Dolutegravir

Structural formula
General
Non-proprietary name	Dolutegravir
other names	(4 R , 12a S ) - N - (2,4-Difluorobenzyl) -7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2 H -pyrido [1 ', 2': 4.5] pyrazino- [2,1- b ] [1,3] oxazine-9-carboxamide; GSK-1349572; DTG;
Molecular formula	C 20 H 19 F 2 N 3 O 5
Brief description	Orange color
External identifiers / databases
EC number	809-888-1
ECHA InfoCard	100.237.735
PubChem	54726191
ChemSpider	25051637
DrugBank	DB08930
Wikidata	Q937224
properties
Molar mass	419.38 g mol −1
safety instructions
GHS hazard labeling ; no classification available
GHS hazard labeling ; no classification available
Toxicological data	> 1000 mg kg −1 ( LD 50 , rat , oral , sodium salt)
	As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Dolutegravir (Tivicay®) is a drug selected from the group of INSTI ( English integrase beach transfer inhibitor , in addition to raltegravir and elvitegravir ), which is used in the treatment of HIV. The sodium salt is used, which was approved in August 2013 and is marketed by GlaxoSmithKline .

Clinical information

Application areas (indications)

Dolutegravir is an inhibitor of the viral integrase of HIV 1 , and is used in the treatment of HIV 1 infected patients from the age of 12 years. The therapy is generally only carried out in combination with other HAART drugs ( highly active antiretroviral combination therapy) . As of 2017, dolutegravir together with lamivudine (Zeffix® / Epivir®) and abacavir (Ziagen®) are both from the group of nucleoside reverse transcriptase inhibitors (NRTI) in the form of a single tablet to be taken once a day (single drug regime) marketed under the trade name Triumeq® . Dolutegravir is also offered individually as Tivicay®. In addition to dolutegravir, elvitegravir is currently the only other representative in this generation of this INSTI drug class . However, due to its pharmacological properties, dolutegravir is clearly superior to the AUC as well as the plasma and intracellular half-life , since elvitegravir is supported by a so-called booster such as B. cobicistat or ritonavir , which strongly inhibits the metabolism of elvitegravir by inhibiting the isoenzyme CYP3A4 (from the cytochrome P450 family), must be combined in order to achieve a sufficient AUC and a prolonged half-life suitable for the single-drug regimen . Dolutegravir, on the other hand, has a half-life of 13–15 hours. Therefore, dolutegravir without a booster is given only once a day. In addition, dolutegravir po offers good bioavailability regardless of any food intake and can therefore be administered independently of this.

Adverse effects (side effects)

The following undesirable side effects can occur:

Very common: headache, diarrhea and nausea.
Common: rash, itching, vomiting, stomach pain, difficulty sleeping, dizziness, abnormal dreams, depression, anxiety, fatigue, gas, increases in liver enzymes and increases in creatine phosphokinase.
Uncommon: hepatitis , joint pain, muscle pain. In addition, suicide attempt and suicidal ideation (especially in people who have previously been mentally ill, e.g. from depression )
Rare: liver failure

also

Hypersensitive reactions: 1% or less in phase 3 clinical trials
Influencing the serum liver enzymes in patients with hepatitis B or C - coinfection : increased risk of increase in serum transaminase
Redistribution or accumulation of body fat
Immune Reconstitution Syndrome

Teratology

When taking dolutegravir in the first few months of pregnancy, a slightly increased risk of malformations has been observed, in particular neural tube defects such as spina bifida are more common . In an observational study in Botswana with almost 120,000 births, a neural tube defect was found in 0.08% of all children born to non-HIV-infected mothers and 0.10% of all children born to HIV-infected mothers whose antiretroviral therapy did not contain dolutegravir at the time of conception , and 0.30% of all children whose HIV-infected mothers were taking dolutegravir at conception, an increase of 0.20 percentage points. Folic acid antagonism was suspected and shown in cell cultures .

Pharmacological properties

Mechanism of action (pharmacodynamics)

Dolutegravir is a second generation integrase strand transfer inhibitor and represents a further development of the existing class of integrase inhibitors , with raltegravir (Isentress) being the only representative of its class of the first generation. Dolutegravir is given as the sodium salt in medicines . The manipulation of the viral integrase (viral protein) represents an important therapeutic intervention in the replication of the HI virus within the T cells with retroviral DNA (reverse transcripted virus RNA after DNA) . It is used as a nucleotidyl transferase for the incorporation of viral DNA - Strands in the cell's chromosome are responsible, and therefore one of the three key molecules that play a role in the replication of HI viruses , alongside protease and reverse transcriptase . As an endonuclease , it is able to cut the human chromosome and insert the newly created viral DNA .

Dolutegravir also has the property of being less susceptible to resistance through mutations as a result of not completely inhibited virus replication . It is being discussed that dolutegravir binds more strongly to the viral integrase . The dissociative half-life is longer than that of elvitegravir and raltegravir and thus compensates for mutations that reduce the antiviral effect.

Dolutegravir pharmacophore model

Absorption and distribution in the body (pharmacokinetics)

The drug has a half-life of 13 to 15 hours. The plasma concentration remains above the IC90 value for more than 30 hours . This means that virus replication is inhibited by 90% during this period. The efficacy and safety has been proven by four phase III studies involving 2553 HIV patients. Compared to raltegravir , a first-generation INSTI, dolutegravir was able to lower the viral load comparably effectively, and compared to Atripla even significantly more effectively.

Dolutegravir inhibits the organic cation transporter 2, which leads to a decreased tubular secretion of creatinine and thus to an increase in the serum creatinine value, although this could not be associated with a decreased glomerular filtration rate or possible kidney damage.

The degradation takes place via uridine diphosphate glucuronosyl transferase 1A1 and isoenzyme CYP3A4 of the cytochrome P450 family. Here are CYP isoenzymes nor induce neither inhibited. Certain dietary supplements and other drugs can greatly reduce the absorption of dolutegravir from the intestine after ingestion. These include u. a. Iron and calcium-containing food supplements or multivitamin preparations that contain calcium and iron. Dolutegravir should therefore be taken 4 hours before or 6 hours after taking appropriate preparations. Caution should be exercised with medicinal products known to be inducers of the isoenzyme CYP3A4 , as they can greatly reduce the plasma concentration of dolutegravir and lead to therapy failure through development of resistance. If the concomitant use of drugs that induce CYP3A4 is required, a dose adjustment of dolutegravir is required. The inducers of CYP34A include: (the list is not exhaustive ...) antacids , rifampicin , St. John's wort and certain anti-epileptic drugs . In contrast, inhibitors such. B. cobicistat , or ritonavir (list not exhaustive ...) lead to a sharp increase in dolutegravir and a prolonged half-life with the occurrence of undesirable side effects and / or the intensification of existing side effects. In animal experiments on rats and monkeys, however, no toxicity could be determined despite the high overdose (24 to 27 of the daily dose recommended for human therapy) . Maternal toxicity was only observed in pregnant rabbits. (Reduced feed consumption, reduced weight gain, reduced urine excretion) In a long-term study over 26 weeks on rats and 38 weeks on monkeys, the above-mentioned overdoses led to gastrointestinal disorders which are presumably due to oral administration .

Furthermore, undesirable interactions with reverse transcriptase inhibitors such as etravirine and efavirenz as well as with protease inhibitors such as forsamprenavir can occur (... list not exhaustive). It may be necessary to increase the dose to twice the daily dose or, as a precaution, to refrain from taking it at the same time due to the lack of clinical studies.

In-vitro on bacteria and mammalian cell cultures as well as in-vivo in micronucleus tests on rodents , dolutegravir has not been shown to be a mutagen or clastogen in long-term tests and, moreover, not to be a carcinogen in long-term tests on rats .

synthesis

Synthesis of dolutegravir

patent

Patent WO2006116764 : Polycyclic carbamoylpyridone derivative having HIV integrase inhibitory activity. Filed April 28, 2006 , published November 2, 2006 , Applicants: Brian Alvin Johns, Takashi Kawasuji, Teruhiko Taishi, Yoshiyuki Taoda, Inventors: SmithKline Beecham Corporation; Shionogi & Co., Ltd ..

Early benefit assessment

In Germany, since 2011, newly approved drugs with new active ingredients must be subjected to an " early benefit assessment " by the Federal Joint Committee (G-BA) in accordance with Section 35a SGB V if the pharmaceutical manufacturer wants to achieve a higher sales price than just the fixed amount . Only if there is an additional benefit can the pharmaceutical manufacturer negotiate a price with the umbrella association of statutory health insurance companies. The dossier evaluations, on the basis of which the G-BA makes its decisions, are created by the Institute for Quality and Efficiency in Health Care (IQWiG) .

The first early benefit assessment in 2014 focused on the treatment of treatment-naive and antiviral-pretreated adults and adolescents aged 12 and over with dolutegravir in combination with other antiretroviral drugs. In the case of pretreated adults, a further differentiation was made according to whether treatment with an integrase inhibitor was the first or a subordinate treatment option. According to the G-BA decision, there is evidence of a considerable additional benefit for treatment-naive adults and an indication of a minor additional benefit for pretreated adults for whom treatment with an integrase inhibitor is the first treatment option. For the remaining three patient groups, an added benefit compared to the respective ACT is not proven.

In 2015, the same division into five patient groups was made for the active ingredient combination dolutegravir / abacavir / lamivudine. According to the G-BA decision, there is an indication of a considerable additional benefit for treatment-naive adults compared to efavirenz in combination with tenofovir disoproxil plus emtricitabine. An added benefit has not been proven for the four other patient groups.

In 2017, the evidence for HIV-infected children aged 6 to under 12 was examined. According to the G-BA decision, an additional benefit has been proven for pretreated and non-pretreated children.

After its approval, the combination dolutegravir / rilpivirine was evaluated in 2018 for the treatment of HIV-1 infected adults who were virologically suppressed and had been on a stable antiretroviral regimen for at least six months, no past virological failure and no known or suspected resistance to non - Have nucleoside reverse transcriptase inhibitors or integrase inhibitors. According to the G-BA decision, an additional benefit compared to individual antiretroviral therapy depending on the previous therapies and possibly taking into account side effects has not been proven for these patients.

After the combination dolutegravir / lamivudine was approved for the treatment of HIV-1-infected adults and adolescents (from 12 years of age, body weight at least 40 kg) who have no known or suspected resistance to the class of integrase inhibitors or lamivudine, in In a further early benefit assessment, a further distinction was made between adults and adolescents and between treatment-naïve and antiratroviral patients. According to the G-BA decision, an additional benefit of this combination of active ingredients compared to the respective appropriate comparator therapy has not been proven for any of the four groups.

Individual evidence

↑ Patent EP2602260 : Process for the preparation of a compound with HIV integrase-inhibiting action. Applied on August 4, 2011 , published on September 28, 2016 , applicant: Shionogi & Co., Ltd., inventor: Yukihito Sumino, Kazuya Okamoto, Moriyasu Masui, Daisuke Yamada, Fumiya Ikarashi. ‌

↑ This substance has either not yet been classified with regard to its hazardousness or a reliable and citable source has not yet been found.

↑ Data sheet TRIUMEQ TABLETS ( page no longer available , search in web archives ) Info: The link was automatically marked as defective. Please check the link according to the instructions and then remove this notice. , accessed June 4, 2017.@1@ 2Template: Dead Link / www.msds-gsk.com

↑ Entry on dolutegravir. In: Römpp Online . Georg Thieme Verlag, accessed on June 4, 2017.

↑ ^a ^b FDA: Highlights of Prescribing Information Tivicay , August 2014, accessed on June 4, 2017.

↑ GSK: Package Leaflet Information for Patients , November 2018, accessed on April 10, 2019.

↑ Rebecca Zash, Lewis Holmes, Modiegi Diseko, Denise L. Jacobson, Sean Brummel, Gloria Mayondi, Arielle Isaacson, Sonya Davey, Judith Mabuta, Mompati Mmalane, Tendani Gaolathe, M. Essex, Shahin Lockman, Joseph Makhema, Roger L. Shapiro : Neural-Tube Defects and Antiretroviral Treatment Regimens in Botswana , New England Journal of Medicine 2019, Volume 381, Issue 9, August 29, 2019, Pages 827-840 , DOI: 10.1056 / NEJMoa1905230

↑ ^a ^b M. L. Cottrell, T. Hadzic, AD Kashuba: Clinical pharmacokinetic, pharmacodynamic and drug-interaction profile of the integrase inhibitor dolutegravir. In: Clinical Pharmacokinetics . Volume 52, number 11, November 2013, pp. 981-994, doi : 10.1007 / s40262-013-0093-2 , PMID 23824675 , PMC 3805712 (free full text) (review).

↑ ^a ^b GlaxoSmithKline Pharmaceuticals SA: Specialist information Dolutegravir (Tivicay®). Retrieved September 25, 2017 (German, German).

↑ PK Quashie, RD Sloan, MA Wainberg: Novel therapeutic strategies targeting HIV integrase. In: BMC Medicine . Volume 10, April 2012, p. 34, doi : 10.1186 / 1741-7015-10-34 , PMID 22498430 , PMC 3348091 (free full text) (review).