Ver el código de «Lopinavir»

==Background==

Lopinavir is a [[Special:MyLanguage/HIV|HIV]] protease inhibitor always given in combination with low-dose [[Special:MyLanguage/ritonavir|ritonavir]] (which boosts lopinavir plasma levels by inhibiting CYP3A4 metabolism). Although previously a preferred first-line protease inhibitor, lopinavir/ritonavir is '''no longer recommended for treatment-naive adults''' due to higher pill burden, GI intolerance, and metabolic side effects compared to newer alternatives (e.g., boosted darunavir, dolutegravir-based regimens).<ref name="NIH">HIVinfo. Kaletra Patient Drug Record. National Institutes of Health. https://clinicalinfo.hiv.gov/en/drugs/lopinavir-ritonavir/patient</ref> It remains in use in some resource-limited settings as a second-line option and in select pediatric populations.<ref name="aidsmap">Lopinavir/ritonavir. aidsmap. https://www.aidsmap.com/about-hiv/arv-background-information/lopinavirritonavir</ref>

Lopinavir/ritonavir was studied for COVID-19 treatment early in the pandemic. Multiple large randomized trials (RECOVERY, WHO SOLIDARITY) have '''definitively shown no clinical benefit''' for hospitalized COVID-19 patients (see Comments section).<ref name="RECOVERY">RECOVERY Collaborative Group. Lopinavir-ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2020;396(10259):1345-1352.</ref><ref name="SOLIDARITY">WHO Solidarity Trial Consortium. Repurposed Antiviral Drugs for Covid-19 — Interim WHO Solidarity Trial Results. N Engl J Med. 2021;384(6):497-511.</ref>

==Administration==

*Type: [[Special:MyLanguage/antiviral|Antiviral]] (HIV protease inhibitor, boosted)
*Dosage Forms: 100 mg/25 mg, 200 mg/50 mg (tabs); oral solution 80 mg/20 mg per mL (400 mg/100 mg per 5 mL)
**'''Oral solution contains 42.4% alcohol (v/v) and 15.3% propylene glycol (w/v)''' — relevant for neonates, pregnancy, and patients on metronidazole or disulfiram<ref name="FDAlabel">KALETRA (lopinavir and ritonavir) [package insert]. AbbVie Inc. FDA label. 2016.</ref>
*Routes of Administration: PO
*Common Trade Names: Kaletra (lopinavir/ritonavir)
*Tablets can be taken with or without food; '''oral solution should be taken with food'''<ref name="FDAlabel"/>

==Adult Dosing==

*[[Special:MyLanguage/HIV|HIV]] treatment
**400 mg/100 mg PO BID
**Once-daily dosing (800 mg/200 mg) may be used in treatment-naive patients not receiving efavirenz, nevirapine, nelfinavir, or amprenavir<ref name="FDAlabel"/>
**Dose may need to be increased when used in combination with efavirenz or nevirapine (500 mg/125 mg PO BID or 533 mg/133 mg PO BID with solution)<ref name="FDAlabel"/>
*[[Special:MyLanguage/HIV post-exposure prophylaxis|HIV post-exposure prophylaxis]]
**400 mg/100 mg PO BID (typically for 28 days as part of a 3-drug regimen)
**Note: Lopinavir/ritonavir is no longer a preferred PEP regimen in most current guidelines; newer integrase inhibitor-based regimens (e.g., dolutegravir or raltegravir) are preferred when available

==Pediatric Dosing==

*[[Special:MyLanguage/HIV|HIV]] treatment
**14 days-12 months old: 16 mg/4 mg/kg PO BID (solution)
**13 months and older, <15 kg:
***Treatment-naive: 12 mg/3 mg/kg PO BID (solution)
***Treatment-experienced: 13 mg/3.25 mg/kg PO BID (solution)
**13 months and older, 15-45 kg: 11 mg/2.75 mg/kg PO BID (solution)
**13 months and older, >45 kg: 400 mg/100 mg PO BID
**Children <18 years should NOT use once-daily dosing<ref name="FDAlabel"/>
*[[Special:MyLanguage/HIV post-exposure prophylaxis|HIV post-exposure prophylaxis]]
**14 days-12 months old: 16 mg/4 mg/kg PO BID (solution)
**13 months and older, <15 kg: 12 mg/3 mg/kg PO BID (solution)
**13 months and older, 15-40 kg: 10 mg/2.5 mg/kg PO BID (solution)
**13 months and older, >40 kg: 400 mg/100 mg PO BID

==Special Populations==

===Pregnancy===

*Tablets may be used in pregnancy
*'''Oral solution is CONTRAINDICATED in pregnancy''' due to high alcohol (42.4%) and propylene glycol content — no safe level of alcohol exposure during pregnancy<ref name="FDAlabel"/>
*No adequate well-controlled studies; weigh risks/benefits; enrollment in the Antiretroviral Pregnancy Registry is encouraged

===Lactation===

*Women with HIV should NOT breastfeed (risk of HIV transmission to infant via breast milk regardless of viral load)<ref name="FDAlabel"/>

===Renal Dosing===

*No adjustment required<ref name="FDAlabel"/>

===Hepatic Dosing===

*Not studied; use with caution in hepatic impairment
*Lopinavir is primarily hepatically metabolized — plasma levels may be increased<ref name="FDAlabel"/>
*Contraindicated in severe hepatic impairment (for tablet formulation)

==Contraindications==

*Allergy to lopinavir or ritonavir
*'''Neonates <14 days postnatal age''' (or <42 weeks postmenstrual age) due to toxicity risk from alcohol and propylene glycol in the oral solution<ref name="FDAlabel"/>
*Congenital [[Special:MyLanguage/Long QT syndrome|long QT syndrome]]
*[[Special:MyLanguage/Hypokalemia|Hypokalemia]] (uncorrected)
*Co-administration with drugs highly dependent on CYP3A4 for clearance where elevated levels may cause serious or life-threatening events (see Drug Interactions)

==Drug Interactions==

'''This is a critically important section for emergency physicians'''

*Lopinavir/ritonavir is a '''potent CYP3A4 inhibitor''' and a '''P-glycoprotein inhibitor''' — it significantly increases levels of many co-administered drugs<ref name="FDAlabel"/>
*'''Contraindicated combinations''' (risk of serious/life-threatening reactions):
**[[Special:MyLanguage/Amiodarone|Amiodarone]], [[Special:MyLanguage/flecainide|flecainide]] (cardiac arrhythmias)
**[[Special:MyLanguage/Ergotamine|Ergotamine]], dihydroergotamine (ergotism/vasospasm)
**[[Special:MyLanguage/Midazolam|Oral midazolam]], [[Special:MyLanguage/triazolam|triazolam]] (prolonged sedation) — '''IV midazolam may be used with caution and monitoring'''
**[[Special:MyLanguage/Simvastatin|Simvastatin]], [[Special:MyLanguage/lovastatin|lovastatin]] (rhabdomyolysis)
**Sildenafil when used for pulmonary arterial hypertension
**Rifampin (substantially decreases lopinavir levels)
*'''Clinically significant interactions:'''
**[[Special:MyLanguage/Warfarin|Warfarin]] — monitor INR closely
**[[Special:MyLanguage/Methadone|Methadone]] — decreased methadone levels; may precipitate withdrawal
**Oral contraceptives — ethinyl estradiol levels decreased; use alternative/additional contraception
**[[Special:MyLanguage/Fentanyl|Fentanyl]] — increased fentanyl levels; risk of respiratory depression
**Colchicine — dose reduction required; contraindicated in renal/hepatic impairment

==Adverse Reactions==

===Serious===

*QT prolongation/[[Special:MyLanguage/Torsade de pointes|Torsade de pointes]]
*PR prolongation/AV block (2nd or 3rd degree reported)
*[[Special:MyLanguage/Pancreatitis|Pancreatitis]] (can be fatal; suspend therapy if suspected)
*Hepatotoxicity (elevated transaminases ± bilirubin; monitor LFTs)
*Hyperglycemia/new-onset [[Special:MyLanguage/diabetes mellitus|diabetes mellitus]]
*Hypercholesterolemia/hypertriglyceridemia
*[[Special:MyLanguage/Immune reconstitution syndrome|Immune reconstitution inflammatory syndrome]]
*[[Special:MyLanguage/Stevens-Johnson syndrome|Stevens-Johnson syndrome]] / [[Special:MyLanguage/Toxic epidermal necrolysis|toxic epidermal necrolysis]]
*Angioedema
*Hemolytic anemia
*'''Neonatal toxicity''' — life-threatening cardiac toxicity, lactic acidosis, renal failure, and CNS depression reported in premature neonates receiving the oral solution<ref name="FDAlabel"/>

===Common===

*[[Special:MyLanguage/Diarrhea|Diarrhea]] (most common; up to 27% moderate-severe)
*[[Special:MyLanguage/Nausea|Nausea/vomiting]] (up to 16%)
*Abdominal pain
*[[Special:MyLanguage/Dysgeusia|Dysgeusia]]
*Fatigue/asthenia
*Headache
*Rash
*AST, ALT, GGT, CK elevation
*Lipodystrophy (with prolonged use)

==Pharmacology==

*Half-life: 5-6 hours
*Metabolism: Hepatic, primarily via '''CYP3A4''' (ritonavir inhibits CYP3A4, markedly boosting lopinavir levels)
*Excretion: Primarily fecal (~83%); renal (~11%)
*Protein binding: 98-99% (bound to albumin and alpha-1-acid glycoprotein)

==Mechanism of Action==

Lopinavir binds to the active site of HIV-1 protease, preventing cleavage of viral Gag-Pol polyprotein precursors into mature, functional proteins required for viral assembly. This results in production of immature, non-infectious viral particles. Ritonavir serves as a pharmacokinetic booster by inhibiting CYP3A4-mediated metabolism of lopinavir, increasing its plasma half-life and trough concentrations.

==Comments==

===COVID-19: No Benefit Demonstrated===

Lopinavir/ritonavir was investigated for COVID-19 based on in-vitro activity against SARS-CoV-2 and prior data from SARS-CoV-1. Multiple large randomized controlled trials have now conclusively shown '''no clinical benefit''':

*'''RECOVERY trial''' (N=4,970): No significant difference in 28-day mortality (23% lopinavir/ritonavir vs 22% usual care; RR 1.03, 95% CI 0.91-1.17; p=0.60). No benefit in time to discharge or risk of progression to mechanical ventilation.<ref name="RECOVERY"/>
*'''WHO SOLIDARITY trial''' (>11,000 patients): No reduction in mortality, initiation of ventilation, or duration of hospitalization.<ref name="SOLIDARITY"/>
*'''Cao et al.''' (N=199, the initial Chinese RCT): No benefit in time to clinical improvement (HR 1.31, 95% CI 0.95-1.80).<ref name="Cao2020">Cao B, Wang Y, Wen D, et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med. 2020;382(19):1787-1799. doi:10.1056/NEJMoa2001282</ref>

Based on these results, '''WHO halted the lopinavir/ritonavir arms of the SOLIDARITY trial in 2020''', and lopinavir/ritonavir is '''not recommended for COVID-19 treatment'''.<ref name="RECOVERY"/><ref name="SOLIDARITY"/>

==See Also==

*[[Special:MyLanguage/HIV|HIV]]
*[[Special:MyLanguage/Ritonavir|Ritonavir]]
*[[Special:MyLanguage/HIV post-exposure prophylaxis|HIV post-exposure prophylaxis]]
*[[Special:MyLanguage/Antiretrovirals|Antiretrovirals]]

==References==
{{Reflist|2}}
[[Category:Pharmacology]]