Lopinavir/ritonavir

Lopinavir/ritonavir

Combination of
Lopinavir	Protease inhibitor
Ritonavir	Protease inhibitor
Clinical data
AHFS/Drugs.com	monograph
MedlinePlus	a602015
Pregnancy cat.	C (US)
Legal status	POM (UK) ℞-only (US)
Routes	Oral
Identifiers
CAS number	369372-47-4 N
ATC code	J05AR10
NIAID ChemDB	003688
N (what is this?)  (verify)

Lopinavir/ritonavir (INNs) is a fixed dose combination drug for the treatment of HIV infection. It combines lopinavir (not available as a single drug) with a sub-therapeutic dose of ritonavir (trade name Norvir) into a fixed-dose pill.

The combination is marketed by Abbott as Kaletra (high-income countries) and Aluvia (low-income countries), as a component of combination therapy to treat HIV/AIDS. The Kaletra formulation has also been used successfully as monotherapy in some studies.^[1]

As of 2006, lopinavir/ritonavir forms part of the preferred combination for first-line therapy recommended by the US DHHS.^[2] It is available as capsules, tablets and oral solution.

History

Lopinavir was developed by Abbott in an attempt to improve on the HIV resistance and serum protein-binding properties of the company's earlier protease inhibitor, ritonavir.^[3] Administered alone, lopinavir has insufficient bioavailability; however, like several HIV protease inhibitors, its blood levels are greatly increased by low doses of ritonavir, a potent inhibitor of cytochrome P450 3A4.^[3] Abbott therefore pursued a strategy of co-administering lopinavir with sub-therapeutic doses of ritonavir, and lopinavir is only marketed as a co-formulation with ritonavir. It is the first multi-drug capsule to contain a drug not available individually.

Lopinavir/ritonavir was approved by the USA FDA on 15 September 2000, and in Europe in April 2001. Its patent will expire in the US on June 26, 2016.

Abbott Laboratories was one of the earliest users of the Advanced Photon Source, a national synchrotron-radiation light source at Argonne National Laboratory. One of the early research projects undertaken at the Advanced Photon Source was the Human Immunodeficiency Virus. Using X-ray crystallography, researchers found the points of attack of the HIV protease inhibitors – agents that block the breakdown of proteins. Protease inhibitors stop HIV from making new copies of itself by blocking the last step in the process, when the virus attempts to replicate – and out of that discovery came the drug Kaletra/Aluvia.^[4]

Adverse effects

The most common adverse effects observed with lopinavir/ritonavir are diarrhea and nausea. In key clinical trials, moderate or severe diarrhea occurred in up to 27% of patients, and moderate/severe nausea in up to 16%.^[5] Other common adverse effects include abdominal pain, asthenia, headache, vomiting and, particularly in children, rash.^[5]

Raised liver enzymes and hyperlipidemia (both hypertriglyceridemia and hypercholesterolemia) are also commonly observed during lopinavir/ritonavir treatment.

Patients with a structural heart disease, preexisting conduction system abnormalities, ischaemic heart disease, or cardiomyopathies should use lopinavir/ritonavir with caution.^[6]

On 8 March 2011 the U.S. Food and Drug Administration notified healthcare professionals of serious health problems that have been reported in premature babies receiving lopinavir/ritonavir oral solution, probably because of its propylene glycol content. They recommend the use should be avoided in premature babies.^[7]

There have been reported cases of Kaletra causing hip dysplasia where due to lipodystrophy due to protease inhibitors the fat cells are redistributed to capillaries cutting off the blood supply to the femer bones of the hips.^{[medical citation needed]}

Access

As a result of high prices and the spread of HIV infection, the government of Thailand issued a compulsory license on 29 January 2007, to produce and/or import generic versions of lopinavir and ritonavir.^[8] In response, Abbott Laboratories withdrew its registration for lopinavir and seven of their other new drugs in Thailand, citing the Thai government's lack of respect for patents.^[9] Abbott's attitude has been denounced by several NGOs worldwide, including a netstrike initiated by Act Up-Paris and a public call to boycott all of Abbott's medicines by the French NGO AIDES.^[10]

References