Antiretroviral Therapy in HIV-infected Adults: Protease Inhibitors
In terms of antiviral activity, PIs inhibit the HIV protease enzyme, which is required for the proteolytic cleavage of viral polyprotein precursors. PIs bind to the active site on the HIV-1 protease enzyme and prevent the processing of viral GaG and GaG-pol polyprotein precursors. This results in the formation of immature, noninfectious viral particles.
Lopinavir/Ritonavir
PIs are indicated for use in conjunction with other antiretroviral agents to treat HIV infection. Lopinavir/ritonavir (LPV/RTV) was the second FDA-approved antiretroviral formulation that used a combination of two drugs from the same class. However, unlike the combination of ZDV + 3TC or ZDV + 3TC + ABC, only LPV is primarily used in this combination because of its antiretroviral activity.
Ritonavir generic (RTV) is used at a decreased dosage because of its ability to inhibit CYP-450 metabolism of LPV, thus increasing LPV plasma levels. Although LPV/RTV is the only co-formulated product that combines a PI with RTV for the pharmacokinetic enhancement, other PI/RTV combinations have been studied to improve dosing schedules, reduce pill burdens, overcome resistance, and alleviate food restrictions.
Resistance
Information on resistance patterns associated with the use of LPV/RTV is more limited than that of the older PIs. HIV-1 isolates have been shown to develop reduced sensitivity to lopinavir in vitro. The presence of RTV does not appear to influence the selection of LPV-resistant viruses in vitro. Initial studies showed that the virologic response was associated with mutations at positions 10, 20, 24, 46, 53, 54, 63, 71, 82, 84, and 90 in HIV protease (P = .019). Of these mutations, F53L was the best predictor of virologic failure, but it was less highly associated with response than with the total number of mutations.
The degree of cross-resistance among PIs has varied, although virologic failure appears to increase with the number of previous PIs to which patients have been exposed.
Contraindications
LPV/RTV is contraindicated in all patients with known hypersensitivity to any of its components, including RTV. Concomitant administration of LPV/RTV is contraindicated with drugs that are highly dependent on CYP-3A or CYP-2D6 for clearance and with drugs in which elevated plasma levels are associated with serious or life-threatening events. These drugs include the following:
- antiarrhythmic agents (e.g., flecainide acetate [Tambo-cor™, 3M] and propafenone [Rythmol®, Knoll])
- antihistamines (e.g., terfenadine [Seldane®, Marion Merrell Dow])
- ergot derivatives (e.g., dihydroergotamine mesylate [DHE 45® and Migranal®, Novartis], ergonovine [Ergotrate], ergotamine [e.g., Wigraine®, Organon] and methylergonovine maleate [Methergine®, Novartis])
- gastrointestinal motility agents (e.g., cisapride [Propulsid®, Janssen])
- neuroleptic agents (e.g., pimozide [Orap®, Gate])
- sedatives/hypnotics (e.g., midazolam and triazolam)
Warnings and Precautions
Caution must be exercised when LPV/RTV is administered with drugs that are metabolized primarily by the CYP-3A or CYP-2D6 hepatic isoenzymes. LPV/RTV can inhibit hepatic metabolism and may result in increased plasma concentrations of the affected drug. Concurrent administration of sildenafil (Viagra generic, Pfizer) and LPV/RTV is expected to substantially increase sildenafil canadian concentrations and may increase the potential for adverse events.
Concomitant use with lovastatin or drug simvastatin (e.g., Mevacor® or Zocor generic, Merck), and St. John’s wort (Hypericum perforatum) are not recommended. When LPV/RTV is used with lovastatin or simvastatin canadian, there is the potential for serious reactions such as myopathy, including rhabdomyolysis. Pancreatitis, hyperglycemia, diabetes mellitus, and lipid abnormalities have been observed in patients taking LPV/RTV. Suspension of antiretroviral therapy should be considered in patients with suspected pancreatitis.
Adverse Effects
Common or severe adverse effects associated with LPV/RTV include diarrhea, nausea, vomiting, rash, headache, asthenia, hyperglycemia, hypertriglyceridemia, and possible increased bleeding episodes in patients with hemophilia.
Drug Interactions
LPV/RTV, which is similar to other PIs such as NFV and amprenavir (AMP) (Agenerase®, GlaxoSmithKline), is both a substrate and an inhibitor of CPY-3A. This predisposes LPV/RTV to a number of drug interactions (see “Warnings and Precautions”). Some common potential drug interactions are included in Table 9.
Table 9 Drug Interactions between Lopinavir/Ritonavir (LPV/RTV) and Selected Drugs
| Drug | Lopinavir/Ritonavir (Kaletra®) |
| Nevirapine
(Viramune®, Roxane) |
Decreased LPV concentration:
Increase dose to 533/133 mg (four capsules or 6.5 ml). |
| Efavirenz drug(Sustiva generic, Bristol-Myers Squibb) | Decreased LPV concentration:
Increase dose to 533/133 mg (four capsules or 6.5 ml). |
| Delavirdine
(Rescriptor®, Pharmacia & Upjohn) |
Increased LPV concentration:
Dose not yet established. |
| Rifampin
(e.g., Rifadin®, Aventis) |
Decreased LPV concentration:
Coadministration contraindicated. |
| Rifabutin
(Mycobutin®, Pharmacia & Upjohn) |
Increased rifabutin and metabolite concentrations:
Reduce rifabutin dose by at least 75% of usual amount; monitor patients closely for adverse events. |
| Ethinyl estradiol | Decreased ethinyl estradiol concentration:
Use alternative or additional contraceptive measures. |
| Ketoconazole canadian(Nizoral generic, Janssen) | Increased ketoconazole generic concentration:High doses of ketoconazole (>200 mg/day) are not recommended. |
| Anticonvulsants: carbamazepine drug (e.g., Carbatrol drug, Shire), phenytoin (Dilantin®, Pfizer), phenobarbital (e.g., Donnatal®, PBM) | Decreased LPV concentrations:
Use with caution; LPV/RTV may be less effective when used in combination with anticonvulsants. |
| Sildenafil citrate (Viagra tablet, Pfizer) | Increased sildenafil levels:
Use with caution at reduced doses of 25 mg every 48 hours; monitor patients closely for adverse events. |
| HMG-CoA reductase inhibitors (e.g., atorvastatin [Lipitor®, Pfizer]) | Increased atorvastatin levels:
Use lowest possible dose of drug with careful monitoring, or consider other agents. |
| Methadone
(Dolophine®, Roxane) |
Decreased methadone concentrations:
May need to increase methadone dosage; monitor patients closely. |
| Adapted from Panel on Clinical Practices for Treatment of HIV Infection and product information for Kaletra®, Abbott Laboratories.40 | |
Pharmacokinetics
The key pharmacokinetic properties of LPV/RTV are summarized in Table 10.
Table 10 Pharmacokinetics of Lopinavir/Ritonavir (LPV/RTV)
| Lopinavir/Ritonavir (Kaletra®) | |
|
Absorption |
After 400/100 mg b.i.d. for three to four weeks, mean LPV Cmax was 9.6 +4.4 mcg/ml; trough concentrations were 5.5 ± 4.0 mcg/ml. |
|
Distribution |
At steady state, LPV is approximately 98% to 99% protein-bound. |
|
Metabolism |
LPV undergoes extensive hepatic metabolism, almost exclusively by the CYP-3A isoenzyme. RTV is a potent inhibitor of this enzyme, thus increasing LPV levels. |
|
Elimination |
Urine: 10.4 ±2.3%
Feces: 82.6 ± 2.5% |
| b.i.d. = twice a day; Cmax = maximum concentration of drug; ml = milliliter. Adapted from Panel on Clinical Practices for Treatment of HIV Infection6 and product information for Kaletra®, Abbott Laboratories. | |
