DOLUTEGRAVIR, LAMIVUDINE AND TENOFOVIR DISOPROXIL FUMARATE
Clinical safety rating: safe
Other nephrotoxic drugs increase risk of renal impairment Can cause renal impairment and decreased bone mineral density.
Dolutegravir is an integrase strand transfer inhibitor that blocks HIV-1 integration into host DNA. Lamivudine and tenofovir disoproxil fumarate are nucleoside reverse transcriptase inhibitors that inhibit HIV-1 reverse transcriptase via DNA chain termination.
| Metabolism | Dolutegravir is metabolized primarily by UGT1A1 with minor contribution by CYP3A4. Lamivudine is minimally metabolized; undergoes intracellular phosphorylation. Tenofovir disoproxil fumarate is a prodrug that undergoes hydrolysis to tenofovir, which is then phosphorylated; tenofovir is eliminated renally by glomerular filtration and active tubular secretion. |
| Excretion | Dolutegravir: ~64% feces (primarily as parent drug), ~32% urine (parent drug and glucuronide conjugate). Lamivudine: ~70% urine as unchanged drug (renal tubular secretion). Tenofovir disoproxil fumarate (TDF): Pro-drug; tenofovir is renally excreted ~70-80% unchanged (glomerular filtration and tubular secretion). |
| Half-life | Dolutegravir: ~14 hours (terminal), supports once-daily dosing with moderate PK variability. Lamivudine: ~18-22 hours (terminal), allows once-daily dosing; intracellular active metabolite (lamivudine triphosphate) has much longer half-life (~22-27 hours). Tenofovir: ~17 hours (terminal), increased to ~32 hours in intracellular diphosphate form; supports once-daily dosing. |
| Protein binding | Dolutegravir: ~99% bound to plasma proteins (mainly albumin). Lamivudine: <36% bound to plasma proteins (mainly albumin). Tenofovir: <7% bound to plasma proteins. |
| Volume of Distribution | Dolutegravir: Vd ~17–20 L/kg, indicating extensive tissue distribution. Lamivudine: Vd ~1.3 L/kg, primarily distributing into total body water. Tenofovir: Vd ~1.2 L/kg, distributing into total body water. |
| Bioavailability | Dolutegravir: Oral bioavailability ~94% (high); absorption unaffected by food but increased by high-fat meal. Lamivudine: Oral bioavailability ~86% (well absorbed). Tenofovir disoproxil fumarate: Oral bioavailability ~25% (pro-drug; TDF increases absorption relative to tenofovir alone). |
| Onset of Action | Oral: Not applicable for immediate clinical effect. Antiviral effect begins after first dose; significant viral load reduction typically seen within 1-4 weeks. |
| Duration of Action | 24 hours: Once-daily dosing maintains therapeutic concentrations. Continuous adherence required; missed doses may lead to virologic failure. Full viral suppression expected by 24 weeks. |
One tablet (50 mg dolutegravir/300 mg lamivudine/300 mg tenofovir disoproxil fumarate) orally once daily
| Dosage form | TABLET |
| Renal impairment | Not recommended if creatinine clearance (CrCl) <30 mL/min. For CrCl 30-49 mL/min: administer every 48 hours. No adjustment for CrCl ≥50 mL/min. |
| Liver impairment | No dose adjustment required for mild to moderate hepatic impairment (Child-Pugh A or B). Not recommended for severe hepatic impairment (Child-Pugh C). |
| Pediatric use | Approved for patients weighing ≥40 kg: one tablet (50 mg dolutegravir/300 mg lamivudine/300 mg tenofovir disoproxil fumarate) orally once daily. For patients weighing 30-39 kg, alternative formulations are used. |
| Geriatric use | No specific dose adjustment; use with caution due to increased risk of renal impairment and decreased bone mineral density. Monitor renal function and bone density. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Other nephrotoxic drugs increase risk of renal impairment Can cause renal impairment and decreased bone mineral density.
| FDA category | Animal |
| Breastfeeding | Dolutegravir: Excreted in human milk; M/P ratio ~1.0. Lamivudine: High transfer into breast milk (M/P ratio ~3.3). Tenofovir: Low transfer (M/P ratio ~0.7). Limited data on long-term effects; in settings where formula is available, breastfeeding is not recommended due to theoretical risk of viral resistance and toxicity. WHO recommends breastfeeding with maternal ART in resource-limited settings. |
| Teratogenic Risk |
■ FDA Black Box Warning
WARNING: POST-TREATMENT ACUTE EXACERBATION OF HEPATITIS B. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued lamivudine or tenofovir disoproxil fumarate. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue the drug.
| Common Effects | Hepatitis B |
| Serious Effects |
["Concomitant administration with dofetilide due to increased dofetilide concentrations and risk of arrhythmia","Concomitant administration with drugs that strongly induce UGT1A1 and/or CYP3A4 (e.g., carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampin, rifapentine, and St. John’s wort)"]
| Precautions | ["Hepatitis B exacerbation upon discontinuation in HIV/HBV coinfected patients","Hepatotoxicity including hepatic steatosis and lactic acidosis","Risk of nephrotoxicity including acute renal failure, Fanconi syndrome, and proximal tubulopathy; monitor renal function before and during therapy","Bone loss and osteomalacia; increased risk of fractures with tenofovir disoproxil fumarate","Immune reconstitution syndrome, including autoimmune disorders","Redistribution/accumulation of body fat","Hypersensitivity reactions, including skin reactions and drug reaction with eosinophilia and systemic symptoms (DRESS)","Pancreatitis, especially in children with history of pancreatitis or risk factors"] |
Loading safety data…
| Dolutegravir: First trimester exposure associated with neural tube defects (NTD) (odds ratio 1.7, absolute risk 0.3%). Increased risk of NTD with periconceptional use. Lamivudine and Tenofovir disoproxil fumarate: No increased risk of birth defects in human studies. Second and third trimester: No specific fetal risks documented; combination ART recommended for maternal health and prevention of vertical transmission. |
| Fetal Monitoring | First trimester: Neural tube defect screening (ultrasound at 18-20 weeks, folate supplementation). Throughout pregnancy: HIV viral load every 4-8 weeks; renal function (serum creatinine, eGFR) at baseline and every 3 months; liver function tests; complete blood count. Third trimester: Repeat HIV RNA at 36 weeks to determine mode of delivery. Fetal: Standard obstetric ultrasound. |
| Fertility Effects | No evidence of impaired fertility in women or men with dolutegravir, lamivudine, or tenofovir disoproxil fumarate. Animal studies show no adverse effects on mating or fertility. Hormonal contraceptive interactions: None significant. |