raltegravir - technische universität darmstadt

RALTEGRAVIR

P. Völker, L. von Haza, C. Wöntz & D. Zakharchuk

DaMocles June 2020

Table of contents: 1. Introduction .......................................................................................................... 2

2. Physical properties ............................................................................................. 3

3. Synthesis ................................................................................................................. 5

3.1 General synthesis ..................................................................................................... 5

4. Pharmacology ....................................................................................................... 7

4.1 Pharmacodynamics .................................................................................................. 7

Integrase: ................................................................................................................................................ 7 Mechanism of Action: ........................................................................................................................ 10

4.2 Pharmacokinetics ................................................................................................... 12

Absorption: ............................................................................................................................................ 12 Food impact: ......................................................................................................................................... 12

Gender, age and ethnic groups: ................................................................................................... 13 Young people and kids: .................................................................................................................... 13

BMI: ......................................................................................................................................................... 14 Use during pregnancy and breastfeeding: ................................................................................ 16

Safety: .................................................................................................................................................... 17 Safety in coinfected patients: hepatitis and tuberculosis: .................................................. 17 Tolerability: ........................................................................................................................................... 18

Table of figures: ...................................................................................................... 20

Sources: ...................................................................................................................... 21

2

1. Introduction

This article will give you an overview about the integrase inhibitor

Raltegravir, the antiviral agent in the medication called Isentress®.

The inhibitor targets the viral integrase, the HIV-1 enzyme that is

responsible for the integration of the viral cDNA into the host cells genome

and therefore the virus replication. In combination with other antiviral

agents Raltegravir can limit the amount of HIV virus load and at the same

time increase the number of CD4-(T)-cells, which are a type of white

blood cells that have an important share in maintaining a healthy immune

system as well as the fight against infections. Compared to other antiviral

agents that are used in a highly active antiretroviral therapy Raltegravir

has a bigger impact on multi resistant viruses.

It is the antiviral agent in the medication Isentress that is produced by

Merck & Co, used to treat the HIV infection. It was approved by the U.S.

Food and Drug Administration (FDA) in 2007 and Switzerland in 2008 as

the first integrase inhibitor. In 2008 it received the “14. PZ-

Innovationspreis”. [2]

3

2. Physical properties The following table presents the physical properties of Raltegravir:

Name Raltegravir

Trade name [4] Isentress

IUPAC name [1]

N-[2-[4-[(4-

fluorophenyl)methylcarbamoyl]-5-

hydroxy-1-methyl-6-oxopyrimidin-2-

yl]propan-2-yl]-5-methyl-1,3,4-

oxadiazole-2-carboxamide

CAS number [2] 518048-05-0

Molecular formula [2] C20H21FN6O5

Molar mass [3] 444.42 g/mol

Solubility [2] Water soluble

Toxicology [2] >2,000 mg/kg (LD50, mouse, oral)

Routes of administration [3] oral

Metabolism [3] Hepatic

Elimination half-life [3] 9 hours

Bioavailability [3] 60%

Protein binding [3] 83%

Figure 1: Physical properties

Raltegravir which is a hydroxypyridinone carboxamide has the β-hydroxy

ketone structural motif, which is characteristic for the diketo acids which

are known to be highly promising integrase inhibitors. The structure of

Raltegravir has been deduced based on an X-ray analysis of the structure

of the integrase it inhibits. Therefore, Raltegravir has a very high

4

specificity and affinity to the viral integrase molecule. It is one of the first

pharmaceuticals this technique has ever been used on and the first

molecule of its class of drugs. This accounts for a very complex structure

and synthesis, which is shown in the following pages. [5]

The following figures show models of the structure of Raltegravir:

Figure 2: 2D-Structure of Raltegravir

Figure 3: 3D-Structure of Raltegravir

5

3. Synthesis The active compound of INSENTRESS is the potassium salt of Raltegravir.

The general synthetic route of Raltegravir Potassium is shown in the

following.

3.1 General synthesis The antiviral drug can be synthesized within few steps beginning with

Strecker reaction of acetone cyanohydrin (34.1,181) to amino nitrile

(34.1.182). Next is to convert aminonitrile into the N-Cbz

(carboxybenzyl)-protected intermediate (34.1.183) by using benzyl

chloroformate in sodium carbonate water solution. The transformation of

the obtained intermediate (34.1.183) to amidoxime (34.1.184) can be

achieved by adding hydroxylamine hydrochloride in methanol.

Figure 4: Synthesis 1

The amidoxime is then treated with dimethylacetylenedicarboxylate

(34.1.185) in chloroform. The obtained product (34.1.186) is put into

toluene and is heated at 145°C to cyclize to pyrimidine-4-

carboxylate (34.1.187).


The compound (34.1.187) is then benzoylated with benzoyl chloride in

pyridine. By N-methylathing the Product (34.1.188) with dimethyl sulfate

in dioxane using lithium as a base the compound (34.1.189) can be

obtained. The N-Cbz-deprotected product (34.1.190) can be achieved

due to hydrogenation.

6


(34.1.190) is treated with 5-methyl-1,3,4- oxadiazole-2-carbonyl chloride

(34.1.191) in the presence of triethylamine in dichloromethane. Refluxing

the product (33.1.192) with p-fluorobenzyl amine in methanol leads to

Raltegravir (34.1.178). [27]


The potassium salt of Raltegravir can be finally achieved by treating

Raltegravir with potassium hydroxide in ethanol at 25°C for 1.5 hours.

[28]


Furthermore, there are other synthesis routes providing more efficiency

for industrial manufacturing. [27]

7

4. Pharmacology

4.1 Pharmacodynamics Integrase is a HIV-1 explicit enzyme which catalyses the inclusion of a

DNA duplicate of the viral genome into the genome of host cells. The use

of Raltegravir results in the limitation of the reproduction of the virus and

thus stops further spread of the infection.

Integrase:

Integrase is an HIV-1 specific enzyme, which is one of the three enzymes

that are involved in viral replication.

It is structurally organized into three domains that are independent from

each other:

(i) the N-terminal region that carries a motif similar to a zinc finger and is

able to bind Zn2+ or other divalent metals like magnesium. This possibly

favours protein multimerization which is a necessity in the integration

process.

(ii) the main region also known as the catalytic region that contains a D,

D-35, E motif which is needed for the enzymes catalytic activity. This

region is also involved in the binding of the viral DNA extremities. These

activities require that a metallic cation cofactor like magnesium or zinc is

present to coordinate it.

(iii) the C-terminal region is able to bind to DNA without a requirement

which predetermines its involvement in ensuring the stability of the

complex with the DNA. [25]

Its main function is to catalyse the integration of viral cDNA ends (which

have been generated by reverse transcription of the viral RNA genome

before) into the host cells genome, marking the last necessary step before

the virus is able to reproduce.

8

The integration of the viral cDNA into the host genome consists of two

consecutive steps: the 3’-processing and the strand transfer.

In order to start the integration process, it is absolutely necessary to have

a complex of viral DNA and the integrase enzyme which has to be formed

beforehand. This complex formation is possible because the HIV integrase

recognizes specific sequences in the LTRs (long terminal repetition) of

viral DNA and binds to them.

At the actual beginning of the integration process the 3’processing takes

place. During this process of the integration two nucleotides are

eliminated from each 3’-end of the double helical viral DNA. Afterwards

the empty slots at the 3’-ends are filled with an OH-substituent each.

Figure 9: The two integrase catalytic reactions

9

In the second step of the integration process, the strand transfer, the

adjusted viral DNA is joined with the DNA of the host cells. This unification

of the two DNAs is taking place in the host cells, nucleus during an

esterification reaction. In the course of the reaction the host DNA and the

viral DNA are joined together via the OH-substituents at the 3’-ends of the

viral DNA and the phosphate-substituents at the 5’-ends of the host DNA.

The coupling of both DNA strands is coordinated by divalent metal co-

factors (with either one or two atoms like for example magnesium or

zinc). [7,6]

Figure 10: The strand transfer mechanism

10

Mechanism of Action:

The integrase inhibitor Raltegravir that is also referred to as a strand

inhibitor because it interferes with the second step of the viral cDNA

integration reaction the strand transfer, the transfer of the viral DNA into

the host cells DNA, without having an effect on the first step of the

integration process the 3’-processing. [9]

It is able to block the transfer of a strand of viral DNA into the host cells

DNA strand by binding at the active sites of the intermediate product of

the first step of the integration reaction the PIC (pre-integration complex).

This pre-integration complex is a ternary complex made up by the HIV-1

integrase, a metallic cation cofactor (a divalent metal like magnesium or

zinc) and the viral cDNA.

The integrase inhibitor binds to the active site of the ternary complex by

chelating the divalent metallic cationic co-factors in the integrase active

site. This is interfering with the usual insertion of linear HIV-1 DNA into

the targeted host cells genome because the metallic cation co-factors that

are supposed to coordinate the second step of the integration process the

strand transfer are disabled and therefore the coupling of both DNA

strands is not taking place. [25]

11

Figure 11: Targeting points for the different antiviral agents

As a consequence of the inhibition of the normal catalytic integration

process, the formation of the HIV-1 provirus, which is an absolute

necessity for the reproduction of virus cells, is prevented and therefore

the viral replication is limited (90-95%) and the spreading of the virus

contained. [13]

12

4.2 Pharmacokinetics

Absorption:

Raltegravir is quickly assimilated in the wake of taking the medication on

an empty stomach, the greatest fixation (StAX) in the blood plasma is

resolved after approximately 3 hours.

The area under the concentration - the time curve (AUC) and the STAC

value increase proportionally to the dose which can range from 100 to

1600 mg. By taking the drug 2 times a day, the equilibrium state is

reached quickly, approximately within 2 days after the start of the

treatment. The values of AUC and Cmax are speaking in favour of a

minimal accumulation of the drug.

The absolute bioavailability of Raltegravir has not been established.

Food impact:

Raltegravir can be taken regardless of mealtime. [29]

The impact of food on the pharmacokinetics of raltegravir is a little difficult

to understand. The AUC of raltegravir relative to fasting, decreased with a

low-fat meal (-46%) and it did not significantly change with a moderate-

fat meal (+13%) and increased twofold with a high-fat meal. (Raltegravir

(RAL) Dose Proportionality and Effect of Food)

In all analysed cases, food seemed to increment an intra-subject

changeability in pharmacokinetic parameters when contrasted with

fasting. It is suggested that raltegravir be taken with or without food

because of the perception that these distinctions in the introduction to

Raltegravir were not related to either decreased antiviral movement or

expanded occurrence of unfavourable occasions.

Approximately 83% of Raltegravir binds to plasma proteins in the

concentration range from 2 to 10 mmol.

13

Raltegravir effectively defeated the placental boundary in test

concentrates on rodents, however, it didn't enter the blood-cerebrum

obstruction. [29]

The terminal elimination half-life of Raltegravir is 9 h, with a shorter a-

phase half-life of ~ 1 h which determines most of the AUC. Raltegravir is

glucuronidated to Raltegravir-glucuronide by the UDP-

glucuronosyltransferase 1A1 (UGT1A1) enzyme. [30]

Following the administration of an oral dose, 51% is excreted in feces in

the form of Raltegravir; most likely, the glucuronide metabolite is

hydrolyzed by glucuronidases in the intestinal tract. A small percentage of

the dose, 32%, is excreted in the urine; only a small part, 9% of the dose,

is excreted in the urine as unchanged Raltegravir, the remaining 24% is

the glucuronide metabolite. [31]

Gender, age and ethnic groups:

Gender has no proved clinically significant effect on the pharmacokinetic

parameters of Raltegravir. In studies on patients older than 18 years of

age, no significant dependence of pharmacokinetic parameters on age was

found. Therefore, a correction of the drug dose depending is not required.

[34,35]

Young people and kids:

As indicated in the report of after-effects in sound grown-up volunteers,

the chewable tablet has a higher oral bioavailability in contrast to the pill

with film-coating, 400 mg each. Taking the chewable tablets with food

with a high fat content has no clinically noteworthy impact on the

pharmacokinetics of Raltegravir. The medication dosage for teenagers and

youngsters over 2 years of age for the treatment of HIV-1 contamination

is prescribed according to the pharmacokinetic parameters of raltegravir,

which is practically identical to that of grown-up patients taking the

medication two times per day. [29,36]

14

BMI:

Modifications in body weight can influence the sedate disposition by

changing the volume of dispersion of the medication. In a

pharmacokinetic examination, in which weight file (BMI) was treated as a

continuous variable, there was no clinically important impact of BMI on

Raltegravir pharmacokinetics. [33]

Patients with renal and hepatic insufficiency:

Renal clearance accounts for a small proportion of the elimination of

Raltegravir from the system. The pharmacokinetics of the drug was

studied on adult patients with a severe degree of renal failure as well as in

a complex pharmacokinetic analysis. [29,34]

Clinically significant discrepancy of pharmacokinetic parameters in

patients with severe renal failure compared to healthy volunteers is not

detected. Raltegravir is dispensed principally by glucuronidation in the

liver. An investigation of the pharmacokinetics of Raltegravir was

conducted on patients with a moderate hepatic inadequacy and matched

healthy control subjects. [34]

The impact of gentle hepatic inadequacy was not assessed in this

investigation, yet given the clinically unimportant outcomes for moderate

hepatic deficiency patients, an absence of clinically significant impact for

mellow inadequacy can be surmised from the data. There were no

clinically significant pharmacokinetic contrasts between patients with

moderate hepatic inadequacy and clinically unremarkable subjects. [33]

Thus, a correction of the drug dose in patients with severe kidney failure

and hepatic insufficiency is not required. [29,34]

15

Figure 12: Arithmetic mean Raltegravir plasma concentration profiles

following administration of a 400-mg single dose to subjects with hepatic

impairment, subjects with renal impairment, and corresponding matched

control subjects with normal hepatic and renal function

Patients with UDPGT polymorphism:

Polymorphisms in drug-metabolizing enzymes may have the

accompanying results: increment or lessening of the successful portion,

stretching or shortening of the length of helpful impact, ADEs, tranquilize

harmfulness and medication sedate communications.

Within this class, UGT1A1 is the specific enzyme that catalyses the

conjugation of bilirubin. On account of antiretroviral operators, various

polymorphisms have been concentrated to affirm their relationship with

hyperbilirubinemia, a condition present in a consider-capable level of

patients treated with ATV or IDV.

16

The results of these studies show that the polymorphism most closely

related with hyperbilirubinemia is UGT1A1*28, which reduces the activity

of the enzyme in individuals who are homozygotes for the rare allele.

These individuals were not excluded from the Raltegravir-development-

program, and they contributed to the robustness of the safety profile for

Raltegravir, further supporting the hypothesis that a substantial reduction

of UGT1A1 activity does not result in a clinically meaningful effect.

Recently, genetic polymorphisms of the iso-enzyme UGT2B7 have also

been studied. This enzyme has been observed to be the principal enzyme

involved in the N-glucuronidation of EFV. The exact incidence of Gilbert’s

syndrome among participants in Raltegravir clinical studies is not known.

[34,37]

Use during pregnancy and breastfeeding:

Controlled studies about the effects of the drug on pregnant women have

not been conducted, so the drug is contraindicated to use during

pregnancy.

There are no data on the intake of Raltegravir in human breast milk.

However, the intake of Raltegravir was detected when the drug was

introduced into milk in rats: when the drug was administered at a daily

dose of 600 mg/kg, the concentration of Raltegravir in milk exceeded the

plasma concentration by about 3 times.

Breastfeeding is not recommended for HIV-infected mothers in order to

avoid transmission of HIV infection to children.

If it is need to use the drug during lactation, it is recommended to stop

breastfeeding. [29]

17

Safety:

Taken together all studies suggest that Raltegravir is well tolerated with

serious drug-related adverse event (SAE) rates that were either similar or

lower than observed in the comparator arms (i.e., placebo in salvage

regimens of efavirenz in treatment-naive patients). For instance, in the

largest study of treatment-experienced patients, 2.8% of the patients on

Raltegravir + OBR reported a drug-related SAE versus 3.8% of the

patients on placebo + OBR.

There has been some concern about the development of cancer in

treatment-experienced patients on Raltegravir. Initially, a trend appeared

to be visible of an increased incidence of cancer but prolonged follow-up

of these patients did not show any differences versus placebo. Also, in

treatment-naive patients comparing Raltegravir with efavirenz, no

difference was noted. [32]

Safety in coinfected patients: hepatitis and tuberculosis:

Other than every so often expanding alanine aminotransferase (ALT) and

aspartate aminotransferase (AST), no extraordinary hepatotoxicity was

seen in clinical preliminaries. Although under-represented, hepatitis B

and/or C patients were included and had similar rates of virologic efficacy

than monoinfected in the study. [38]

Observational studies show that coinfected patients are more likely to

have baseline liver enzyme alterations and to present subsequent

increases after Raltegravir introduction, irrespective of severity and mostly

appearing early after treatment initiation. However, severe abnormalities

are globally rare and hardly warrant. [39]

The REFLATE study has demonstrated that Raltegravir 400 mg or 800 g

twice day by day can be utilized in patients co-tainted with HIV and

tuberculosis albeit still isn't totally clear which is the favoured dosing. In

18

REFLATE multiplying the portion of Raltegravir overcompensated the

impact of rifampicin acceptance. Be that as it may, the standard portion

had just little reductions in AUC0-12 and C12. [40]

Tolerability:

The resistance to the drug has not been fully studied. Despite this, there

is a study that confirms that the presence of mutations in the genes of

patients affects the tolerance and resistance to Raltegravir. According to

the study most mutations occur in genes Q148K, T97A, Y143C and Y143H.

While essential changes were uncommon, baseline secondary mutations

were more common in the two groups of patients. As with primary

mutations, more secondary mutations were found in the treatment failure

group than in the treatment success group.

The level of each Raltegravir-safe transformation was determined by PASS

in every patient. Each symbol represents the percentage of one mutation

occurring in either treatment success (circles) or treatment failure

(triangles) patients.

All detected mutations were present at very low frequencies (<1%),

except of two secondary mutations in two patients (2.2% for L74M and

1.1% for G140S) (Fig. 14). There were no in frequencies of primary

mutations between the treatments (Fig. 15). Every single mutation was

present at extremely low frequencies (<1%). There were no significant

differences in the frequencies of minority mutations in the treatment

success groups compared to the treatment failure groups. [41]

19

Figure 13: Frequency of minority RAL-resistant mutations in each patient

Figure 14: Comparison of frequencies of minority RAL-resistant mutations between treatment success and treatment failure groups

20

Table of figures: Figure 1: Physical properties .............................................................. 3

Figure 2: 2D-Structure of Raltegravir .................................................. 4

Figure 3: 3D-Structure of Raltegravir .................................................. 4

Figure 4: Synthesis 1 ........................................................................ 5





Figure 9: The two integrase catalytic reactions ..................................... 8

Figure 10: The strand transfer mechanism ........................................... 9

Figure 11: Targeting points for the different antiviral agents ................ 11

Figure 12: Arithmetic mean Raltegravir plasma concentration profiles

following administration of a 400-mg single dose to subjects with hepatic

impairment, subjects with renal impairment, and corresponding matched

control subjects with normal hepatic and renal function ....................... 15

Figure 13: Frequency of minority RAL-resistant mutations in each patient

................................................................................................... 19

Figure 14: Comparison of frequencies of minority RAL-resistant mutations

between treatment success and treatment failure groups ..................... 19

21

Sources: [1] https://pubchem.ncbi.nlm.nih.gov/compound/Raltegravir#section=Me

SH-Entry-Terms (10.05.20)

[2] https://de.wikipedia.org/wiki/Raltegravir (10.05.20)

[3] https://en.wikipedia.org/wiki/Raltegravir (10.05.20)

[4] https://www.msd.de/fileadmin/files/fachinformationen/isentress.pdf

(10.05.20)

[5] Yong-Jin Wu, Progress in Heterocyclic Chemistry, 2012

[6] https://onlinelibrary.wiley.com/doi/epdf/10.1002/rmv.350

(10.05.2020)

[7] https://academic.oup.com/cid/article/48/7/931/326321 (11.05.2020)

[8] https://science.sciencemag.org/content/287/5453/646?casa_token=G

pWv0MyADnkAAAAA:2FwJl3xZ2t116PU1YF6bjGl0lqMf1fyzovWsgrQ8cinchn

96BD4l5NAVPGkoPavtLgh-cEaXPxNJyHE (11.05.2020)

[9] https://www.nature.com/articles/nrd1660 (08.05.2020)

[10] https://link.springer.com/article/10.2165/00003495-200868010-

00009 (10.05.2020)

[11] https://link.springer.com/article/10.2165/11204590-000000000-

00000 (14.05.2020)

[12] https://www.drugbank.ca/drugs/DB06817#BE0004855 (13.05.2020)

[13] https://pubchem.ncbi.nlm.nih.gov/compound/Raltegravir#section=Bi

ological-Half-Life (19.05.2020)

[14] www.ncbi.nlm.nih.gov/books/NBK548313 (11.05.2020)

[15] www.ema.europa.eu/en/documents/overview/isentress-epar-

medicine-overview.de.pdf (18.05.2020)

22

[16] www.nature.com/articles/nrd1660 (13.05.2020)

[17] link.springer.com/article/10.2165/00003495-200969080-00007

(11.05.2020)

[18] eurjmedres.boimedcentral.com/articles/10.1186/2047-783X-14-S3-

17 (13.05.2020)

[19] link.springer.com/article/10.1007/s40262-016-0424-1 (12.05.2020)

[20] www.mmp-online.de/heftarchiv/2013/12/integrase-inhibitoren-neue-

wege-für-die-therapie-der-hiv-1-infektion-html (12.05.2020)

[21] docplayer.org/15969678-Isentress-400-mg-filmtabletten.html

(18.05.2020)

[22] dmd.aspetjournals.org/content/35/9/1657 (17.05.2020)

[23] https://www.hivandmore.de/archiv/2008-

1/HIV1_08__FoBiBogner.pdf (18.05.2020)

[24] “Pharmacokinetics and Pharmacodynamics of Once-Daily versus

Twice-Daily Raltegravir in Treatment-Naïve HIV-Infected Patients”,

downloaded from http://aac.asm.org/ on May 3, 2020

[25] https://retrovirology.biomedcentral.com/articles/10.1186/1742-

4690-5-114 (12.05.20)

[26] Öffentlicher Beurteilungsbericht (EPAR) der europäischen

Arzneimittelagentur (EMA) zu: Isentress (11.05.20)

[27] https://www.sciencedirect.com/science/article/pii/B97801241149200

00341 - Synthesis of Best-Seller Drugs, 2016, Chapter 34, Raltegravir-

Insentress (10.05.20)

[28] https://www.thieme-connect.com/products/ejournals/pdf/10.1055/s-

0036-1591624.pdf (10.05.20)

[29] Instruction for Raltegravir: Isentress®

23

[30] Kassahun K, McIntosh I, Cui D, et al. Metabolism and disposition in

humans of raltegravir (MK-0518), an anti-AIDS drug targeting the HIV-1

integrase enzyme. Drug Metab Dispos 2007;35:1657-63

[31] Wenning LA, Petry AS, Kost JT, et al. Pharmacokinetics of raltegravir

in individuals with UGT1A1 polymorphisms. Clin Pharmacol Ther

2009;85:623-7

[32] Raltegravir: a review of its pharmacokinetics, pharmacology and

clinical studies David M Burger 864 Radboud University Nijmegen Medical

Center, Department of Pharmacy, Geert Grooteplein 10, 6525 GA

Nijmegen, the Netherlands

[33] Isentress (raltegravir) tablets [product circular]. Prescribing

information. Whitehouse Station, NJ: Merck; 2008.; Clinical Pharmacology

Profile of Raltegravir, an hiv-1 integrase strand transfer inhibitor Diana M.

Brainard, MD, Larissa A. Wenning, PhD, Julie A. Stone, PhD, John A.

Wagner, MD, PhD, and Marian Iwamoto, MD, PhD

[34] Clinical Pharmacology Profile of Raltegravir, an hiv-1 integrase strand

transfer inhibitor Diana M. Brainard, MD, Larissa A. Wenning, PhD, Julie A.

Stone, PhD, John A. Wagner, MD, PhD, and Marian Iwamoto, MD, PhD

[35] Influence of Sex/Gender and Race on Responses to Raltegravir

Combined With Tenofovir-Emtricitabine in Treatment-Naive Human

Immunodeficiency Virus-1 Infected Patients: Pooled Analyses of the

STARTMRK and QDMRK Studies Kathleen Squires,1 Linda-Gail Bekker,2

Christine Katlama,3 Yazdan Yazdanpanah,4 Yan Zhou,5 Anthony J.

Rodgers,5 Mark J. DiNubile,5 Peter A. Sklar,5 Randi Y. Leavitt,5 and Hedy

Teppler5

[36] Pharmacokinetics and 48-Week Safety and Efficacy of Raltegravir for

Oral Suspension in Human Immunodeficiency Virus Type-1-

InfectedChildren 4 Weeks to 2 Years of Age Sharon Nachman,1 Carmelita

Alvero,2 Edward P. Acosta,3 Hedy Teppler,4 Brenda Homony,4 Bobbie

Graham,5 Terence Fenton,2 Xia Xu,4 Matthew L. Rizk,4 Stephen A.

24

Spector,6 Lisa M. Frenkel,7 Carol Worrell,8Edward Handelsman,9 and

Andrew Wiznia

[37] Rotger M, Taffe P, Bleiber G et al. Gilbert syndrome and the development of antiretroviral therapy-associated

hyperbilirubinemia. J. Infect. Dis. 192(8), 1381–1386 (2005);

[38] Calza L, Danese I, Colangeli V, Vandi G, Manfredi R, Girometti N, et

al. Skeletal muscle toxicity in HIV-1-infected patients treated with a

raltegravir-containing antiretroviral therapy: a cohort study. AIDS Res

Hum Retroviruses. 2014 Dec;30(12):1162-9. doi: 10.1089/aid.2014.0113

[39] A safety evaluation of raltegravir for the treatment of HIVRosa de

Miguel, Rocio Montejano, Natalia Stella-Ascariz & Jose R Arribas

[40]Taburet A-M, Sauvageon H, Grinsztejn B, Assuied A, Veloso V, Pilotto

JH, et al. Pharmacokinetics of Raltegravir in HIV-Infected Patients on

Rifampicin-Based Antitubercular Therapy. Clin Infect Dis 2015; 61:1328–

1335.

[41]Analysis of Low-Frequency Mutations Associated with Drug Resistance

to Raltegravir before Antiretroviral Treatment� Jia Liu,1,4 Michael D.

Miller,2 Robert M. Danovich,2 Nathan Vandergrift,1 Fangping Cai,1

Charles B. Hicks,3 Daria J. Hazuda,2 and Feng Gao1* Duke Human

Vaccine Institute1 and Department of Medicine,3 Duke University Medical

Center, Durham, North Carolina 27710; Merck & Co., Inc., West Point,

Pennsylvania2; and Department of Microbiology, Peking University Health

Science Center, Beijing 100191, China4

25

Picture Sources:

Figure 1: Own work

Figure 2 & 3: Own work, using MolView

Figures 4-7:

https://www.sciencedirect.com/science/article/pii/B978012411492000034

1 - Synthesis of Best-Seller Drugs, 2016, Chapter 34, Raltegravir-

Insentress (10.05.20)

Figure 8: https://www.thieme-

connect.com/products/ejournals/pdf/10.1055/s-0036-1591624.pdf

(10.05.20)

Figure 9: https://www.nature.com/articles/nrd1660/figures/2 (12.05.20)

Figure 10: https://onlinelibrary.wiley.com/doi/epdf/10.1002/rmv.350

(12.05.20)

Figure 11: https://www.nature.com/articles/nrd1660/figures/1 (12.05.20)

Figure 12: Clinical Pharmacology Profile of Raltegravir, an hiv-1 integrase

strand transfer inhibitor Diana M. Brainard, MD, Larissa A. Wenning, PhD,

Julie A. Stone, PhD, John A. Wagner, MD, PhD, and Marian Iwamoto, MD,

PhD

Figures 13,14: Analysis of Low-Frequency Mutations Associated with Drug

Resistance to Raltegravir before Antiretroviral Treatment� Jia Liu,1,4

Michael D. Miller,2 Robert M. Danovich,2 Nathan Vandergrift,1 Fangping

Cai,1 Charles B. Hicks,3 Daria J. Hazuda,2 and Feng Gao1* Duke Human

Vaccine Institute1 and Department of Medicine,3 Duke University Medical

Center, Durham, North Carolina 27710; Merck & Co., Inc., West Point,

Pennsylvania2; and Department of Microbiology, Peking University Health

Science Center, Beijing 100191, China4s

raltegravir - technische universität darmstadt

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