Other Names

Tivicay®, S/GSK 1349572

Combination formulations:  Triumeq®:  abacavir/dolutegravir/lamivudine; Juluca®:  dolutegravir/rilpivirine; Dovato®:  dolutegravir/lamivudine

Dolutegravir is a novel HIV-1 integrase strand transfer inhibitor. Dolutegravir inhibits HIV integrase strand transfer, with an IC50 of 2.7 nM and 12.6 nM. Inhibition of integrase prevents the covalent insertion, or integration, of unintegrated linear HIV-1 DNA into the host cell genome preventing the formation of the HIV-1 provirus.

The bulk drug is a sodium salt of dolutegravir with a molecular weight of 441.36 g/mol.

Activity

• HIV 1- EC50: 0.5 to 2.1 nM (in vitro)
• HIV 1 - diverse, clinical isolates EC50: 0.02 to 2.14 nM (in vitro)
• HIV 2- EC50: 0.09 to 0.61 nM (in vitro)

Tivicay®: 

50 mg tablets, bottles of 30.  DIN 02414945.  Yellow, round, film-coated, biconvex tablets debossed with SV 572 on one side and 50 on the other side.

25 mg tablets, bottles of 30.  DIN 02461226.  Pale yellow, round, film-coated, biconvex tablets debossed with ‘SV 572’ on one side and ‘25’ on the other side.

10 mg tablets, bottles of 30.  DIN 02461218.  White, round, film-coated, biconvex tablets debossed with ‘SV 572’ on one side and ‘10’ on the other side.

Tivicay PD®:  Dolutegravir pediatric dispersible tablets for oral suspension.  5 mg tablets, bottles of 60.  White, round, strawberry cream flavored,film-coated, biconvex tablets debossed with “SV H7S” on one side and “5” on the other side. Each bottle is packaged with one 30-mL dosing cup and one 10-mL oral dosing syringe with 1-mL gradations.

Triumeq®:  abacavir 600mg, dolutegravir 50mg and lamivudine 300mg.  DIN 02430932.  Purple, oval, film-coated, biconvex tablets debossed with “572 Trı” on one side.

Juluca®: dolutegravir 50 mg and rilpivirine 25 mg.  Pink, oval, film-coated, biconvex tablet debossed with "SV J3T" on one side.  DIN 02475774.

Dovato®:  dolutegravir 50 mg and lamivudine 300 mg.  White, oval, biconvex film-coated tablets debossed with "SV 137" on one side.  DIN 02491753.

Tivicay PD®:  5 mg pediatric dispersible tablet for oral suspension.   

Information on crushing or splitting Tivicay® tablets:  10, 25 and 50 mg tablets should ideally be swallowed whole. All tablet strengths may also be split into halves followed by immediate ingestion of both halves or crushed and added to a small amount of semi-solid food or liquid, all of which should be consumed immediately (ViiV Healthcare communication, February 2017).  

Tivicay PD (dispersible tablets for oral suspension): 

• Administer with or without food
• Do not chew, cut or crush tablets
• Swallow the tablets for oral suspension whole (if more than one tablet is required, swallow one tablet at a time to reduce the risk of choking), or
• Fully disperse the tablets for oral suspension in 5 mL of drinking water (if using 1 or 3 tablets for oral suspension) or 10 mL (if using 4, 5, or 6 tablets for oral suspension) in the supplied cup; swirl the suspension so that no lumps remain. After full dispersion, administer the oral suspension within 30 minutes of mixing.

Case reports/clinical compounding:  In comparison to the commercially available tablet, dolutegravir exposures following administration of the granule formulation alone, with different types of water and with formula exceeded that of the tablet, demonstrating the dolutegravir oral granule can be given without restriction on the type of liquid, or can be administered directly to mouth (e.g., when potable water is not available).²⁹⁸⁸

Case report of a critically ill patient with lymphoma requiring enteral administration of ARVs. Both abacavir and 3TC solutions were administered enterally. Crushed dolutegravir 50 mg BID (separated from enteral nutrition by 2 hours) and rilpivirine 25 mg daily (given with a 240-mL bolus of an enteral formula (2 kcal/mL)) were administered via orogastric tube. Crushed tablets were each mixed with 10 mL of water and flushed down the tube at separate administration times.  Trough concentrations were: day 8, rilpivirine 30 ng/mL (reference range 40-120 ng/mL), and day 9, dolutegravir 820 ng/mL (reference range 830 ng/mL steady-state trough concentration for 50 mg once daily dose). Virologic suppression was maintained after ARV enteral administration (hospital day 29). Given somewhat decreased levels of these ARVs, the authors recommended consideration to increase dolutegravir to 150-200 mg total daily dose, particularly in integrase-experienced patients and rilpivirine 50 mg daily (similar to dosing with an inducer such as rifabutin).²⁹⁸⁹

Case report of complex HIV patient with MAC with intractable nausea/vomiting requiring ARVs (tenofovir DF 300 mg/emtricitabine 200 mg as Truvada® and dolutegravir 50 mg daily) via jejunostomy (J)-tube. ARVs were crushed, mixed with 3-5 mL or water, administered, and flushed with 10 mL of water. Concentrations of oral and J-tube administration of ARVs were assessed. DTG and TDF exposures were similar between J-tube and oral administration. FTC AUC was 38% lower for J-tube vs. oral. Compared to a reference population, overall AUC was lower for both routes- DTG 75-76% lower and TDF 55-61% lower. However, FTC via J-tube AUC was similar to the reference population and 71% higher when given orally. Reduced drug absorption was the primary cause for decreased drug exposure. TDM is recommended to assess drug concentrations in patients with the potential for impaired absorption.²⁹⁹⁰

Case report of an HIV patient with difficulty swallowing pills who preferred ARV formulations that he could crush. Tenofovir DF-emtricitabine (Truvada®)  1 tab daily and dolutegravir 50 mg daily were crushed using a pill crusher, added to applesauce, and consumed immediately. The 4- week viral load decreased from 10,800 to < 20 copies/mL.²⁹⁹¹

Case report of a male with HIV, antiretroviral experienced with resistance mutations (K101E, M184V, M230L, A98G, L10I, E35D and M36I), and dysphagia due to eosinophilic esophagitis who was successfully treated with crushed dolutegravir, crushed tenofovir AF (TAF), and liquid abacavir and emtricitabine. The viral load was suppressed after 10 months of follow-up. The patient was intolerant of crushed tenofovir DF (TDF) due to taste and nausea but tolerated crushed TAF.³³⁶⁴

Triumeq®:

• Use abacavir & lamivudine liquid products. Dolutegravir tablets may be crushed (see dolutegravir).
• Triumeq® is film-coated, non-scored, and non-sustained released formulation. Although not studied, splitting or crushing tablets is not expected to affect the dissolution or absorption. Tablets may be crushed and added to a small amount of semi-solid food or liquid, and consumed immediately. (Data on File, ViiV Healthcare, Oct 2014)
• Nasogastric or gastric feeding tubes: No clinical or pharmacokinetic studies done to evaluate. The administration of crushed Triumeq® tablets should not have an effect on the absorption of the components of Triumeq®. The absorption of Triumeq® is thought to occur in the proximal small intestine (duodenum/jejunum). (Data on File, ViiV Healthcare, March 2017)
• Pharmacokinetics of crushed  Triumeq® tablets were studied in healthy volunteers. Whole tablets in fasting state were compared to:
  • I. Crushed and suspended in fasting state  
  • II. Crushed and suspended with enteral nutrition taken PO (Nutrison®-250 mL contains elemental calcium 200 mg, iron 4 mg, protein 10 g, carbohydrates 30.8 g, fat 9.8 g).
  • Intervention I showed 26% and 30% increase in DTG AUC and Cmax.
  • Intervention II showed an 18 % and 21 % increase in DTG AUC and Cmax, respectively.
  • Although bio-equivalence was not demonstrated, the increase in DTG exposure was not considered to be clinically relevant. However, caution is warranted if crushed DTG is given once daily or BID with food, as DTG exposure will likely be higher.²⁸⁸¹ 
• Case report of successful administration of crushed dolutegravir/abacavir/lamivudine tablet with administration via NG tube; adequate antiretroviral concentrations confirmed via TDM and patient achieved rapid viral suppression.³²¹² 
• Case report of a 44 year-old female who presented for a heart and lung transplant who received crushed Triumeq® via nasogastric (NG) tube while on veno-arterial extracorporeal membrane oxygenation (VA ECMO). ARV pharmacokinetics were conducted during and post VA ECMO. The Cmax and AUC were higher for all 3 ARVs during ECMO vs. post-decannulation. ARV dose adjustments were not made and virologic suppression was maintained during 50-day hospitalization.³³⁶⁵

Juluca®:

• The efficacy, safety and pharmacokinetics of crushing dolutegravir/rilpivirine have not been evaluated. The tablet should be swallowed whole and taken with a meal to ensure administration of the entire dose. The tablets are film-coated.
• Based on clinical judgment if the Juluca tablet requires splitting, it should be split in half and both halves ingested immediately with a meal.
• If the Juluca tablet requires crushing, it should be crushed and added to a small amount of liquid or semi-solid food and the full tablet content consumed immediately with a meal. (Data on File, ViiV Healthcare, May 2018)    

Dovato®:

• The manufacturer recommends swallowing the tablet whole. The tablets are film-coated. For patients who cannot swallow the tablet who, in theory, the tablet may be split in halves or crushed and added to a small amount of semi-solid food or liquid and the full contents consumed immediately (e-mail communication, ViiV Healthcare, Med US, March 2019).

Limited data suggest that patients with gastric bypass achieve adequate long-term dolutegravir exposures;^3169  3170  in some patients, a transient decline in dolutegravir bioavailability may occur in the acute post-surgical period.  In some cases, a temporary increase in dolutegravir dose to 50 mg BID may be considered.³¹⁶⁹  

Dolutegravir concentrations were measured in 4 PLWH undergoing gastric bypass surgery.  In 3 patients, HIV infection was diagnosed 6 months-3 years after surgery; the fourth patient was virally suppressed prior to surgery.  The first 3 patients received dolutegravir 50 mg daily and had acceptable dolutegravir levels, but one patient experienced slower than expected viral decay so his dolutegravir dose was increased to 50 mg BID until viral suppression, and then switched back to 50 mg once daily.  The fourth patient had dolutegravir concentration of 0.5 ug/mL at 11.5 hours post-dose at 2 weeks following surgery, so his dolutegravir was increased to 50 mg BID.  After two months, dolutegravir was switched back to once daily dosing with adequate concentrations and durable viral suppression.³¹⁶⁹

In a series of 10 PLWH who underwent sleeve gastrectomy, antiretroviral concentrations (including abacavir, emtricitabine, lamivudine, tenofovir, atazanavir, darunavir, dolutegravir, raltegravir, nevirapine and rilpivirine) measured in 6 patients between 1 and 14 months post-surgery were adequate with maintenance of virologic suppression.  Dolutegravir plasma trough concentrations measured in one patient before and after surgery (months 2, 11, 15, 18, and 20) remained stable throughout.³¹⁷⁰  

A 36-year-old man on abacavir/lamivudine/dolutegravir underwent sleeve gastrectomy.³⁶²⁷ Trough concentration of abacavir was 12-fold-higher 6-month post-surgery (103.3 ng/mL) compared with baseline (8.7 ng/mL). Trough concentrations of lamivudine (161 ng/mL) and dolutegravir (2,347 ng/mL) were about 2.5-fold-higher at 6-month post-surgery compared with baseline (of 60 and 919 ng/mL, respectively). No short-term adverse effects, clinical or lab abnormalities were reported. However, due to concern with long-term cardiovascular disease, neurologial and hepatic toxicities, the regimen was swtiched to dolutegravir and lamivudine. 

In a retrospective analysis of 9 HIV patients who underwent laparoscopic sleeve gastrectomy, all had undetectable viral loads at 1 year post-operatively, including 1 patient on dolutegravir/abacavir/lamivudine.³⁶⁴⁶

In a case series of 7 patients, 6/6 patients on dolutegravir-based regimens maintained viral suppression 9 months after sleeve gastrectomy (n = 3), Roux-en-Y Gastric Bypass (n = 3), and adjustable-gastric banding (n = 1).³⁶²⁹

A 53 year old male (BMI 18.5, viral load 560 copies/mL, CD4 160 cells/mm3) underwent emergency Roux-en-Y gastric bypass surgery due to septic shock and perforated gastric viscus with a suspected gastric tumor.  He was administered dolutegravir 50 mg BID plus abacavir/lamivudine; two weeks post surgery, the morning dolutegravir Ctrough was decreased vs. refererence Cmin but the supper Ctrough was within range (1137 ng/mL and 2167 ng/mL, respectively vs. reference of 2120 ng/mL).  His viral load suppressed to <40 copies/mL at 1 month and remained suppressed at 5 months post-surgery.³⁷⁰⁸   

Dolutegravir should be administered 2 hours before or 6 hours after taking medications containing polyvalent cations (Mg, Al, Fe, Ca)

Effect of Dolutegravir on the Kinetics of Other Agents

• Inhibits OCT2 in vitro Does NOT inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, UGT1A1, UGT2B7, P-gp, BRCP, OATP1B1, OATP1B3, OCT1 or MRP2 in vitro
• Does NOT induce CYP1A2, CYP2B6, or CYP3A4 in vitro

Effect of Other Agents on the Pharmacokinetics of Dolutegravir

• Strong inducers of UGT1A1 (ex Rifampin) will reduce plasma concentrations of dolutegravir
• Strong inhibitors of UGT1A1 (Ex ATV/r) will increase plasma concentrations of dolutegravir
• Strong inducers of UGT1A3, UGT1A9, BCRP, and P-gp may decrease dolutegravir plasma concentration in vitro
  

Oral Bioavailability:

The absolute bioavailability of dolutegravir has not been established.

Neonatal liquid formulations in development:  5 mg/mL suspension in miglyol, and 2 mg/mL solution in glycerol.  In an open label pharmacokinetic study in healthy adults, bioavailability for both formulations was comparable to the dolutegravir dispersible tablet formulation with marginally higher Cmax for the 2 mg/mL solution.  Both formulations were well tolerated.³⁴²⁷

Protein Binding:

≥ 98.9% protein bound

Vd:

Estimated 17.4 L following 50-mg once-daily administration.

Tmax:

Dolutegravir is rapidly absorbed with T_max 2 hours in the fasted state. Low-, moderate-, and high-fat meals prolonged T_max to 3, 4 and 5 hours respectively.

Serum T½:

Terminal half-life of approximately 13- 14 hours

Intracellular T½:

No data are available.

Metabolism:

Dolutegravir is not an inhibitor of cytochrome P450 enzymes, major UGTs, or P-glycoprotein and does not induce CYP3A. It is primarily metabolized via UGT1A1 with some contribution from CYP3A.  Dolutegravir is not a substrate of OATP1B1 or OATP1B3.

Excretion:

Feces 53% (dolutegravir unchanged)

Urine: 31% (dolutegravir glucuronide 18.9% + metabolite 3% + hydrolytic N-dealkylation product 3.6%)

Note: For more complete information and the most current safety data on antiretrovirals in pregnancy refer to the current US DHHS Perinatal Guidelines. 

In 2018 Health Canada and the US DHHS issued safety alerts regarding possible increased risk of neural tube defects associated with dolutegravir use in pregnancy: (Health Canada Dolutegravir Safety Alert 2018). The US DHHS has since revised its recommendations to include dolutegravir as a preferred drug for use throughout pregnancy and for people who are trying to conceive.

In 2019 the WHO recommended dolutegravir based regimens for first line therapy due to their risk/benefit analysis for population based treatment recommendations in sub-Saharan Africa. WHO Recommendations DTG news release - Mexico City 22 July 2019. .

Published data

• In May 2018, preliminary results from an interim analysis of an ongoing observational study (the Tsepamo study) based in Botswana, reported 4 cases (among 426) of neural tube defects in infants born to women who became pregnant while taking dolutegravir, representing an incidence of 0.9% vs. 0.1% (14 of 11,173) in women receiving non dolutegravir containing regimens. There were no cases of neural tube defects in infants born to a woman who started dolutegravir during pregnancy. WHO Statement on DTG - Geneva 18 May 2018, European Medicines Agency Statement DTG 18 May 2018
• In July 2019, further study data from the Tsepamo study was released. Updated data reported that the prevalence of neural tube defects associated with dolutegravir use in the first trimester was 0.3% (5 of 1683) vs. 0.1% (15 of 14,792) in women receiving non dolutegravir containing regimens.WHO Recommendation DTG news release - Mexico City 22 July 2019
  
• In July 2021, the Tsepama study released further data up until March 2021. Updated data reported that the prevalence of neural tube defects associated with dolutegravir use in the first trimester was 0.15% (9 of 5860) vs. 0.10% (22 of 22,475) in women receiving non dolutegravir containing regimens. NTD prevalence differed non-significantly between dolutegravir and any non-dolutegravir antiretrovirals at conception (0.06% risk difference; 95% CI -0.03%-0.20%).³⁵⁶⁶ 
  
• Data from 22 sites in Botswana, not included in the Tsepama study, reported a rate of neural tube defects on dolutegravir exposed pregnancies of 0.65% vs. 0.08% in non-dolutegravir exposed pregnancies.³²⁴⁸
• Canadian surveillance data on congenital anomalies in pregnancies exposed to dolutegravir pre-conception and in the first trimester did not show a significant difference in rate of non-chromosomal congenital anomalies among 80 neonates born to mothers on doluegravir during the first trimester of pregnancy (n=4 cases, 5%, 95% CI 1.4-12.3%) compared to the baseline rate of congenital anomalies in the Canadian population. None of the anomalies reported in these 4 cases were neural tube defects. Among 69 neonates born to women who were taking dolutegravir at conception, there were no neural tube defects.³²⁴⁹ 
• US data has reported data using 2 insurance databases on the rate neural tube defects in pregnancies in women living with HIV receiving dolutegravir (n=235) vs. HIV negative women. Similar rates of NTDs were reported in both groups 0% vs. 0.48% (commercial insurance) and 0% vs. 0.58% (Medicaid insurance).³⁴¹³
• Data from animal studies, as well as from the Antiretroviral Pregnancy Registry, clinical trials, and post-marketing use, has not indicated a similar safety issue.

The US DHHS has made the following recommendations: (DHHS Perinatal Guidelines)

• The prevalence of infant NTDs was statistically significantly higher in women who were taking DTG at the time of conception (0.19%) than in women without HIV infection (0.07%) or women receiving EFV-based ART at the time of conception (0.07%). The risk of infant NTDs is not significantly higher in women who were taking DTG at the time of conception (0.15%) compared to infants exposed to any non-DTG containing ART around conception (0.10%); prevalence difference 0.06% (95% CI -0.03-0.20%).
  
• The Panels encourage all providers to prospectively report the pregnancy exposures of individuals with HIV receiving ART to the Antiretroviral Pregnancy Registry.

Pharmacokinetics:

In the Impaact P1026 study, the pharmacokinetics of dolutegravir were assessed in 21 pregnant women and their infants.  In pregnant women, compared to postpartum, Cmin was reduced in 2nd and 3rd trimesters by 50%, However, when compared to historical data, dolutegravir postpartum Cmin was higher in this study. The reduction of dolutegravir Cmin compared to historical data was 23%. These results may be explained by the induction of CYP 3A4 and UGT1A1 during pregnancy.  

Infants: Washout sampling was performed up until 9 days post delivery. Median (IQR) Cmax, and T1/2 were 1.96 (1.42 - 2.48) mcg/mL and 34.5 (28.6-39.9) hrs. Infant half-life is twice the one observed in pregnant and non pregnant patients.²⁹⁸¹

Unbound dolutegravir plasma concentrations were evaluated in 6 HIV+ pregnant women in an open-label, multi-centre, observational, phase IV study (PANNA Network). Patients took DTG 50 mg daily as part of their ARV regimen and were evaluated in the 3rd trimester and 3-7 weeks postpartum. Total DTG exposure was 28% lower, however unbound DTG Cmin remained unchanged in the 3rd trimester of pregnancy. The viral load was suppressed in all patients near the time of delivery. This data suggests that the dose of DTG 50 mg daily is efficacious in pregnancy.³¹⁰⁴   

Lactation

• It is not known if dolutegravir is secreted in human milk.
• Dolutegravir is secreted in the milk of lactating rats.
• It is recommended that HIV infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV

• Hypersensitivity reactions have been reported, characterized by rash, constitutional findings, and sometimes, organ dysfunction, including liver injury. Discontinue dolutegravir and other suspect agents immediately if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema). Clinical status including liver aminotransferases should be monitored and appropriate therapy initiated.
• During the clinical studies of dolutegravir in adults, the most common moderate-to-severe adverse reactions were insomnia and headache
• Worsening or new transaminase elevations in patients with underlying hepatitis B or C
• May be associated with fat redistribution and immune reconstitution syndrome

Baseline Assessment

CD4, viral load

Routine Labs

CD4, viral load

Store at room temperature 25°C; excursions permitted 15° to 30°C

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