Raltegravir Potassium
Raltegravir potassium was first approved by the U.S. Food and Drug Administration (FDA) on Oct 12, 2007, then approved by the European Medicines Agency (EMA) on Dec 20, 2007 and approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on Jun 24, 2008. It was developed and marketed as Isentress® by Merck Sharp & Dohme.
Raltegravir is first in a novel class of antiretroviral drugs known as integrase inhibitors. It has demonstrated potent anti HIV activity in both antiretroviral treatment-naïve and experienced patients. It is in combination with other antiretroviral agents for the treatment of HIV-1 infection in patients 4 weeks of age and older.
Isentress® is available as film-coated tablet for oral use, containing 400 mg of free Raltegravir. Coadministration with rifampin in adults, the dose is 800 mg twice daily. For children and adolescents the dose is 400 mg twice daily.
Update Date：2016-03-14
- Drug Name：
- Raltegravir Potassium
- Research Code：
- MK-0518
- Trade Name：
- Isentress®
- MOA：
- HIV-1 integrase inhibitor
- Indication：
- HIV infection
- Status：
- Approved
- Company：
- Merck Sharp & Dohme (Originator)
- Sales：
-
$1,511 Million (Y2015);
$1,673 Million (Y2014);
$1,643 Million (Y2013);
$1,515 Million (Y2012);
$1,359 Million (Y2011); - ATC Code：
- J05AX08
Update Date：2015-07-29
| Approval Date | Approval Type | Trade Name | Indication | Dosage Form | Strength | Company | Review Classification |
|---|---|---|---|---|---|---|---|
| 2013-12-20 | New dosage form | Isentress | HIV infection | Powder | Eq. 100mg base/packet | Merck Sharp & Dohme | Priority |
| 2011-12-21 | New dosage form | Isentress | HIV infection | Tablet, Chewable | Eq. 25 mg/100 mg base | Merck Sharp & Dohme | Priority |
| 2007-10-12 | Marketing approval | Isentress | HIV infection | Tablet, Film coated | Eq. 400 mg Raltegravir | Merck Sharp & Dohme | Priority |
| Approval Date | Approval Type | Trade Name | Indication | Dosage Form | Strength | Company | Review Classification |
|---|---|---|---|---|---|---|---|
| 2007-12-20 | Marketing approval | Isentress | HIV infection | Tablet, Chewable | 25 mg/100 mg | Merck Sharp & Dohme | |
| 2007-12-20 | Marketing approval | Isentress | HIV infection | Tablet, Film coated | 400 mg | Merck Sharp & Dohme |
| Approval Date | Approval Type | Trade Name | Indication | Dosage Form | Strength | Company | Review Classification |
|---|---|---|---|---|---|---|---|
| 2008-06-24 | Marketing approval | Isentress | HIV infection | Tablet, Film coated | 400 mg | Merck Sharp & Dohme |
| Approval Date | Approval Type | Trade Name | Indication | Dosage Form | Strength | Company | Review Classification |
|---|---|---|---|---|---|---|---|
| 2013-10-09 | Marketing approval | 艾生特/Isentress | HIV infection | Tablet | 400 mg | Merck Sharp & Dohme |
Update Date：2015-08-27
|
Molecular Weight | 482.51 | ||||||||||||
| Formula | C20H20FN6O5 • K | |||||||||||||
| CAS No. |
518048-05-0 (Raltegravir ); 871038-72-1 (Raltegravir Potassium); |
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| Chemical Name | Monopotassium 4-[(4-fluorobenzyl)carbamoyl]-1-methyl-2- (1-methyl-1-{[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl]amino}ethyl)-6-oxo-1,6- dihydropyrimidin-5-olate | |||||||||||||
| Raltegravir （Free Acid/Base）Parameters： | ||||||||||||||
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| *：Calculated by ACD/Labs software V11.02. | ||||||||||||||
Update Date：2015-11-17
Update Date：2015-10-09
Update Date：2016-06-07
Mechanism of Action
Raltegravir potassium, an integrase strand transfer inhibitor, inhibited the strand transfer activity of HIV-1 integrase with IC50 of 10 nM.
Raltegravir potassium inhibited the catalytic activity of HIV-1 integrase, thereby prevented the covalent insertion or integration of the HIV-1 genome into the host cell genome. HIV genomes that fail to integrate cannot direct the production of new infectious viral particles.
Raltegravir potassium did promote a 15.8-fold increase in the abundance of 2-LTR circular DNA, and reduced the abundance of integrated (Alu-LTR) DNA by approximately 50-fold.
Binging of raltegravir was high in mouse, rat, dog and human plasma with average 70%, 74%, 70% and 83%.
At 10 μM or greater raltegravir potassium, no marked off-target inhibitory activities were observed.
In Vitro Efficacy
Raltegravir potassium inhibition of a laboratory HIV-1 or HIV-2 isolate replication in cell culture:
● HIV-1 replication in MT-4 human T-lymphoid cell line: IC95 = 18.7 nM (10% FBS), 31 nM (50% NHS).
● HIV-2 replication in CEMx174 cell line: IC95 = 6.3 nM.
Raltegravir potassium inhibited clinical isolates viruses from HIV-1-infected persons in human PBMCs: IC95 = 6 to 50 nM.
Cell-based resistance selection studies:
● In H9 cells infected with HIV-1IIIB: Q148K substitution as a primary substitution, sequentially supplemented by E138A, G140A, I208M, S230R, Y143C and D10F after the selection over 18 months.
The phenotypic studies with viruses constructed by site-directed mutagenesis:
● Fold-change IC50 = 1-521.
● Infectivity values (%): 14%-123%.
Effects of integrase mutations in clinical isolates on raltegravir potassium sensitivity:
● IC50 = 17-4861 nM.
● Fold-changed IC50 >8-211.
Update Date：2016-06-07
Absorption of Raltegravir
The AUC and Cmax increased in a dose-proportional manner in the dose range 100 to 800 mg in healthy subjects after a single oral dose of raltegravir in the fasted state, while slightly less than dose proportionally in the dose range 100 to 1600 mg. The AUC was nearly linear over the dose range of 40 to 120 mg/kg in rats after oral administration. The AUC and Cmax increased proportionally in the dose range of 5 to 45 mg/kg in dogs after oral administration.
Had a good oral bioavailability in rats (62%) and dogs (70%).
Was absorbed rapidly (Tmax = 0.4-1.0 h) in rats and dogs, but slowly in humans (Tmax = 2.5-4.5 h).
Showed a half-life of 0.2 h in rats and dogs (1.6 h) after intravenous administration, and 0.99-1.09 h in humans after oral administration of poloxamer formulation.
Had a high clearance in rats (45.5 mL/min/kg), but moderate in dogs (7.4 mL/min/kg), compared to the liver blood flow, after intravenous administration.
Exhibited an extensive tissue distribution in rats but confined in dogs, with an apparent volume of distribution at 2.2 and 0.4 L/kg, respectively.
Distribution of Raltegravir
Exhibited moderate protein binding in mice (70%-71%), rats (73%-75%), dogs (69%-71%), and humans (82%-83%), which was independent of raltegravir concentration in all species.
Had a Cb:Cp ratio of 0.6 in humans, suggesting that the drug did not well distribute into red blood cells.
In rats following a single oral administration:
● The drug was rapidly and widely distributed into most tissues, except for central nervous system, with little radioactivity in the brain.
● Relatively higher concentration levels were observed in stomach, small intestine, liver, kidneys and urinary bladder at 0.5 h post-dose.
● The levels in most tissues were below the limit of quantitation by 24 h post-dose.
Metabolism of Raltegravir
Could be minimally metabolized by hepatocytes of rats, dogs and humans, with phenolic glucuronide derivative (M2) as the major metabolite.
Raltegravir was mainly catalyzed by UGT1A1 with a minor contribution from UGT1A9 and 1A3. Raltegravir was not a substrate of CYP450 enzymes.
UGT1A1 was the major metabolic enzyme for the formation of glucuronide metabolite (M2).
Overall, the parent drug represented the most abundant component in plasma of rats, dogs and humans, with glucuronide derivative (M2) as the major metabolite. However, M2 was the major circulating component in mice.
Excretion of Raltegravir
Was predominantly eliminated in feces in humans (51%), rats (53% vs. 64% for p.o. vs. i.v.) and dogs (57.6% vs. 73.9% for p.o. vs. i.v.), with the parent drug as the most significant component in humans, while M2 was identified as the major component in urines of rats and humans.
Drug-Drug interaction
Raltegravir was neither a substrate nor an inhibitor of CYP450 enzymes (IC50 >100 μM).
Raltegravir weakly inhibited UGT1A1 and UGT2B7 (IC50 >50 μM).
Raltegravir was a substrate, but not an inhibitor of P-gp.
Update Date：2016-06-07
Single-Dose Toxicity
Single-dose oral toxicity studies with raltegravir were conducted in mice, rats and dogs:
● The mouse NOAEL was 1000 mg/kg, and LD50 was >2000 mg/kg.
● Treatment-related decreased activity, bradypnea, and ptosis were observed at 1500 and 2000 mg/kg in mice.
● The rat LD50 was >2000 mg/kg, without any effects.
● Treatment-related physical signs consisted of emesis at 500 and 1000 mg/kg in dogs.
Repeated-Dose Toxicity
Repeated-dose toxicity studies were conducted by oral administration of raltegravir for up to 14, 27 or 53 weeks in mice, rats and dogs:
● In mice: Treatment-related findings included mortality, a variety of physical sings and body weight loss, and/or decreases in body weight gain at doses ≥500 mg/kg. Histomorphologic changes were seen in the stomach, due to the irritant effect.
● In rats: Treatment-related findings included mortality at 600 mg/kg/day (27 weeks), stomach inflammation (5 weeks) and post-dosing salivation audible respiratory sounds and inflammation in the nose and nasopharynx (27 weeks).
● In dogs: Emesis was observed, likely due to poor palatability of raltegravir.
Safety Pharmacology
Both in vitro and in vivo safety pharmacology studies were conducted to assess the effects of raltegravir on neurological, cardiovascular, respiratory, renal, and GI system:
● 16% inhibition of hERG current was observed as compared to the vehicle control.
● There was no toxicologically significant adverse effects on cardiovascular, neurological, respiratory, renal, or GI function.
Genotoxicity
Raltegravir was not mutagenic in the in vitro Ames assay.
Raltegravir was not clastogenic in the in vitro chromosomal aberration assays in mammalian cells, or in vivo mouse bone marrow micronucleus assay.
Raltegravir did not induce a significant increase in DNA single strand breaks.
Reproductive and Developmental Toxicity
Fertility and early embryonic development in rats:
● There was no treatment-related findings in the F0 generation and on embryonic/fetal survival in the F1 generation.
● There was no treatment-related effects on mating performance, fertility, embryonic/fetal survival, sperm count, sperm motility, testicular weights, gross or microscopic in the testes or epididymides in males.
Embryo-fetal development in rabbits, combined embryo-fetal, pre- and postnatal developmental in rats:
● Dose-related increases in the numbers of fetuses and litters with supernumerary ribs were observed in rats.
● There were increases in the incidence of increased ossification of hyoid in rabbits.
● Raltegravir was found to readily cross blood-brain and blood-placental barriers and secreted in milk.
Juvenile in rats:
● The only treatment effects were those related to the irritation of the stomach mucosal surface at doses ≥200 mg/kg/day.
● The only indication of toxicity was slightly decreased mean serum glucose values in males at 450 and 600 mg/kg.
Carcinogenicity
Carcinogenicity studies with raltegravir were conducted in mice and rats for 104 or 105 weeks, respectively:
● In mice: No neoplasms of the nose or nasopharynx have been observed. Histomorphologic changes in the nose, nasopharynx and trachea included inflammation, epithelial hyperplasia and metaplasia.
● In rats: Five squamous cell carcinomas of the nose/nasopharynx were identified in high dose females, due to chronic irritation and inflammation. One chondrosarcoma of the nose was observed in one mid dose male.
