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NEWS AND NEW DEVELOPMENTS

FDA Approves Lopinavir/Ritonavir (Kaletra): On September 15, 2000 the FDA approved Lopinavir/Ritonavir. This appears to be the only antiretroviral agent that will be FDA approved this year. The drug profile is provided below:

Lopinavir/Ritonavir

Trade name: Kaletra (Abbott)

Formulation: 133.3 mg lopinavir and 33.3 mg of ritonavir per capsule.
80 mg lopinavir and 20 mg ritonavir per milliliter (oral solution)
Oral solution contains 42.4% alcohol

Price: $3.76/cap or $22.56/day and $677/month; oral liquid: $338.55/160mL bottle

Patient assistance program: (800) 659-9050

Product information: (800) 633-9110

Class: Protease inhibitor

Dosage: Lopinavir 400 mg/ritonavir 100 mg (3 capsules or 5 ml) twice daily with food

Price: $3.76/cap or $22.56/day and $677/month; oral liquid: $338.55/160ml bottle.

Pharmacology

Bioavailability: Kaletra capsule and oral solution when administered with a moderate fat meal (23-25% of calories from fat) resulted in an increased in bioavailability of 48% and 80%, respectively. It is recommended to take Kaletra with food to maximize bioavailability.
Protein binding: High protein binding, 98-99%.
Metabolism: Lopinavir undergoes extensive oxidative metabolism, almost exclusively by CYP3A isozyme.
Elimination: Half-life= 5-6 hours. Primarily biliary excretion with less than 3% excreted unchanged in the urine.

Drug interactions: Lopinavir/ritonavir inhibits CYP3A and to a lesser extent CYP2D6.

Drugs that are contraindicated with lopinavir/ritonavir: Flecainide, propafenone, astemizole, terfenadine, dihydroergotamine, ergonovine, ergotamine, methylergonovine, cisapride, pimozide, midazolam, triazolam.
Drugs that should not be co-administered with lopinavir/ritonavir: Rifampin, hypericum perforatum (St John's wort), lovastatin and simvastatin

Effects of drug interactions with lopinavir/ritonavir and dosage recommendations:
Co-administered drug	Effects on Co-administered drug	Effects on lopinavir (LPV)	Dosage recommendation
Amprenavir (APV)		Not reported	APV 750 mg bid/ LPV/r 400mg/100mg bid
Atorvastatin	AUC by 6-fold	No change	Start with lowest possible dose of atorvastatin; monitor for myopathy including rhabdomyolysis
Efavirenz (EFV)	No change	Cmin by 39%	LPV/r 533mg/133mg bid EFV 600 mg qhs
Ethinyl Estradiol	AUC by 42%	Not reported	Recommend an alternative form of contraception.
Indinavir	Cmin by 2.9-fold	Not reported	IDV 600 mg bid/ LPV/r 400mg/100mg bid
Ketoconazole	Cmax=unchanged AUC=by 3-fold	No change	Usual dose, clinical significance not known
Methadone	AUC by 53%	Not reported	Monitor for methadone withdrawal; increase methadone accordingly
Nevirapine	No change	Cmin by 55%	LPV/r 533mg/133mg bid NVP usual dose
Norethindrone	AUC; Cmin by 32%	Not reported	Recommend an alternative form of contraception
Pravastatin	No change	Not reported	Pravastatin or fluvastatin are the preferred HMG-CoA Reductase inhibitor when used with Lopinavir/ritonavir.
Rifabutin	Cmin by 4.9-fold	No change	Rifabutin 150 mg qod/ LPV/r 400mg/100 mg bid
Rifampin	Not reported	Cmin by 99%	Co-administration not recommended.
Saquinavir	Cmin by 3.55-fold	Not reported	SQV 800 mg bid/ LPV/r 400mg/100 mg bid

Adverse reactions:
The most common adverse event is diarrhea in 13.8% to 23.8% of patients. Nausea, vomiting, abdominal pain, asthenia, headache and rash have also been reported. Like other protease inhibitor, class adverse events such as hyperlipidemia, fat redistribution and hyperglycemia are possible.

Pregnancy: Category C. No treatment-related malformation seen in animal studies. No embryonic and fetal development toxicities seen in rabbits. No human data available.

Clinical Trials: Lopinavir (LPV) serum levels exceed the IC50 by over 25-fold throughout the dosing interval. This enhanced pharmacokinetic profile will enable lopinavir to have activity against some PI resistant strains and may have advantages for initial therapy based on pharmacokinetics and favorable side effect profile.

A phase III trial compared lopinavir/ritonavir (LPV/r) vs. nelfinavir (NFV), each with d4T + 3TC, in 693 treatment na�ve patients [40th ICAAC, Sept 17-20, 2000, Abstract #693]. The 40 week data by intent to treat analysis showed a VL<50 c/ml in 70% of LPV/r recipients compared to 54% in the NFV arm (p=<0.001). By on-treatment analysis, the data for <50 c/ml were 84 and 70%, respectively.

A trial of 57 patients with virologic failure to a PI containing regimen compared two doses of LPV/r: 400/100 mg bid (3 caps bid) vs. 533/133 mg bid (4 caps bid), each in combination with EFV, 600 mg qhs and 2 NRTIs [40th ICAAC, Sept 17-20, 2000, Abstract #697]. Results at 24 weeks showed a VL <50 c/ml in 72% by on-treatment analysis and 62 and 64% by intent-to-treat analysis. This favorable response was noted even in patients who had multiple mutations showing PI resistance and good responses with strains that showed <40-fold reduction in LPV resistance. posted 10/2/2000

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