Dolutegravir: Uses, Dosage, Side Effects, and Pharmacological Aspects

Overview

Dolutegravir (DTG) is a potent antiretroviral medication that plays a crucial role in the management of human immunodeficiency virus (HIV) infection. As a member of the integrase strand transfer inhibitor (INSTI) class, DTG targets a key enzyme involved in the replication of the virus, offering an effective approach to controlling HIV.

DTG is an FDA (Food and Drug Administration) approved drug for pediatric patients who are at least four weeks old and weigh a minimum of 6.61 pounds (3 kg). It received approval on August 12, 2013. Dolutegravir stands as a valuable component in the arsenal against HIV, providing an effective and versatile option for both adult and pediatric patients.

This article discusses its mechanism of action, broad indications, and various dosage forms that contribute to its significance in contemporary HIV treatment regimens concerning pediatric patients.

Drug Group

Dolutegravir belongs to the class of antiretroviral drugs known as integrase strand transfer inhibitors (INSTIs). These drugs target the integrase enzyme of the human immunodeficiency virus, inhibiting its ability to integrate the viral DNA (deoxyribonucleic acid) into the host cell's DNA. By blocking this step in the viral life cycle, Dolutegravir helps prevent the replication of the virus and is used in the treatment of HIV infection.

Indications

Dolutegravir is recommended for use with other antiretroviral agents for managing human immunodeficiency virus type 1 (HIV-1) infection in individuals aged 12 years and above, encompassing adults and children, weighing at least 88.18 pounds.

Dosage Forms and Available Strengths

Dolutegravir is available in tablet form. Dolutegravir tablets are circular, film-coated, and biconvex, bearing yellow.

The available strengths are

• Dispersible tablets are designed for oral suspension with a strength of 5 mg (milligrams).

• Film-coated tablets are available in 10 mg, 25 mg, and 50 mg strengths.

Warnings and Precautions

The associated warnings and precautions are

• Hypersensitivity Reactions: Some people may have allergic reactions to Dolutegravir, with symptoms like rash, fatigue (loss of energy), and liver problems. If indications of an allergic response emerge (like a severe rash or difficulty breathing), Dolutegravir should be stopped immediately.

• Effects on Liver in Hepatitis B or C: People with hepatitis B or C (live inflammation) may see liver issues while using Dolutegravir. Regular monitoring is needed, especially if anti-hepatitis therapy is stopped.

• Fat Redistribution: Dolutegravir might cause changes in body fat distribution, like fat accumulation or loss in certain areas. The reasons for and long-term effects of these changes need to be clarified.

• Immune Reconstitution Syndrome: Starting Dolutegravir may trigger an inflammatory response in some patients, leading to problems like infections. Autoimmune disorders (the body attacking itself) are also possible, even months after starting treatment.

For Patients:

What Is Pediatric Antiretroviral Treatment?

Pediatric antiretroviral treatment refers to the medical care provided to children infected with the human immunodeficiency virus. This treatment involves using antiretroviral drugs to suppress the replication of the virus, slow the progression of the disease, and enhance the overall health and well-being of the pediatric patient. The goal is to manage HIV infection and allow children to live healthier lives. Therapy is frequently tailored to suit the child's age, weight, and specific health requirements.

How Does the Dolutegravir Work?

Dolutegravir is an INSTI used to treat HIV. It blocks the integrase enzyme, preventing the virus from incorporating genetic material into the host cell DNA. This disruption inhibits HIV replication, reducing viral load and slowing disease progression. Dolutegravir's effectiveness and resistance prevention are key components in antiretroviral therapy.

Dolutegravir, an HIV integrase inhibitor, is used with other drugs to treat HIV infection in adults and children weighing at least 6.6 lbs (3 kg). In certain adults, it combines with Rilpivirine to replace current HIV medications. While not curing HIV, it decreases virus levels, reduces the risk of developing AIDS (acquired immunodeficiency syndrome), and, when combined with lifestyle changes, lowers the chance of spreading the virus.

What Is the Dosage of the Dolutegravir?

The frequently recommended dosage is 50 mg. Each tablet contains 50 mg of Dolutegravir (in the form of Dolutegravir sodium). The pediatric dosing is available in other strengths of 5 mg, 10 mg, and 25 mg, depending on the weight and condition of the patient.

How Is Dolutegravir Administered?

Dolutegravir is typically administered orally in the form of tablets. The tablets can be taken with or without food, as directed by a healthcare professional.

Dispersible tablets are preferred for pediatric patients under 44 pounds (20 kg), while film-coated tablets are unsuitable for those under 31 pounds (14 kg). If dispersible tablets are unavailable, the 10 mg and 50 mg tablets can be halved, crushed, and mixed with food or liquid for prompt consumption. Administration through tubes is possible but requires complete dispersion and flushing to prevent clogging.

What Are the Side Effects of Dolutegravir?

Dolutegravir may lead to side effects. Inform the doctor if these symptoms persist or worsen:

• Difficulty falling or staying asleep.

• Headache.

• Stomach pain.

• Gas.

• Diarrhea.

• Weight gain.

Some of the side effects are serious. If the patient encounters any of the following symptoms, cease Dolutegravir and contact the doctor immediately or seek emergency medical attention:

• Rash.

• Fever.

• Feeling sick.

• Excessive tiredness.

• Muscle or joint pain.

• Blistering or peeling skin.

• Blisters or sores in the mouth.

• Red or swollen eyes.

• Swelling of the eyes, face, lips, mouth, tongue, or throat.

• Difficulty breathing or swallowing.

• Yellowing of eyes or skin.

• Dark urine.

• Pale-colored bowel movements.

• Nausea.

• Vomiting.

• Appetite loss.

• Pain in the upper right part of the stomach.

Dolutegravir may cause other side effects. Contact the doctor if one encounters any unusual problems while taking this medication.

What Are the Things to Inform the Doctor Before Taking Dolutegravir?

The things to inform the doctor before taking Dolutegravir:

• Detailed medical history emphasizing liver problems or hepatitis (liver inflammation).

• Disclose prescribed, over-the-counter (OTC) medications and vitamin supplements, including herbal products.

• Notify of known allergies, particularly to Dolutegravir or similar medications.

• If pregnant, planning pregnancy, or breastfeeding, inform the doctor.

• Share details of previous antiretroviral therapy and any experienced issues or side effects.

• Inform the doctor about kidney problems or ongoing dialysis (a blood-cleansing medical procedure).

• Disclose mental health history, including depression or suicidal thoughts.

• Mention recreational drug use or a history of substance abuse.

• Inform any other pre-existing conditions, such as bone problems or osteoporosis (weak and brittle bones).

• Discuss potential drug interactions, especially with medications for other health conditions.

• Patients must inform the doctor about specific genetic factors (if aware) that may affect medication processing.

Dietary Considerations:

DTG can be consumed independently of meals. It is recommended to take DTG either two hours before or six hours after ingesting specific medications, including cation-containing antacids or laxatives (intestinal stimulants), sucralfate, iron supplements, oral calcium supplements, or buffered medications.

Missed Dose: If a dose is missed, take it as soon as remembered. If close to the next dose, skip the missed one; do not double up. It is also necessary to inform the doctor about the missed dose.

Overdose: Limited exposure to single higher doses (up to 250 mg in healthy subjects) showed no distinct symptoms or signs beyond those mentioned as side effects (mentioned above). There is no specific remedy for Dolutegravir overdose. In cases of overdose, monitoring the patient and applying standard supportive treatment are recommended. Given the high binding of Dolutegravir to plasma proteins, dialysis is unlikely to eliminate it significantly.

Storage and Handling: The tablets come in bottles. Each bottle comprises 30 tablets featuring a child-resistant closure. It is recommended to store them at 25 degrees Celsius (77 degrees Fahrenheit), with excursions allowed between 15 and 30 degrees Celsius (59 and 86 degrees Fahrenheit).

Disposal: Dispose of medications according to specific instructions on the packaging or provided by healthcare professionals. Utilize drug take-back programs if available. Follow local community guidelines for safe disposal; if allowed, medications can be disposed of in household trash with proper precautions. Avoid flushing unless explicitly instructed. Remove personal information from the packaging before disposal.

For Doctors

Chemical Taxonomy

• Dolutegravir sodium's chemical name is sodium (4R,12aS)-9-{[(2,4-difluorophenyl)methyl]carbamoyl}-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1,2:4,5]pyrazino[2,1-b][1,3]oxazin-7-olate.

• It has an empirical formula of C20H18F2N3NaO5 and a molecular weight of 441.36 g/mol (gram per molecule).

• Dolutegravir sodium is a white to light yellow powder, slightly soluble in water.

Dose:

The dosage recommendations for Dolutegravir for pediatric patients and adults vary based on age, weight, and specific formulation. Here is a summary of the dosage information:

Neonate Dose (Aged More Than or Equal to Four Weeks and Weighing More Than Equal to 6.61 Pounds): Dolutegravir is not FDA-approved for use in neonates.

Infant, Child, and Adolescent Dose:

• 6.61 Pounds to Less Than 13.23 Pounds: 5 mg once daily (1 tablet).

• 13.23 Pounds to Less Than 17.64 Pounds: 15 mg once daily (3 tablets).

• 22.05 Pounds to Less Than 26.46 Pounds: 20 mg once daily (4 tablets).

• 30.87 Pounds to Less Than 44.09 Pounds: 25 mg once daily (5 tablets).

• More Than or Equal to 44.09 Pounds: 30 mg once daily (6 tablets).

Film-Coated Tablets for Pediatric Patients Weighing More Than or Equal to 30.87 Pounds and Who Can Swallow Tablets:

• 30.87 Pounds to Less Than 44.09 Pounds: 40 mg once daily (4 x 10 mg tablets).

• More Than or Equal to 44.09 Pounds: 50 mg once daily (1 x 50 mg tablet).

Pediatric Dosing (For Kids 12 Years and Older):

• For pediatric patients aged 12 and above, with a minimum weight of 88.18 pounds (40 kgs), Dolutegravir is recommended at 50 mg once daily. If co-administering with specific medications or Rifampin, the dose is 50 mg twice daily. Safety and effectiveness are not established for those under 12 or 88.18 pounds. It has not been studied in pediatric patients with INSTI experience or resistance to Raltegravir and Elvitegravir.

Dosing Considerations: Individuals treated with Dolutegravir 50 mg twice daily exhibited a suboptimal virologic response when possessing an INSTI-resistance Q148 substitution and two or more additional INSTI-resistance substitutions.

What Are the Pharmacological Actions of Dolutegravir?

The pharmacological actions of Dolutegravir are:

• Pharmacodynamics: In a randomized trial, Dolutegravir monotherapy at 2 mg, 10 mg, and 50 mg once daily demonstrated rapid and dose-dependent antiviral effects, with the 50 mg dose showing a mean reduction in HIV-1 RNA (ribonucleic acid). This response persisted for three to four days after the last 50 mg dose. In a separate study, a single oral dose of 250 mg of Dolutegravir suspension did not prolong the QTc interval in 42 healthy subjects. Regarding renal function, a trial with 37 healthy subjects revealed that both 50 mg once daily and 50 mg twice daily doses resulted in a decrease in creatinine clearance (nine percent and 13 percent, respectively) but did not significantly impact actual glomerular filtration rate or adequate renal plasma flow compared to placebo.

• Mechanism of Action: Dolutegravir hinders the activity of HIV integrase by binding to its active site, thereby obstructing the strand transfer phase of retroviral deoxyribonucleic acid integration, a crucial step in the HIV replication cycle.

• Pharmacokinetics: Dolutegravir's pharmacokinetics were studied in healthy and HIV-1-infected adults, showing similar exposure. In HIV-1-infected individuals, 50 mg twice daily exhibited non-linear exposure due to antiretroviral regimen interactions. When administered with or without food, absorption occurs two to three hours post-dose, reaching a steady state in around five days. Steady-state pharmacokinetics for 50 mg once daily and twice daily differed in AUC (area under the curve), Cmax (maximum concentration), and Cmin (minimum concentration). Highly bound to plasma proteins, Dolutegravir has a volume of distribution of 17.4 L (liters), and its concentration in cerebrospinal fluid was 18 ng/mL (nanograms per milliliter) after two weeks of treatment. Metabolism involves UGT1A1 (UDP Glucuronosyltransferase 1A1) and CYP3A (Cytochrome P450 3A), with minimal renal elimination (less than one percent). Dolutegravir has a half-life of approximately 14 hours and an apparent clearance of 1.0 L/h (liter per hour).

Non-Clinical Toxicity:

• Carcinogenesis: Two-year studies in mice and rats found no significant increase in drug-related tumors, even at doses up to 500 mg/kg (milligram per kilogram) in mice (14 times higher than the human recommended dose) and 50 mg/kg in rats (10 to 15 times higher than the human recommended dose).

• Mutagenesis: Dolutegravir showed no genotoxic effects in bacterial mutation assays, mouse lymphoma assays, or in vivo rodent micronucleus assays.

• Impairment of Fertility: In rat studies, Dolutegravir at 1,000 mg/kg/day (milligrams per kilogram daily) showed no impact on mating or fertility, with exposure 24 times higher than the human recommended dose of 50 mg twice daily.

What Are the Contraindications Of Dolutegravir?

Combining Dolutegravir with Dofetilide is prohibited because it may elevate Dofetilide plasma levels, posing a risk of severe and potentially life-threatening events.

What Are the Drug Interactions of Dolutegravir?

The drug interactions are:

• Dofetilide, Metformin.

• Etravirine (reduces Dolutegravir levels).

• Efaviren, Nevirapine, Fosamprenavir and Ritonavir, Tipranavir and Ritonavir, Oxcarbazepine, Phenytoin, Phenobarbital, and Carbamazepine.

• Medications containing polyvalent cations (Mg, Al, Fe, and Ca).

• Cation-containing antacids or laxatives.

• Sucralfate.

• Oral iron supplements.

• Oral calcium supplements.

• Close monitoring is recommended while using Metformin (when starting or stopping Dolutegravir).

Clinical Studies

IMPAACT P1093 is an ongoing trial at multiple centers involving around 160 pediatric subjects aged six weeks to less than 18 years with HIV-1 infection. Among them, 23 treatment-experienced subjects, aged 12 to less than 18 years, who were new to integrase strand transfer inhibitors (INSTIs) were enrolled. The adverse reaction profile resembled that observed in adults. Grade 2 adverse drug reactions (ADRs) included rash, abdominal pain, and diarrhea (each reported once). No Grade 3 or 4 ADRs were reported. Grade 3 laboratory abnormalities involving elevated total bilirubin and lipase were reported in one subject each, with no Grade 4 abnormalities. Changes in mean serum creatinine were comparable to those observed in adults.

Use in Specific Populations

• Pregnancy: Dolutegravir is pregnancy category B, not recommended during pregnancy except when essential.

• Nursing Mothers: HIV-1-infected U.S. mothers on Dolutegravir are advised not to breastfeed due to the risk of transmission and potential adverse effects on infants.

• Geriatric Use: Caution is advised when giving Dolutegravir to patients aged 65 and older due to limited data in this age group and potential variations in health conditions and drug interactions.

• Hepatic Impairment: Dosage adjustments are unnecessary for individuals with mild to moderate hepatic impairment, as no significant pharmacokinetic differences were observed.

• Renal Impairment: Individuals with significant renal dysfunction may exhibit lower Dolutegravir concentrations. No dosage adjustments are required for mild to severe impairment, except for caution in INSTI-experienced patients with severe renal impairment to prevent therapeutic loss and resistance. No dialysis study is available.