DOLUTEGRAVIR, EMTRICITABINE and TENOFOVIR ALAFENAMIDE
Clinical safety rating: safe
Other nephrotoxic drugs increase risk of renal impairment Can cause renal impairment and decreased bone mineral density.
Dolutegravir is an HIV-1 integrase strand transfer inhibitor (INSTI) that blocks viral DNA integration. Emtricitabine is a nucleoside reverse transcriptase inhibitor (NRTI) that terminates viral DNA chain elongation. Tenofovir alafenamide is an NRTI that inhibits HIV reverse transcriptase after intracellular conversion to tenofovir diphosphate.
| Metabolism | Dolutegravir is primarily metabolized by UGT1A1 with minor contribution from CYP3A. Emtricitabine is minimally metabolized via oxidation and glucuronidation. Tenofovir alafenamide is hydrolyzed to tenofovir by cathepsin A or CES1; tenofovir is not significantly metabolized. |
| Excretion | Dolutegravir: ~64% feces (as parent), ~31% urine (as glucuronide conjugate, <1% parent). Emtricitabine: ~86% urine (as parent and metabolites), ~14% feces. Tenofovir alafenamide: <1% renal (as parent), ~82% feces (as metabolite tenofovir). |
| Half-life | Dolutegravir: ~14 hours (single dose), ~12 hours (steady state). Emtricitabine: ~10 hours. Tenofovir alafenamide: ~0.5 hours (parent), but its active metabolite tenofovir diphosphate has intracellular half-life >60 hours. Clinically, tenofovir alafenamide is dosed once daily due to intracellular accumulation. |
| Protein binding | Dolutegravir: >99% (albumin). Emtricitabine: <4% (albumin). Tenofovir alafenamide: ~80% (albumin). |
| Volume of Distribution | Dolutegravir: ~12.5 L (0.18 L/kg for 70 kg). Emtricitabine: ~92 L (1.3 L/kg). Tenofovir alafenamide: ~0.72 L/kg. Clinically, dolutegravir distributes into tissues; emtricitabine and tenofovir alafenamide penetrate cells for intracellular triphosphate formation. |
| Bioavailability | Dolutegravir: ~60% (oral). Emtricitabine: ~93% (oral). Tenofovir alafenamide: ~40% (oral under fed conditions); food increases absorption. |
| Onset of Action | Oral: Rapid absorption; plasma concentrations reach near-peak within 1-2 hours. Virologic suppression typically achieved within 4-8 weeks of therapy. |
| Duration of Action | Oral: Once-daily dosing provides sustained virologic suppression. Duration of action over 24 hours; adherence crucial due to short plasma half-lives, though intracellular tenofovir diphosphate provides extended activity. |
One tablet (50 mg dolutegravir/200 mg emtricitabine/25 mg tenofovir alafenamide) taken orally once daily with or without food.
| Dosage form | TABLET |
| Renal impairment | Not recommended for patients with creatinine clearance (CrCl) <30 mL/min. For CrCl ≥30 mL/min, no dosage adjustment required. If CrCl declines to <30 mL/min during therapy, discontinue. |
| Liver impairment | No dosage adjustment required for mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. Not recommended for severe (Child-Pugh C) hepatic impairment due to lack of data. |
| Pediatric use | Approved for body weight ≥40 kg (age ≥12 years): one tablet (50/200/25 mg) orally once daily. For weight 25 kg to <40 kg: use individual components per weight-based guidelines (dolutegravir 50 mg once daily, emtricitabine 200 mg once daily, tenofovir alafenamide 25 mg once daily). Insufficient data for weight <25 kg. |
| Geriatric use | No specific dose adjustment recommended; select dose with caution due to age-related decreased renal function. Monitor renal function (CrCl) prior to and during therapy. |
| 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 is excreted in human milk with a milk-to-plasma ratio of 0.03; emtricitabine has an M/P ratio of 1.0; tenofovir alafenamide is excreted in negligible amounts. Breastfeeding is not recommended due to potential for viral transmission and adverse effects, but if unavoidable, the benefits may outweigh risks. |
| Teratogenic Risk |
■ FDA Black Box 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 products containing emtricitabine and/or tenofovir alafenamide. Hepatic function should be monitored closely in these patients.
| Common Effects | Hepatitis B |
| Serious Effects |
["Concurrent use with dofetilide (due to dolutegravir inhibition of OCT2 leading to increased dofetilide levels and risk of arrhythmia)","Coadministration with rifampin (reduces dolutegravir concentrations significantly)"]
| Precautions | ["Hepatotoxicity: Monitor liver enzymes; risk of hepatitis B exacerbation upon discontinuation.","Lactic acidosis/severe hepatomegaly with steatosis: Reported with NRTIs, including emtricitabine and tenofovir.","Renal impairment: Not recommended in patients with CrCl <30 mL/min for fixed-dose combination; monitor renal function.","Immune reconstitution syndrome: May occur during combination antiretroviral therapy.","Decrease in bone mineral density: Observed with tenofovir alafenamide; monitor if history of pathological fracture or osteoporosis."] |
Loading safety data…
| Dolutegravir is associated with an increased risk of neural tube defects when used at conception and during the first trimester. Emtricitabine and tenofovir alafenamide are generally considered low risk, but data are limited. In the second and third trimesters, the risk is not significantly elevated. |
| Fetal Monitoring | Monitor HIV viral load, CD4 count, complete blood count, renal function (serum creatinine, eGFR, urine protein), hepatic function, and fetal ultrasound for neural tube defects during first trimester. Consider therapeutic drug monitoring for dolutegravir. |
| Fertility Effects | No significant impairment in fertility reported for these agents in animal studies. Dolutegravir may reduce ovarian response in some women; clinical significance unknown. |