TIVICAY

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-Do not interchange tablets and tablets for oral suspension on a milligram-per-milligram basis due to differing pharmacokinetic profiles.
-Administer with or without food.
-Administer at least 2 hours before or 6 hours after taking cation-containing antacids or laxatives (i.e., magnesium, aluminum), sucralfate, oral calcium supplements, oral iron supplements, or buffered medications. Alternatively, may administer oral calcium and iron supplements concurrently if administered with food.
Oral Solid Formulations
Regular tablets
-For patients who have difficulty swallowing tablets whole, tablets may be either split into halves followed by immediate ingestion of both halves of the tablet or crushed and added to a small amount of semisolid food or liquid, all of which should be consumed immediately.

Oral tablets for suspension (2 administration methods)
-Do not chew, cut, or crush.

Intact tablets
-Swallow whole.
-If more than 1 tablet is required, swallow 1 tablet at a time to reduce the risk of choking.

Dispersed in water
-1 to 3 tablets: Fully disperse in 5 mL of drinking water in the supplied cup.
-4 to 6 tablets: Fully disperse in 10 mL of drinking water in the supplied cup.
-Swirl the suspension so that no lumps remain.
-After full dispersion, administer within 30 minutes of mixing.

Based on data from a small ongoing pediatric clinical trial, the safety profile of dolutegravir appears to be similar in pediatric and adult patients. In 75 pediatric patients ages 4 weeks to 17 years, no Grade 3 or 4 adverse drug reactions were reported and no adverse drug reactions led to discontinuation.

Renal impairment was observed in less than 2% of dolutegravir recipients during premarketing adult clinical trials. The drug is known to increase serum creatinine (SCr) by inhibiting tubular secretion of creatinine; it does not alter renal glomerular function. During clinical trials, the mean change in SCr from baseline was 0.15 mg/dL (range: -0.32 to 0.65 mg/dL), with elevations occurring within the first 4 weeks of treatment and remaining stable through weeks 48 to 96. Increases in serum creatinine observed in pediatric patients were similar to those seen in adults.

Elevated hepatic enzymes may occur during dolutegravir therapy. During adult clinical trials, increases in ALT and AST (Grade 2 to 4) were observed in approximately 1% to 9% and 1% to 8% of patients, respectively. When the drug was administered to patients coinfected with HIV and hepatitis B or hepatitis C, the incidence of Grade 2 to 4 ALT elevations increased to 13% to 18%. Other hepatobiliary disorders experienced by dolutegravir-treated adult patients during clinical trials include hepatitis (less than 2%) and Grade 2 to 4 increases in total bilirubin (i.e., hyperbilirubinemia, up to 3%). Liver injury, including hepatitis, can also occur as a component of a hypersensitivity reaction. Acute hepatic failure has been noted during postmarketing use. Due to the voluntary nature of postmarketing reports, neither a frequency nor a definitive causal relationship can be established.

Hypersensitivity reactions, characterized by rash, constitutional findings, and organ dysfunction, including liver injury, have been associated with dolutegravir treatment. Pruritus (less than 2%) and rash (less than 1%) were reported by patients receiving dolutegravir in combination with other antiretroviral agents in adult clinical trials. According to the manufacturer, the rashes were defined as generalized rash, macular rash, maculopapular rash, pruritic rash, and drug eruptions. Immediately discontinue use and initiate appropriate therapy if signs or symptoms of a hypersensitivity reaction develop (e.g., severe rash or rash accompanied by fever, malaise, fatigue, muscle or joint pain, blisters/peeling skin, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, or difficulty breathing).

Insomnia was reported in up to 7% of adult dolutegravir recipients during clinical trials. According to the manufacturer, cases of insomnia were not treatment-limiting. Other neurologic adverse events associated with dolutegravir treatment include headache (2% or less), abnormal dreams (less than 1%), and dizziness (less than 1%).

Gastrointestinal adverse events experienced by less than 2% of adult patients treated with dolutegravir during clinical trials include abdominal pain, diarrhea, flatulence, nausea, and vomiting. Weight gain has been reported in postmarketing surveillance. Data from postmarketing trials found treatment-naive patients who started an integrase inhibitor-containing regimen (such as dolutegravir) gained more weight than patients who began a protease inhibitor- or NNRTI-based regimen. Among agents within the integrase inhibitor class, the mean increase in weight from baseline was similar for dolutegravir and bictegravir (approximately 3.5 kg) and lower for elvitegravir. It is unknown whether the increase in weight is reversible upon treatment discontinuation.

Fatigue and myositis were reported by less than 2% of adult patients receiving treatment with dolutegravir during clinical trials. Cases of arthralgia and myalgia have been noted in postmarketing reports. Due to the voluntary nature of postmarketing reports, neither a frequency nor a definitive causal relationship can be established.

Decreased neutrophil counts (neutropenia) were reported in 11 pediatric patients (Grade 3 or 4) treated with dolutegravir in a small ongoing pediatric clinical trial of 75 patients ages 4 weeks to 17 years. Other Grade 3 or 4 laboratory abnormalities reported in pediatric patients include increased lipase (n = 2), decreased bicarbonate (n = 4), decreased hemoglobin (i.e., anemia; n = 3), and increased blood potassium (i.e., hyperkalemia; n = 2). Additional laboratory abnormalities observed in adult patients treated with dolutegravir during clinical trials include hyperglycemia (more than 125 mg/dL; 6% to 14%) and increased creatine kinase (at least 6 x ULN; 2% to 7%). Increased total cholesterol was reported in 10% of adult patients, with a mean change from a fasting baseline of 8.1 to 24 mg/dL. An increase in fasting triglyceride concentrations (mean change as compared to baseline; 6.7 to 13.6 mg/dL) was also observed.

Depression was reported in up to 1% of adult patients treated with dolutegravir in clinical trials. Suicidal ideation, attempt, behavior, or completion was reported in less than 2% of patients. These events were observed primarily in patients with a pre-existing history of depression or other psychiatric illness. Anxiety has been noted in postmarketing reports. Due to the voluntary nature of postmarketing reports, neither a frequency nor a definitive causal relationship can be established.

Unplanned antiretroviral therapy interruption may be necessary in specific situations such as serious drug toxicity, intercurrent illness or surgery precluding oral intake (e.g., gastroenteritis or pancreatitis), severe hyperemesis gravidarum unresponsive to antiemetics, or drug non-availability. If short-term treatment interruption is necessary (i.e., < 1-2 days), in general, it is recommended that all antiretroviral agents be discontinued simultaneously, especially if the interruption is because of serious toxicity. However, if a short-term treatment interruption is anticipated in the case of elective surgery, the pharmacokinetic properties and food requirements of specific drugs should be considered. When the antiretroviral regimen contains drugs with differing half-lives, stopping all drugs simultaneously may result in functional monotherapy of the drug with the longest half-life. For example, after discontinuation, the duration of detectable drug concentrations of efavirenz and nevirapine ranges from < 1 week to > 3 weeks. Simultaneously stopping all drugs in a regimen containing these agents may result in functional monotherapy with the NNRTI and may increase the risk of NNRTI-resistant mutations. Planned long-term treatment interruptions are not recommended due to the potential for HIV disease progression (i.e., declining CD4 counts, viral rebound, acute viral syndrome), development of minor HIV-associated manifestations or serious non-AIDS complications, development of drug resistance, increased risk of HIV transmission, and increased risk for opportunistic infections. If therapy must be discontinued, counsel patient on the potential risks and closely monitor for any clinical or laboratory abnormalities.

Administration of dolutegravir is contraindicated in patients with a history of dolutegravir hypersensitivity. Cases of severe hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction, including liver injury, have been reported in up to 1% of dolutegravir recipients. Monitor the clinical status of patients, including liver function tests, during treatment. Immediately discontinue dolutegravir and initiate appropriate therapy in any patient who develops signs of hypersensitivity reactions, such as serious rash or rash accompanied by fever, fatigue, general malaise, muscle or joint aches, blisters/peeling of skin, oral lesions, conjunctivitis, hepatitis, facial edema, angioedema, difficulty breathing, or eosinophilia. Failure to promptly discontinue therapy may result in a life-threatening reaction.

Dolutegravir use is not recommended for patients with severe hepatic disease (Child-Pugh C) because its effects have not been studied in this population. No dosage adjusts are required for patients with mild or moderate hepatic impairment (Child-Pugh A or B). Cases of hepatotoxicity, including elevated hepatic enzymes, hepatitis, and acute liver failure, have been reported in patients receiving a dolutegravir-containing regimen who had no pre-existing hepatic disease or identifiable risk factors. Drug-induced liver injury requiring liver transplant has also been reported with dolutegravir-containing treatment regimens. Monitor patients for hepatotoxicity during treatment. In addition, cautious administration is also recommended for patients with hepatitis. In general, the safety profile in patients with hepatitis B and HIV coinfection or hepatitis C and HIV coinfection is similar to patients without hepatitis B or C coinfection; however, patients with underlying hepatitis B or C may be at increased risk for worsening or development of transaminase elevations. To monitor for hepatotoxicity, patients with hepatic disease should undergo appropriate laboratory testing before and during treatment. All patients who present with HIV infection should also be screened for hepatitis B virus (HBV) coinfection to assure appropriate treatment. Patients with hepatitis B and HIV coinfection who require treatment for either infection should be started on a fully suppressive antiretroviral regimen that contains NRTIs with activity against both viruses. Avoid using single-drug therapy to treat HBV (i.e., lamivudine, emtricitabine, or tenofovir as the only active agent) due to the risk of developing resistant strains of HIV. The HIV guidelines recommend that coinfected pediatric patients 2 years or older receive an antiretroviral regimen that contains tenofovir in combination with either lamivudine or emtricitabine as the dual NRTI backbone. If tenofovir cannot be used, another agent with anti-HBV activity should be used in combination with lamivudine or emtricitabine to assure adequate treatment of HBV infection. Management of HIV should be continued with the goal of maximal suppression. Hepatitis C virus (HCV) screening should also be performed in any child whose mother is known to have HCV infection and all HIV-infected adolescents. Treatment of HCV infection in a child younger than 3 years is not usually recommended; however, treatment should be considered for all pediatric patients 3 years or older with hepatitis C and HIV coinfection who have no contraindications to treatment. For antiretroviral-naive adolescent patients with CD4 counts greater than 500 cells/mm3, consideration may be given to deferring ARV therapy until the hepatitis C treatment regimen has been completed. Conversely, for adolescent patients with CD4 counts less than 200 cells/mm3, consider delaying initiation of the hepatitis C treatment regimen until the patient is stable on a fully suppressive ARV regimen. All HIV-infected pediatric patients, regardless of HIV and HCV status, should receive standard vaccination with hepatitis A and B vaccines. Additionally, HIV and HCV-coinfected adolescents should be counseled to avoid alcohol.

Caution is advised if administering the dolutegravir to INSTI-experienced adults with renal failure; however, dolutegravir is not indicated for use in pediatric patients who are INSTI-experienced. Dolutegravir plasma concentrations are decreased in patients with severe renal impairment. Use of dolutegravir in patients who are INSTI-experienced with severe renal impairment may result in loss of therapeutic effect and development of resistance.

Testing for human immunodeficiency virus (HIV) infection resistance is recommended in all antiretroviral treatment-naive patients at the time of HIV diagnosis, regardless of whether treatment will be initiated. Additionally, perform resistance testing prior to initiating or changing any HIV treatment regimen. Transmission of drug-resistant HIV strains has been both well documented and associated with suboptimal virologic response to initial antiretroviral therapy. Therefore, resistance testing at baseline can help optimize treatment and, thus, virologic response. In the absence of therapy, resistant viruses may decline over time to less than the detection limit of standard resistance tests, but may still increase the risk of treatment failure when therapy is eventually initiated. Thus, if therapy is deferred, resistance testing should still be performed during acute HIV infection with the genotypic resistance test results kept in the patient's medical record until they become clinically useful. Additionally, because of the possibility of acquisition of another drug-resistant virus before treatment initiation, repeat resistance testing at the time therapy is initiated would be prudent. Efficacy of dolutegravir 50 mg PO twice daily is reduced in patients with an integrase strand transfer inhibitor (INSTI)-resistance Q148 substitution plus 2 or mores additional INSTI-resistance substitutions, including T66A, L74I/M, E138A/K/T, G140S/A/C, Y143R/C/H, E157Q, G163S/E/K/Q, or G193E/R.

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of HIV treatment, patients whose immune system responds to dolutegravir therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as mycobacterium avium complex (MAC), cytomegalovirus (CMV), Pneumocystis pneumonia (PCP), or tuberculosis (TB)), which may necessitate further evaluation and treatment. In addition, autoimmune disease (including Graves' disease, Guillain-Barre syndrome, and polymyositis) may also develop; the time to onset is variable and may occur months after treatment initiation.

Patients with a history of depression or other psychiatric illness may be at increased risk for psychiatric adverse events. Depression was reported in <= 1% of adult patients treated with dolutegravir in clinical trials. Suicidal ideation, attempt, behavior, or completion was reported in < 2% of patients. These events were observed primarily in patients with a pre-existing history of depression or other psychiatric illness.

Counsel adolescents of childbearing potential about the potential reproductive risk and contraception requirements associated with dolutegravir therapy. Preliminary study data identified a small increase in the incidence of neural tube birth defects (involving the brain, spine, and spinal cord) in infants born to mothers who received dolutegravir around the time of conception (periconception exposure). If the decision to use dolutegravir in a patient of childbearing potential is made, the patient should be informed of the potential risk for birth defects, undergo pregnancy testing before initiating treatment, and be counseled on contraception requirements (i.e., consistent use of effective birth control). Males of reproductive potential should also be counseled on contraception requirements.

Description: Dolutegravir is an HIV integrase strand transfer inhibitor (INSTI) indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. The INSTI class of antiretrovirals is designed to slow the advancement of HIV infection by blocking the HIV integrase enzyme needed for viral multiplication. FDA-approval for use in the pediatric population is limited to those who are INSTI-naive. Dolutegravir, in combination with other antiretroviral agents, is FDA-approved for use in pediatric patients 4 weeks and older weighing at least 3 kg.

Initiation of HIV therapy
-Antiretroviral drug resistance testing (preferably genotypic testing) is recommended prior to initiation of therapy in antiretroviral treatment (ART)-naive patients and prior to changing therapy for treatment failure.
-Initiation of treatment immediately or within days after HIV diagnosis is recommended in all pediatric patients, except for patients with cryptococcal meningitis, disseminated Mycobacterium avium complex disease, or Mycobacterium tuberculosis disease. In these patients, initiate treatment for the opportunistic infection first, ahead of ART initiation. The urgency of rapid treatment initiation is especially critical for all patients younger than 1 year, who carry the highest risk of rapid disease progression and mortality. If therapy is deferred for certain circumstances, closely monitor the patient's virologic, immunologic, and clinical status at least every 3 to 4 months. If therapy is deferred, initiate treatment when HIV RNA concentrations increase, CD4 count or percentage values decline (i.e., approaching CDC Stage 2 or 3), the patient develops new HIV-related clinical symptoms, or the ability of the caregiver and patient to adhere to the prescribed regimen has improved.

Place in therapy for HIV
-For treatment-naive infants and children 4 weeks and older weighing at least 3 kg, dolutegravir plus a 2-nucleoside reverse transcriptase inhibitor (NRTI) backbone option is recommended as a preferred INSTI-based regimen for initial therapy.
-For treatment-naive adolescents, dolutegravir plus a 2-NRTI backbone option is recommended as a preferred INSTI-based regimen for initial therapy. Dolutegravir plus lamivudine is also a regimen that may be used as initial therapy in treatment-naive adolescents unable to take abacavir or tenofovir (if pre-treatment HIV RNA less than 500,000 copies/mL and without HBV coinfection).

Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: human immunodeficiency virus (HIV)
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.

For the treatment of human immunodeficiency virus (HIV) infection in combination with other antiretroviral agents:
Oral dosage (tablets):
NOTE: Do not interchange tablets and tablets for oral suspension on a milligram-per-milligram basis due to differing pharmacokinetic profiles.
NOTE: Tablets for oral suspension are preferred in pediatric patients weighing less than 20 kg.
Children weighing 14 to 19 kg who are treatment-naive or treatment-experienced but INSTI-naive: 40 mg PO once daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children and Adolescents weighing 20 kg or more who are treatment-naive or treatment-experienced but INSTI-naive: 50 mg PO once daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children and Adolescents weighing 40 kg or more who are INSTI-experienced with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance*: 50 mg PO twice daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Dolutegravir has less resistance overlap with raltegravir than does elvitagravir and may retain activity against strains containing the Y143 and N155 pathway mutations. The efficacy of dolutegravir 50 mg PO twice daily is reduced in patients with an INSTI-resistance Q148 substitution plus 2 or more additional INSTI-resistance substitutions, including T66A, L74I/M, E138A/K/T, G140S/A/C, Y143R/C/H, E157Q, G163S/E/K/Q, or G193E/R.
Oral dosage (tablets for oral suspension):
NOTE: Do not interchange tablets and tablets for oral suspension on a milligram-per-milligram basis due to differing pharmacokinetic profiles.
NOTE: Tablets for oral suspension are preferred in pediatric patients weighing less than 20 kg.
Infants 4 weeks and older weighing 3 to 5 kg who are treatment-naive or treatment-experienced but INSTI-naive: 5 mg PO once daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Infants 4 weeks and older weighing 6 to 9 kg who are treatment-naive or treatment-experienced but INSTI-naive: 15 mg PO once daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Infants and Children 4 weeks and older weighing 10 to 13 kg who are treatment-naive or treatment-experienced but INSTI-naive: 20 mg PO once daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children weighing 14 to 19 kg who are treatment-naive or treatment-experienced but INSTI-naive: 25 mg PO once daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children and Adolescents weighing 20 kg or more who are treatment-naive or treatment-experienced but INSTI-naive: 30 mg PO once daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

For human immunodeficiency virus (HIV) prophylaxis* after nonoccupational exposure to HIV, including sexual assault:
Oral dosage (tablets):
Adolescents: 50 mg PO once daily with tenofovir and emtricitabine for 28 days is a preferred HIV post-exposure prophylaxis (PEP) regimen in adolescents. Dolutegravir in combination with zidovudine and lamivudine for 28 days is a preferred HIV PEP regimen in adolescents with renal dysfunction (CrCl 59 mL/minute or less). A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective. Higher risk exposures for which prophylaxis is recommended include exposure of vagina, rectum, eye, mouth, or other mucous membrane, nonintact skin, or percutaneous contact with blood, semen, vaginal secretions, rectal secretions, breast milk, or any body fluid that is visibly contaminated with blood when the source is known to be HIV-positive. Exposures to a source patient with unknown HIV status should be assessed on a case-by-case basis.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established.
-Infants
weight less than 3 kg: Safety and efficacy have not been established.
weight 3 to 5 kg: 10 mg/day PO tablets for oral suspension; regular tablets are not FDA-approved.
weight 6 to 9 kg: 30 mg/day PO tablets for oral suspension; regular tablets are not FDA-approved.
weight 10 to 13 kg: 40 mg/day PO tablets for oral suspension; regular tablets are not FDA-approved.
-Children
weight less than 14 kg: 40 mg/day PO tablets for oral suspension; regular tablets are not FDA-approved.
weight 14 to 19 kg: 50 mg/day PO tablets for oral suspension; 80 mg/day PO regular tablets.
weight 20 kg or more: 60 mg/day PO tablets for oral suspension; 100 mg/day PO regular tablets.
-Adolescents
60 mg/day PO tablets for oral suspension; 100 mg/day PO regular tablets.

Patients with Hepatic Impairment Dosing
Mild to moderate hepatic impairment (Child-Pugh A or B): No dosage adjustment is necessary.
Severe hepatic impairment (Child-Pugh C): Use is not recommended.

Patients with Renal Impairment Dosing
No dosage adjustment is necessary. Although caution is advised if administering dolutegravir to INSTI-experienced adults who have severe renal impairment, dolutegravir is not indicated for use in INSTI-experienced pediatric patients.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Dolutegravir inhibits the catalytic activity of HIV integrase, which is an HIV encoded enzyme required for viral replication. Integrase is one of 3 HIV-1 enzymes required for viral replication. Integration of HIV into cellular DNA is a multi-step process. First, the assembly of integrase in a stable complex with the viral DNA occurs. Second, the terminal dinucleotides from each end of the viral DNA are removed by endonucleolytic processing. Lastly, the viral DNA 3' ends are covalently linked to the cellular (target) DNA by strand transfer. The last 2 processes, which are catalytic, require integrase to be appropriately assembled on a specific viral DNA substrate. Inhibition of integrase by dolutegravir prevents the covalent insertion, or integration, of unintegrated linear HIV DNA into the host cell genome preventing the formation of the HIV provirus. The provirus is required to direct the production of progeny virus; therefore, inhibiting integration prevents propagation of the viral infection.

The antiviral activity of dolutegravir is not antagonistic when administered concurrently with raltegravir, maraviroc, enfuvirtide, non-nucleoside reverse transcriptase inhibitors (efavirenz and nevirapine), nucleoside reverse transcriptase inhibitors (abacavir and stavudine), protease inhibitors (amprenavir and lopinavir), adefovir, or ribavirin.

Pharmacokinetics: Dolutegravir is administered orally. It is at least 98.9% bound to human plasma protein, with an estimated volume of distribution of 17.4 L in adults. Although the clinical relevance has not been established, dolutegravir distributes into the cerebrospinal fluid (CSF) at a median concentration of 18 ng/mL. Metabolism occurs via UDP-glucuronosyltransferase (UGT)1A1 (major) and by the hepatic isoenzyme CYP3A (minor). The terminal half-life in adults is approximately 14 hours, with more than half of the total dose (53%) excreted unchanged in the feces. Excretion in the urine accounts for 31% of the total dose; however, less than 1% of the renally eliminated drug is unchanged.

Affected cytochrome P450 enzymes and drug transporters: CYP3A (minor), UGT1A1, UGT1A3, UGT1A9, P-glycoprotein (P-gp), BCRP, OCT2, and MATE1
Dolutegravir is metabolized by UGT1A1 and, to a lesser extent, CYP3A. Dolutegravir is also a substrate of UGT1A3, UGT1A9, BCRP, and P-gp in vitro; drugs that induce or inhibit these enzymes and transporters may decrease or increase dolutegravir plasma concentrations. Dolutegravir is an inhibitor of the renal organic cation transporter OCT2 and potentially the multidrug and toxin extrusion transporter MATE1, which results in the inhibition of the tubular secretion of creatinine and possibly drugs eliminated by OCT2 or MATE1. It is an inhibitor of the renal organic anion transporters OAT1 and OAT3 in vitro; however, in vivo, dolutegravir did not alter the plasma concentrations of tenofovir, which is a substrate of OAT1 and OAT3. Dolutegravir does not inhibit the following: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, UGT1A1, UGT2B7, P-gp, BCRP, bile salt export pump (BSEP), organic anion transporter polypeptide (OATP)1B1, OATP1B3, OCT1, multidrug resistant protein (MRP)2, or MRP4. Additionally, the drug does not induce CYP1A2, CYP2B6, or CYP3A4.


-Route-Specific Pharmacokinetics
Oral Route
Tablets
The absolute bioavailability of dolutegravir is unknown. Peak plasma concentrations are obtained 2 to 3 hours after an oral dose in adults, with steady-state concentrations achieved within 5 days. The drug may be administered with or without food; however, administration with food increases the extent and slows the rate of absorption. When given with a low-, moderate-, and high-fat meal, the AUC is increased by 33%, 41%, and 66%, respectively; the Cmax is increased by 46%, 52%, and 67%, respectively; and the Tmax is prolonged from 2 hours (under fasting conditions) to 3 hours, 4 hours, and 5 hours, respectively. At doses more than 50 mg/day, dolutegravir exhibits non-linear pharmacokinetics, with increasing doses producing less than proportional increases in plasma concentrations. An evaluation of the drug's steady-state pharmacokinetics found doses of 50 mg once daily produced an AUC of 53.6 mcg x hour/mL, whereas a dose of 50 mg twice daily produced an AUC of only 75.1 mcg x hour/mL.

Tablets for oral suspension
Dolutegravir tablets and dolutegravir PD tablets for oral suspension are not bioequivalent. The relative bioavailability of dolutegravir PD tablets is approximately 1.6-fold higher than dolutegravir tablets; therefore, the 2 dosage forms are not interchangeable on a milligram-per-milligram basis. The tablets for oral suspension may be adminstered with or without food.


-Special Populations
Pediatrics
The pharmacokinetics of dolutegravir in a study of 115 HIV-infected pediatric patients 4 weeks to 17 years of age were similar to those seen in adult patients receiving 50 mg PO once or twice daily. The mean Cmax was higher in pediatric patients, but the increase is not considered clinically significant as the safety profiles were similar in pediatric and adult subjects. Patients weighing 3 to 24 kg received weight-banded doses of dolutegravir PD tablets for oral suspension (5, 15, 20, 25, or 30 mg PO once daily) and patients weighing 20 kg or more received dolutegravir tablets 50 mg PO once daily. The mean Cmax after doses of 5, 15, 20, 25, and 30 mg PO once daily was 3.8, 5.27, 5.99, 5.97, and 7.16 mcg/mL, respectively. The mean Cmax after a dose of 50 mg PO once daily was 4.92 mcg/mL. The mean AUC after doses of 5, 15, 20, 25, and 30 mg PO once daily was 49.37, 57.17, 68.75, 58.97, and 71.53 mcg x hour/mL, respectively. The mean AUC after a dose of 50 mg PO once daily was 54.98 mcg x hour/mL.

Hepatic Impairment
Pharmacokinetic data for dolutegravir in pediatric patients with hepatic impairment are not available. In a study in 8 adult patients with moderate hepatic impairment (Child-Pugh B), dolutegravir exposure was similar to that seen in healthy subjects. Pharmacokinetic data are unavailable for patients with severe hepatic impairment (Child-Pugh C).

Renal Impairment
Pharmacokinetic data for dolutegravir in pediatric patients with renal impairment are not available. In a study of 8 adult patients with severe renal impairment (CrCl less than 30 mL/minute), dolutegravir AUC, Cmax, and C24 were decreased by 40%, 23%, and 43%, respectively, compared to patients with normal renal function. Population pharmacokinetic data revealed no clinically relevant effect on the exposure of dolutegravir in patients with mild and moderate renal impairment. Dolutegravir has not been adequately studied in patients requiring dialysis.

Other
UGT1A1 Polymorphism
In a meta-analysis of healthy adult subject trials, individuals with UGT1A1 genotypes that result in poor dolutegravir metabolism (n = 7) had a 32% lower clearance and 46% higher drug exposure than individuals with UGT1A1 genotypes that are associated with normal metabolism (n = 41).