Radotinib
- Janus kinase
- Lestaurtinib
- Momelotinib
- Ruxolitinib
- Pacritinib
- MAP2K
- Cobimetinib
- Selumetinib
- Trametinib
- Binimetinib
- EML4-ALK
- Alectinib
- Ceritinib
- Crizotinib
|
|
|
| Other |
- fusion protein against VEGF (Aflibercept)
- proapoptotic peptide against ANXA2 and prohibitin (Adipotide)
- exotoxin against IL-2 (Denileukin diftitox)
- mTOR inhibitors
- hedgehog inhibitors
- CDK inhibitor (Palbociclib)
|
|
Growth factor receptor modulators
|
|
| Angiopoietin |
- Agonists: Angiopoietin 1
- Angiopoietin 4
- Antagonists: Angiopoietin 2
- Angiopoietin 3
- Antibodies: Evinacumab (against angiopoietin 3)
- Nesvacumab (against angiopoietin 2)
|
|
| CNTF |
- Agonists: Axokine
- CNTF
- Dapiclermin
|
|
| EGF (ErbB) |
|
EGF
(ErbB1/HER1)
|
- Agonists: Amphiregulin
- Betacellulin
- EGF (urogastrone)
- Epigen
- Epiregulin
- Heparin-binding EGF-like growth factor (HB-EGF)
- Murodermin
- Nepidermin
- Transforming growth factor alpha (TGFα)
- Antibodies: Cetuximab
- Depatuxizumab
- Depatuxizumab mafodotin
- Futuximab
- Imgatuzumab
- Matuzumab
- Necitumumab
- Nimotuzumab
- Panitumumab
- Zalutumumab
- Kinase inhibitors: Afatinib
- AG-490
- Agerafenib
- Brigatinib
- Canertinib
- Dacomitinib
- Erlotinib
- Gefitinib
- Grandinin
- Icotinib
- Lapatinib
- Neratinib
- Osimertinib
- Vandetanib
- WHI-P 154
|
|
|
ErbB2/HER2
|
- Antibodies: Ertumaxomab
- Pertuzumab
- Trastuzumab
- Trastuzumab duocarmazine
- Trastuzumab emtansine
- Kinase inhibitors: Afatinib
- AG-490
- Lapatinib
- Mubritinib
- Neratinib
|
|
|
ErbB3/HER3
|
- Agonists: Neuregulins (heregulins) (1, 2, 6 (neuroglycan C))
- Antibodies: Duligotumab
- Patritumab
- Seribantumab
|
|
|
ErbB4/HER4
|
- Agonists: Betacellulin
- Epigen
- Heparin-binding EGF-like growth factor (HB-EGF)
- Neuregulins (heregulins) (1, 2, 3, 4, 5 (tomoregulin, TMEFF))
|
|
|
| FGF |
|
FGFR1
|
- Agonists: Ersofermin
- FGF (1, 2 (bFGF), 3, 4, 5, 6, 8, 10 (KGF2), 20)
- Repifermin
- Trafermin
- Velafermin
|
|
|
FGFR2
|
- Agonists: Ersofermin
- FGF (1, 2 (bFGF), 3, 4, 5, 6, 7 (KGF), 8, 9, 10 (KGF2), 17, 18, 22)
- Palifermin
- Repifermin
- Sprifermin
- Trafermin
- Antibodies: Aprutumab
- Aprutumab ixadotin
|
|
|
FGFR3
|
- Agonists: Ersofermin
- FGF (1, 2 (bFGF), 4, 8, 9, 18, 23)
- Sprifermin
- Trafermin
- Antibodies: Burosumab (against FGF23)
|
|
|
FGFR4
|
- Agonists: Ersofermin
- FGF (1, 2 (bFGF), 4, 6, 8, 9, 19)
- Trafermin
|
|
|
Unsorted
|
|
|
|
| HGF (c-Met) |
- Agonists: Hepatocyte growth factor
- Potentiators: Dihexa (PNB-0408)
- Antibodies: Emibetuzumab
- Ficlatuzumab
- Flanvotumab
- Onartuzumab
- Rilotumumab
- Telisotuzumab
- Telisotuzumab vedotin
- Kinase inhibitors: AM7 (drug)
- AMG-458
- Amuvatinib
- BMS-777607
- Cabozantinib
- Crizotinib
- Foretinib
- Golvatinib
- INCB28060
- JNJ-38877605
- K252a
- MK-2461
- PF-04217903
- PF-2341066
- PHA-665752
- SU-11274
- Tivantinib
- Volitinib
|
|
| IGF |
|
IGF-1
|
- Agonists: des(1-3)IGF-1
- Insulin-like growth factor-1 (somatomedin C)
- IGF-1 LR3
- Insulin-like growth factor-2 (somatomedin A)
- Insulin
- Mecasermin
- Mecasermin rinfabate
- Antibodies: AVE1642
- Cixutumumab
- Dalotuzumab
- Figitumumab
- Ganitumab
- Robatumumab
- R1507
- Teprotumumab
- Kinase inhibitors: Linsitinib
- NVP-ADW742
- NVP-AEW541
- OSl-906
|
|
|
IGF-2
|
- Agonists: Insulin-like growth factor-2 (somatomedin A)
|
|
|
Others
|
- Binding proteins: IGFBP (1, 2, 3, 4, 5, 6, 7)
- Cleavage products/derivatives with unknown target: Glypromate (GPE, (1-3)IGF-1)
- Trofinetide
|
|
|
| LNGF |
- Agonists: BDNF
- Cenegermin
- NGF
- NT-3
- NT-4
- Antibodies: Against NGF: Fasinumab
- Fulranumab
- Ranevetmab
- Tanezumab
|
|
| PDGF |
- Agonists: Becaplermin
- Platelet-derived growth factor (A, B, C, D)
- Antibodies: Olaratumab
- Ramucirumab
- Tovetumab
- Kinase inhibitors: Agerafenib
- Axitinib
- Crenolanib
- Imatinib
- Lenvatinib
- Masitinib
- Motesanib
- Nintedanib
- Pazopanib
- Radotinib
- Quizartinib
- Sunitinib
- Sorafenib
- Toceranib
|
|
| RET (GFL) |
|
GFRα1
|
- Agonists: Glial cell line-derived neurotrophic factor (GDNF)
- Liatermin
- Kinase inhibitors: Vandetanib
|
|
|
GFRα2
|
- Agonists: Neurturin (NRTN)
- Kinase inhibitors: Vandetanib
|
|
|
GFRα3
|
- Kinase inhibitors: Vandetanib
|
|
|
GFRα4
|
- Agonists: Persephin (PSPN)
- Kinase inhibitors: Vandetanib
|
|
|
Unsorted
|
- Kinase inhibitors: Agerafenib
|
|
|
| SCF (c-Kit) |
- Agonists: Ancestim
- Stem cell factor
- Kinase inhibitors: Agerafenib
- Axitinib
- Dasatinib
- Imatinib
- Masitinib
- Nilotinib
- Pazopanib
- Quizartinib
- Sorafenib
- Sunitinib
- Toceranib
|
|
| TGFβ |
|
|
| Trk |
|
TrkA
|
- Agonists: Amitriptyline
- Cenegermin
- Gambogic amide
- NGF
- Tavilermide
- Kinase inhibitors: Entrectinib
- K252a
- Lestaurtinib
- LOXO-101
- Antibodies: Against NGF: Fasinumab
- Fulranumab
- Ranevetmab
- Tanezumab
|
|
|
TrkB
|
- Agonists: 3,7-DHF
- 3,7,8,2'-THF
- 4'-DMA-7,8-DHF
- 7,3'-DHF
- 7,8-DHF
- 7,8,2'-THF
- 7,8,3'-THF
- Amitriptyline
- BDNF
- Deoxygedunin
- Diosmetin
- HIOC
- LM22A-4
- N-Acetylserotonin
- NT-3
- NT-4
- Norwogonin (5,7,8-THF)
- R7
- TDP6
- Antagonists: ANA-12
- Cyclotraxin B
- Gossypetin (3,5,7,8,3',4'-HHF)
- Kinase inhibitors: Entrectinib
- K252a
- Lestaurtinib
- LOXO-101
|
|
|
TrkC
|
- Kinase inhibitors: Entrectinib
- K252a
- Lestaurtinib
- LOXO-101
|
|
|
| VEGF |
- Agonists: Placental growth factor (PGF)
- Telbermin
- VEGF (A, B, C, D (FIGF))
- Allosteric modulators: Cyclotraxin B
- Antibodies: Alacizumab pegol
- Bevacizumab
- Icrucumab
- Ramucirumab
- Ranibizumab
- Kinase inhibitors: Agerafenib
- Axitinib
- Cabozantinib
- Cediranib
- Lapatinib
- Lenvatinib
- Motesanib
- Nintedanib
- Pazopanib
- Pegaptanib
- Regorafenib
- Semaxanib
- Sorafenib
- Sunitinib
- Toceranib
- Tivozanib
- Vandetanib
- WHI-P 154
- Decoy receptors: Aflibercept
|
|
| Others |
- Additional growth factors: Adrenomedullin
- Colony-stimulating factors (see here instead)
- Connective tissue growth factor (CTGF)
- Ephrins (A1, A2, A3, A4, A5, B1, B2, B3)
- Erythropoietin (see here instead)
- Glucose-6-phosphate isomerase (GPI; PGI, PHI, AMF)
- Glia maturation factor (GMF)
- Hepatoma-derived growth factor (HDGF)
- Interleukins/T-cell growth factors (see here instead)
- Leukemia inhibitory factor (LIF)
- Macrophage-stimulating protein (MSP; HLP, HGFLP)
- Midkine (NEGF2)
- Migration-stimulating factor (MSF; PRG4)
- Oncomodulin
- Pituitary adenylate cyclase-activating peptide (PACAP)
- Pleiotrophin
- Renalase
- Thrombopoietin (see here instead)
- Wnt signaling proteins
- Additional growth factor receptor modulators: Cerebrolysin (neurotrophin mixture)
|
|
- See also: Peptide receptor modulators
- Cytokine receptor modulators
|
|
GlaxoSmithKline
|
|
| Subsidiaries |
- GlaxoSmithKline Pakistan
- GlaxoSmithKline Pharmaceuticals Ltd
- Stiefel Laboratories
- ViiV Healthcare (85%)
|
|
Predecessors,
acquisitions |
- Allen & Hanburys
- Beecham Group
- Block Drug
- Burroughs Wellcome
- Glaxo
- Glaxo Wellcome
- Human Genome Sciences
- Recherche et Industrie Thérapeutiques
- Reliant Pharmaceuticals
- S. E. Massengill Company
- SmithKline Beecham
- Smith, Kline & French
|
|
| Products |
|
Current
|
|
Pharmaceuticals
|
- Advair
- Alli
- Augmentin
- Avandia
- Beconase
- Boniva
- Flixonase
- Hycamtin
- Lamictal
- Paxil/Seroxat
- Serlipet
- Tagamet
- Ventolin
- Wellbutrin/Zyban
- Zantac … more
|
|
|
Vaccines
|
- Hepatyrix
- Pandemrix
- Twinrix
|
|
|
Other
|
- Aquafresh
- Horlicks
- Nicoderm
- Nicorette
- NiQuitin
- Sensodyne
- Tums … more
|
|
|
|
Former
|
- BC Powder
- Geritol
- Goody's Powder
- Lucozade
- Ribena
|
|
|
| People |
|
Governance
|
- Chris Gent (chair)
- Andrew Witty (CEO)
|
|
|
Other
|
- Thomas Beecham
- Silas M. Burroughs
- Mahlon Kline
- John K. Smith
- Henry Wellcome
|
|
|
| Litigation |
- Canada v. GlaxoSmithKline Inc.
- Christopher v. SmithKline Beecham Corp.
- GlaxoSmithKline Services Unlimited v Commission
- United States v. Glaxo Group Ltd.
- United States v. GlaxoSmithKline
|
|
| Other |
- Drug Industry Document Archive
- GlaxoSmithKline Prize
- Side Effects
- Study 329
|
|
|
|
