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a weak protease inhibitor (trade name Invirase) used in treating HIV (同)Invirase

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/01/01 12:57:08」(JST)

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Saquinavir, sold under the brand names Invirase and Fortovase, is an antiretroviral drug used together with other medications to treat or prevent HIV/AIDS.^[2] Typically it is used with ritonavir or lopinavir/ritonavir. It is taken by mouth.^[2]

Common side effects include nausea, vomiting, diarrhea, and feeling tired. More serious side effects include problems with QT prolongation, heart block, high blood lipids, and liver problems. It appears to be safe in pregnancy. It is in the protease inhibitor class and works by blocking the HIV protease.^[2]

Saquinavir was first sold in 1995.^[3] It is on the World Health Organization's List of Essential Medicines, the most important medication needed in a basic health system.^[4] As of 2015 it is not available as a generic medication and is expensive.^[5] The wholesale cost is about 4.50 USD per day.^[6]

Medical uses

Saquinavir is used together with other medications to treat or prevent HIV/AIDS.^[2] Typically it is used with ritonavir or lopinavir/ritonavir.^[2]

Side effects

The most frequent adverse events with saquinavir in either formulation are mild gastrointestinal symptoms, including diarrhea, nausea, loose stools & abdominal discomfort. Invirase is better tolerated than Fortovase.

Bioavailability and drug interactions

Saquinavir, in the Invirase formulation, has a low and variable oral bioavailability, when given alone. The Fortovase formulation at the standard dosage delivers approximately eightfold more active drug than Invirase, also at the standard dosage.^[7]

In the clinic, it was found that the oral bioavailability of saquinavir in both formulations significantly increases when patients also receive the PI ritonavir. For patients, this has the major benefit that they can take less saquinavir, while maintaining sufficient saquinavir blood plasma levels to efficiently suppress the replication of HIV.

The mechanism behind this welcome observation was not directly known, but later it was determined that ritonavir inhibits the cytochrome P450 3A4 isozyme. Normally, this enzyme metabolizes saquinavir to an inactive form, but with the ritonavir inhibiting this enzyme, the saquinavir blood plasma levels increased considerably. Additionally, ritonavir also inhibits multidrug transporters, although to a much lower extent.

Unlike other protease inhibitors, the absorption of saquinavir seems to be improved by omeprazole.^[8]

Mechanism of action

Saquinavir is a protease inhibitor. Proteases are enzymes that cleave protein molecules into smaller fragments. HIV protease is vital for both viral replication within the cell and release of mature viral particles from an infected cell. Saquinavir binds to the active site of the viral protease and prevents cleavage of viral polyproteins, preventing maturation of the virus. Saquinavir inhibits both HIV-1 and HIV-2 proteases.

History

HIV deaths in the United States fell from approximately 50,000 per year to 18,000 in the two years following the FDA approval of saquinavir^[9]

Saquinavir was developed by the pharmaceutical company Roche. Saquinavir was the first protease inhibitor (and sixth antiretroviral) approved by the Food and Drug Administration (FDA). Within 2 years of its approval, and that of ritonavir 4 months later, annual deaths from AIDS in the United States fell from over 50,000 to approximately 18,000.^[10] The manufacturer, Roche, requested and received approval of Invirase via the FDA's "Accelerated Approval" program, a process designed to speed drugs to market for the treatment of serious diseases. This decision was controversial, amid disagreement between AIDS activists over the benefits of thorough testing versus early access to new drugs.^[11]

It was approved again on Nov 7, 1997 as Fortovase, a soft gel capsule reformulated for improved bioavailability. Roche announced in May 2005 that, owing to reduction in demand, Fortovase would cease being marketed early in 2006 in favour of Invirase boosted with ritonavir.^[12]

Society and culture

Cost

As of 2015 it is not available as a generic medication and is expensive.^[5] The wholesale cost is about 4.50 USD per day.^[6]

Formulations

Two formulations have been marketed:

a hard-gel capsule formulation of the mesylate, with trade name Invirase, which requires combination with ritonavir to increase the saquinavir bioavailability;
a soft-gel capsule formulation of saquinavir (microemulsion,^[13] orally-administered formulation), with trade name Fortovase, which was discontinued worldwide in 2006.^[14]

References

^ "Invirase (saquinavir mesylate) Capsules and Tablets, for Oral Use. Full Prescribing Information" (PDF). Genentech, Inc. Retrieved 23 November 2015.
^ ^a ^b ^c ^d ^e "Saquinavir". The American Society of Health-System Pharmacists. Retrieved Sep 5, 2015.
^ Minor, Lisa K. (2006). Handbook of Assay Development in Drug Discovery. Hoboken: CRC Press. p. 117. ISBN 9781420015706.
^ "WHO Model List of Essential Medicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
^ ^a ^b Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 72. ISBN 9781284057560.
^ ^a ^b "Saquinavir". International Drug Price Indicator Guide. Retrieved 6 September 2015.
^ Fortovase^TM (saquinavir) soft gelatin capsules. Product information (November 1997)
^ Winston A, Back D, Fletcher C, et al. (2006). "Effect of omeprazole on the pharmacokinetics of saquinavir-500 mg formulation with ritonavir in healthy male and female volunteers". AIDS 20 (10): 1401–6. doi:10.1097/01.aids.0000233573.41597.8a. PMID 16791014.
^ "www.cdc.gov" (PDF).
^ "HIV Surveillance --- United States, 1981--2008". Retrieved 8 November 2013.
^ "Drugs! Drugs! Drugs! An Overview of the Approved Anti-HIV Medications". The Body. Retrieved 20 February 2013.
^ Withdrawal of Fortovase (PDF)
^ Gibaud, S. P.; Attivi, D. (2012). "Microemulsions for oral administration and their therapeutic applications". Expert Opinion on Drug Delivery: 1. doi:10.1517/17425247.2012.694865.
^ News-Medical.Net. May 18, 2005 Roche to discontinue the sale and distribution of Fortovase (saquinavir)

External links

Saquinavir bound to proteins in the PDB

UpToDate Contents

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1. HIVプロテアーゼ阻害剤 hiv protease inhibitors
2. HIV抗レトロウイルス療法に関する臨床試験：プロテアーゼ阻害剤 clinical trials of hiv antiretroviral therapy protease inhibitors
3. HIV抗レトロウイルス療法に関する臨床試験：プロテアーゼ阻害剤と非ヌクレオシド系逆転写酵素阻害剤の比較 clinical trials of hiv antiretroviral therapy protease inhibitors versus non nucleoside reverse transcriptase inhibitors
4. 抗レトロウイルス療法の潜在的副作用に関するHIV感染患者を対象としたカウンセリング counseling hiv infected patients regarding potential side effects of antiretroviral therapy
5. HIV薬剤耐性検査の解釈についての手引 primer on interpretation of hiv drug resistance testing

English Journal

Pharmacokinetics of a multipurpose pod-intravaginal ring simultaneously delivering five drugs in an ovine model.

Moss JA, Malone AM, Smith TJ, Kennedy S, Nguyen C, Vincent KL, Motamedi M, Baum MM.SourceDepartment of Chemistry, Oak Crest Institute of Science, Pasadena, California, USA.
Antimicrobial agents and chemotherapy.Antimicrob Agents Chemother.2013 Aug;57(8):3994-7. doi: 10.1128/AAC.00547-13. Epub 2013 Jun 10.
Multipurpose technologies that simultaneously protect from sexually transmitted infections and unintended pregnancy are urgently needed. Pod-intravaginal rings (IVRs) formulated with the antiretroviral agents (ARVs) tenofovir, nevirapine, and saquinavir and the contraceptives etonogestrel and estrad
PMID 23752507

A Contribution to the Drug Resistance Mechanism of Darunavir, Amprenavir, Indinavir, and Saquinavir Complexes with HIV-1 Protease Due to Flap Mutation I50V: A Systematic MM-PBSA and Thermodynamic Integration Study.

Leonis G, Steinbrecher TB, Papadopoulos MG.AbstractThe emergence of HIV-1 drug-resistant mutations is the major problem against AIDS treatment. We employed molecular dynamics (MD) calculations and free energy (MM-PBSA and Thermodynamic Integration) analyses on wild type (WT) and mutated HIV-1 protease (HIV-1 PR) complexes with darunavir, amprenavir, indinavir and saquinavir to clarify the mechanism of resistance due to the I50V flap mutation. Conformational analysis showed that the protease flaps are increasingly flexible in the I50V complexes. In the WT, stabilization of the HIV-1 PR structure is achieved via inter-flap and water-mediated hydrogen bonding interactions between the flaps. Furthermore, hydrogen bonds between drugs and binding cavity residues (Asp29/29'/30/30') are crucial for effective inhibition. All these interactions were significantly diminished (or absent) in the mutated forms, thus denoting their importance toward binding. Thermodynamic Integration calculations reproduced the experimental data to within ≈1 kcal mol-1 and showed that the I50V mutation results in weaker binding free energies for all analyzed complexes with respect to the WT. It was observed that the loss in binding energy upon mutation was mostly enthalpically driven in all complexes, with the greatest effect coming from the reduction of van der Waals interactions. Our results motivated us to test two novel compounds that have been synthesized to maximize interactions with HIV-1 PR. MM-PBSA and TI calculations showed that compound 3c (Ghosh et al. Bioorg. Med. Chem. Lett. 2012, 22, 2308) is a promising protease inhibitor, which presents very effective binding to the WT PR (ΔGMM-PBSA = - 17.2 kcal mol-1, ΔGexp = - 16.1 kcal mol-1), and upon I50V mutation, the complex binding free energy was weakened by a ΔΔGTI of 1.8 kcal mol-1, comparable to the marketed inhibitors. This predicts that I50V may confer low resistance to 3c. This computational comparative study contributes toward elucidation of the I50V drug-resistance mechanism in HIV-1 PR.
Journal of chemical information and modeling.J Chem Inf Model.2013 Jul 8. [Epub ahead of print]
The emergence of HIV-1 drug-resistant mutations is the major problem against AIDS treatment. We employed molecular dynamics (MD) calculations and free energy (MM-PBSA and Thermodynamic Integration) analyses on wild type (WT) and mutated HIV-1 protease (HIV-1 PR) complexes with darunavir, amprenavir,
PMID 23834142

Targeting delivery of saquinavir to the brain using 83-14 monoclonal antibody-grafted solid lipid nanoparticles.

Kuo YC, Ko HF.SourceDepartment of Chemical Engineering, National Chung Cheng University, Chia-Yi, Taiwan 62102, Republic of China. chmyck@ccu.edu.tw
Biomaterials.Biomaterials.2013 Jul;34(20):4818-30. doi: 10.1016/j.biomaterials.2013.03.013. Epub 2013 Mar 29.
83-14 monoclonal antibody (MAb) was modified on solid lipid nanoparticles (SLNs) to improve the brain-targeting delivery of saquinavir (SQV). The endocytosis of 83-14 MAb-grafted SQV-loaded SLNs (83-14 MAb/SQV-SLNs) into human brain-microvasscular endothelial cells (HBMECs) was studied by staining c
PMID 23545288

Japanese Journal

Analysis of the Pharmacokinetic Boosting Effects of Ritonavir on Oral Bioavailability of Drugs in Mice

TOMARU Atsuko,TAKEDA-MORISHITA Mariko,BANBA Hirokazu,TAKAYAMA Kozo
Drug Metabolism and Pharmacokinetics 28(2), 144-152, 2013
… The area under the plasma concentration-time curves (AUC) for orally administered saquinavir after coadministration with 50 mg/kg ritonavir dramatically increased (325-fold). … Moreover, the AUC0–12 for saquinavir was affected negligibly by itraconazole. … These results indicate ritonavir mainly affects the first-pass effect of saquinavir in the small intestine, increasing the bioavailability of orally administered saquinavir. …
NAID 130004933527

Large-Scale Quantum Chemical Calculation on the Complexes of HIV-1 Protease and Inhibitors: A Relationship of Calculation Energies with Drug Effects of Inhibitors

Yagi Yoichiro,Hattori Yousuke,Naoshima Yoshinobu
日本シミュレーション学会論文誌 4(2), 41-50, 2012
… In addition, similar FMO computations on the complexes of a human protease renin with two HIV-1 protease inhibitors, Ritonavir and Saquinavir, show that the binding energy for Ritonavir with many side effects is negatively larger than that for Saquinavir with few side effects. …
NAID 130004544045

Garlic Flavonoids and Organosulfur Compounds : Impact on the Hepatic Pharmacokinetics of Saquinavir and Darunavir

BERGINC Katja,MILISAY Irina,KRISTL Albin
Drug metabolism and pharmacokinetics 25(6), 521-530, 2010-12-25
NAID 10027743722

Related Pictures

★リンクテーブル★

リンク元	「薬理学」「サキナビル」「Invirase」「SQV」
拡張検索	「saquinavir mesilate」

「薬理学」

Saquinavir
Systematic (IUPAC) name
	(2S)-N-[(2S,3R)-4-[(3S)-3-(tert-butylcarbamoyl)-decahydroisoquinolin-2-yl]-3-hydroxy-1-phenylbutan-2-yl]-2-(quinolin-2-ylformamido)butanediamide
Clinical data
Trade names	Invirase, Fortovase
AHFS/Drugs.com	monograph
MedlinePlus	a696001
Pregnancy; category	B1 (Australia);
Pharmacokinetic data
Bioavailability	~4% (without ritonavir boosting)
Protein binding	98%
Metabolism	Hepatic, mainly by CYP3A4
Biological half-life	9–15 hours
Excretion	feces (81%) and urine (3%)
Identifiers
CAS Number	127779-20-8
ATC code	J05AE01
PubChem	CID: 441243
IUPHAR/BPS	4813
DrugBank	DB01232
ChemSpider	390016
UNII	L3JE09KZ2F
KEGG	D00429
ChEMBL	CHEMBL114
NIAID ChemDB	000640
Chemical data
Formula	C38H50N6O5
Molecular mass	670.841 g/mol
	SMILES O=C(N)C[C@H](NC(=O)c1nc2c(cc1)cccc2)C(=O)N[C@@H](Cc3ccccc3)[C@H](O)CN5[C@H](C(=O)NC(C)(C)C)C[C@@H]4CCCC[C@@H]4C5 ;
	InChI InChI=1S/C38H50N6O5/c1-38(2,3)43-37(49)32-20-26-14-7-8-15-27(26)22-44(32)23-33(45)30(19-24-11-5-4-6-12-24)41-36(48)31(21-34(39)46)42-35(47)29-18-17-25-13-9-10-16-28(25)40-29/h4-6,9-13,16-18,26-27,30-33,45H,7-8,14-15,19-23H2,1-3H3,(H2,39,46)(H,41,48)(H,42,47)(H,43,49)/t26-,27+,30-,31-,32-,33+/m0/s1 ; Key:QWAXKHKRTORLEM-UGJKXSETSA-N ;
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　　[★]

英: pharmacology
関: drug entries

定義

生物系と化学物質の選択的な相互作用を研究する学問 (SPC.2)

生物系と薬の相互作用

薬の生物系に対する相互作用：薬理作用 <-化学の視点
生物系の薬に対する相互作用：薬物動態 <-生物の視点

薬品の命名

Ending of the drug name	Category	Example
～afil	Erectile dysfunction	sildenafil
～ane	Inhalatinal general anesthetic	halothane
～azepam	Benzodiaizepine	diazepam
～azine	Phenothiazine (neuroleptic, antiemetic)	chlorpromazine
～azole	Ailtifungal	ketoconazole
～barbital	Barbiturate	phenobarbital
～caine	Local anesthetic	lidocaine
～cillin	Penicillin	methicillin
～cycline	Antibiotic, protein syntlesis inhibitor	tetracycline
～ipramine	TCA	iimipramine
～navir	Protease inhibitor	saquinavir
～olol	β-antagonist	propranolol
～operidol	Butyrophenone ( neuroleptic )	haloperidol
～oxin	Cardiac glycoside ( inotropic agent )	digoxin
～phylline	Methylxanthine	theophylline
～pril	ACE inhibitor	captopril
～terol	β₂ agonist	albuterol
～tidine	H₂ antagonist	cimtidine
～triptyline	TCA	amitriptyline
～tropine	Pituitary hormone	somatotropine
～zosin	a₁ antagonist	prazosin

薬一覧

薬物代謝

薬理動態

神経伝達物質

貧血治療薬

甲状腺関連物質

甲状腺ホルモン製剤

レボチロキシン levothyroxine
リオチニシン liothyronine

抗甲状腺薬

痛風治療薬

痛風発作予防薬

コルヒチン colchicine

尿酸排泄促進薬

尿酸生成抑制薬

アロプリノール allopurinol

「サキナビル」

　　[★]

英: saquinavir, SQV
化: メシル酸サキナビル saquinavir mesilate
商: インビラーゼ、Invirase

「Invirase」

　　[★]

インビラーゼ

関: saquinavir

「SQV」

　　[★] サキナビル saquinavir

「saquinavir mesilate」

　　[★]

メシル酸サキナビル

関: saquinavir

[1] "Invirase (saquinavir mesylate) Capsules and Tablets, for Oral Use. Full Prescribing Information" (PDF). Genentech, Inc. Retrieved 23 November 2015.

[AHFS2015-2] "Saquinavir". The American Society of Health-System Pharmacists. Retrieved Sep 5, 2015.

[Min2006-3] Minor, Lisa K. (2006). Handbook of Assay Development in Drug Discovery. Hoboken: CRC Press. p. 117. ISBN 9781420015706.

[4] "WHO Model List of Essential Medicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.

[Ric2015-5] Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 72. ISBN 9781284057560.

[ERC2014-6] "Saquinavir". International Drug Price Indicator Guide. Retrieved 6 September 2015.

[7] Fortovase^TM (saquinavir) soft gelatin capsules. Product information (November 1997)

[8] Winston A, Back D, Fletcher C, et al. (2006). "Effect of omeprazole on the pharmacokinetics of saquinavir-500 mg formulation with ritonavir in healthy male and female volunteers". AIDS 20 (10): 1401–6. doi:10.1097/01.aids.0000233573.41597.8a. PMID 16791014.

[9] "www.cdc.gov" (PDF).

[10] "HIV Surveillance --- United States, 1981--2008". Retrieved 8 November 2013.

[11] "Drugs! Drugs! Drugs! An Overview of the Approved Anti-HIV Medications". The Body. Retrieved 20 February 2013.

[12] Withdrawal of Fortovase (PDF)

[13] Gibaud, S. P.; Attivi, D. (2012). "Microemulsions for oral administration and their therapeutic applications". Expert Opinion on Drug Delivery: 1. doi:10.1517/17425247.2012.694865.

[14] News-Medical.Net. May 18, 2005 Roche to discontinue the sale and distribution of Fortovase (saquinavir)

Systematic (IUPAC) name


(2S)-N-[(2S,3R)-4-[(3S)-3-(tert-butylcarbamoyl)-decahydroisoquinolin-2-yl]-3-hydroxy-1-phenylbutan-2-yl]-2-(quinolin-2-ylformamido)butanediamide
Clinical data
Trade names	Invirase, Fortovase
AHFS/Drugs.com	monograph
MedlinePlus	a696001
Pregnancy category	B1 (Australia)
Pharmacokinetic data
Bioavailability	~4% (without ritonavir boosting)^[1]
Protein binding	98%
Metabolism	Hepatic, mainly by CYP3A4
Biological half-life	9–15 hours
Excretion	feces (81%) and urine (3%)
Identifiers
CAS Number	127779-20-8^Y
ATC code	J05AE01
PubChem	CID: 441243
IUPHAR/BPS	4813
DrugBank	DB01232^Y
ChemSpider	390016^Y
UNII	L3JE09KZ2F^Y
KEGG	D00429^Y
ChEMBL	CHEMBL114^Y
NIAID ChemDB	000640
Chemical data
Formula	C₃₈H₅₀N₆O₅
Molecular mass	670.841 g/mol
SMILES O=C(N)C[C@H](NC(=O)c1nc2c(cc1)cccc2)C(=O)N[C@@H](Cc3ccccc3)[C@H](O)CN5[C@H](C(=O)NC(C)(C)C)C[C@@H]4CCCC[C@@H]4C5
InChI InChI=1S/C38H50N6O5/c1-38(2,3)43-37(49)32-20-26-14-7-8-15-27(26)22-44(32)23-33(45)30(19-24-11-5-4-6-12-24)41-36(48)31(21-34(39)46)42-35(47)29-18-17-25-13-9-10-16-28(25)40-29/h4-6,9-13,16-18,26-27,30-33,45H,7-8,14-15,19-23H2,1-3H3,(H2,39,46)(H,41,48)(H,42,47)(H,43,49)/t26-,27+,30-,31-,32-,33+/m0/s1^Y Key:QWAXKHKRTORLEM-UGJKXSETSA-N^Y
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匿名

検索

案内

saquinavir