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Drugs

, Volume 63, Issue 8, pp 769–802 | Cite as

Lopinavir/Ritonavir

A Review of its Use in the Management of HIV Infection
  • Risto S. CvetkovicEmail author
  • Karen L. Goa
Adis Drug Evaluation

Summary

Abstract

Lopinavir is a novel protease inhibitor (PI) developed from ritonavir. Coadministration with low-dose ritonavir significantly improves the pharmacokinetic properties and hence the activity of lopinavir against HIV-1 protease. Coformulated lopinavir/ritonavir was developed for ease of administration and to ensure both drugs are taken together, as part of combination therapy with other antiretroviral agents.

Coformulated lopinavir/ritonavir-based regimens provide adequate and durable suppression of viral load and sustained improvements in CD4+ cell counts, as demonstrated in randomised trials in antiretroviral therapy-naive and -experienced adults and children. To date, development of primary resistance to lopinavir/ ritonavir has not been observed in 470 antiretroviral therapy-naive patients treated for >48 weeks. The lopinavir/ritonavir-based regimen was more effective than nelfinavir in antiretroviral therapy-naive HIV-1-infected patients in a phase III trial. The coformulation is also effective as ‘salvage’ therapy, as shown by low cross-resistance rates in patients who failed to respond to treatment with other PIs in phase II trials.

Coformulated lopinavir/ritonavir was well tolerated in both antiretroviral therapy-naive and -experienced HIV-1-infected adults and children with low rates of study drug-related treatment discontinuations. The most common adverse event in adults associated with lopinavir/ritonavir was diarrhoea, followed by other gastrointestinal disturbances, asthenia, headache and skin rash. The incidence of moderate-to-severe adverse events in children was low, skin rash being the most common. Changes in body fat composition occurred with equal frequency in lopinavir/ritonavir- and nelfinavir-treated naive patients, through week 60 in a phase III study. Although laboratory abnormalities occurred with similar frequency in both treatment groups, triglycerides grade 3/4 elevations were significantly more frequent with lopinavir/ritonavir. Total cholesterol and triglycerides grade 3/ 4 elevations appear to occur more frequently in PI-experienced than in PI-naive lopinavir/ritonavir-treated patients.

A number of clinically important drug interactions have been reported with lopinavir/ritonavir necessitating dosage adjustments of lopinavir/ritonavir and/or the interacting drugs, and several other drugs are contraindicated in patients receiving the coformulation.

Conclusion: Coformulated lopinavir/ritonavir is a novel PI that, in combination with other antiretroviral agents, suppresses plasma viral load and enhances immunological status in therapy-naive and -experienced patients with HIV-1 infection. Lopinavir/ritonavir appears more effective than nelfinavir in ‘naive’ patients and is also suitable for ‘salvage’ therapy, because of its high barrier to development of resistance. Given its clinical efficacy, a tolerability profile in keeping with this class of drugs, favourable resistance profile and easy-to-adhere-to administration regimen, coformulated lopinavir/ritonavir should be regarded as a first-line option when including a PI in the management of HIV-1 infection.

Overview of Pharmacodynamic Properties

Lopinavir/ritonavir is a coformulation of two structurally related protease inhibitor (PI) antiretroviral agents. Lopinavir is a highly potent and selective inhibitor of the HIV type 1 (HIV-1) protease, an essential enzyme for production of mature, infective virus. It acts by arresting maturation of HIV-1 thereby blocking its infectivity. Thus, the main antiviral action of lopinavir is to prevent subsequent infections of susceptible cells; it has no effect on cells with already integrated viral DNA. Lopinavir has an ≈10-fold higher in vitro activity against both wild-type and mutant HIV-1 proteases than ritonavir; however, its in vivo activity is greatly attenuated by a high first-pass hepatic metabolism. The low-dose ritonavir coadministered with lopinavir inhibits metabolic inactivation of lopinavir and acts only as its pharmacokinetic enhancer. Therefore, the antiretroviral activity of coformulated lopinavir/ritonavir 400/100mg twice daily is derived solely from lopinavir plasma concentrations. Combining lopinavir with low-dose ritonavir produces lopinavir concentrations far exceeding those needed to suppress 50% of in vitro and in vivo viral replication in CD4+ cells and monocyte/macrophages (main human reservoirs of HIV-1 infection).

Thus far, no resistance to lopinavir has been detected in clinical trials in antiretroviral therapy-naive patients treated for up to 204 weeks and only 12% of HIV-1 strains from patients in whom prior treatment with multiple PIs have failed, have been observed to develop resistance to coformulated lopinavir/ritonavir. A strong negative correlation was found between the number of PI mutations at baseline and the viral response rates achieved with lopinavir/ritonavir-based regimens in PI-experienced patients, indicating that resistance to lopinavir increases with increasing number of PI mutations and that five PI mutations represent the clinically relevant genotypic breakpoint for lopinavir.

Overview of Pharmacokinetic Properties

The absolute bioavailability of lopinavir coformulated with ritonavir in humans has not yet been established. Multiple-dosage absorption pharmacokinetics of lopinavir/ritonavir 400/100mg twice daily (the mean peak [Cmax] and trough [Ctrough] plasma concentrations at steady-state and the 12-hour area under the plasma concentration-time curve [AUC12] of either drug) were stable in antiretroviral therapy-naive and single PI-experienced adult patients receiving therapy over a 24-week evaluation period. The Ctrough values of lopinavir, achieved with lopinavir/ritonavir 400/100mg twice daily, were median 84-fold higher than the protein binding-adjusted 50% effective concentration (EC50) of lopinavir against wild-type HIV-1 in antiretroviral therapy-naive HIV-1-infected patients in aphase II study.

Bioavailability of lopinavir administered in either the capsule or the liquid lopinavir/ritonavir formulation can be increased substantially with concurrent ingestion of food with moderate-to-high fat content. At steady state, lopinavir is ≈98–99% plasma protein bound and the percentage of its unbound (i.e. pharmacologically active) fraction is dependent on total drug plasma concentration. Both lopinavir and ritonavir penetrate poorly into the human genital tracts and the cerebrospinal fluid.

Both agents undergo extensive and rapid first-pass metabolism by hepatic cytochrome P450 (CYP) 3A4 isoenzyme. However, ritonavir also potently inhibits this enzyme and acts as a pharmacokinetic enhancer of lopinavir. The elimination half-life and apparent oral clearance of lopinavir average ≈4–6 hours and ≈6–7 L/h, respectively, with lopinavir/ritonavir 400/100mg twice daily administration. Less than 3% and 20% of the lopinavir dose is excreted unchanged in the urine and faeces, respectively. Limited data show similar pharmacokinetics of lopinavir in children as in adults.

Drug Interactions

Coformulated lopinavir/ritonavir has the potential to interact with wide variety of drugs via several mechanisms, mostly involving the CYP enzymes. Coadministration of lopinavir/ritonavir is contraindicated with certain drugs (i.e. flecainide, propafenone, astemizole, terfenadine, ergot derivatives, cisapride, pimozide, midazolam and triazolam) that are highly dependent on CYP3A or CYP2D6 for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. Coadministration with lopinavir/ritonavir is also not recommended for drugs or herbal products (i.e. rifampicin [rifampin] and St. John’s wort [Hypericum perforatum]) that may substantially reduce lopinavir plasma concentrations, or drugs whose plasma concentrations elevated by the coformulation may lead to serious adverse reactions (i.e. simvastatin and lovastatin). However, a recent study in healthy volunteers suggests that adequate lopinavir concentrations may be achieved during rifampicin coadministration by increasing the twice-daily dosage of lopinavir/ritonavir in conjunction with therapeutic drug monitoring. The liquid (but not the capsule) formulation of lopinavir/ ritonavir contains 42.4% ethanol (v/v) and should not be coadministered with drugs capable of producing disulfiram-like reactions (e.g. disulfiram, metronidazole).

Coadministration with saquinavir or indinavir requires no dosage adjustment, whereas coadministration with amprenavir, nevirapine or efavirenz requires a dosage increase of the coformulation typically by 33%. As the oral bioavailability of both didanosine and lopinavir/ritonavir is significantly affected by concurrent food ingestion, didanosine should be administered 1 hour before or 2 hours after lopinavir/ritonavir has been taken with food. Interactions between lopinavir/ ritonavir and other nucleoside reverse transcriptase inhibitors (NRTIs) are not expected.

The coformulation is also likely to increase plasma concentrations of non-antiretroviral drugs metabolised through the CYP3A pathway. To reduce the risk of their toxicity when coadministered with lopinavir/ritonavir, the recommended actions include: (i) monitoring of the drug plasma concentration (antiarrhythmics and immunosuppressants) or the international normalised ratio (warfarin); (ii) the use of alternative treatment (atorvastatin) or birth control methods (ethinylestradiol); and (iii) dosage adjustment (clarithromycin [only in patients with renal failure], rifabutin, dihydropyridine calcium-channel blockers, atorvastatin, ketoconazole and itraconazole). Coadministration of lopinavir/ritonavir 400/100mg twice daily significantly reduces the Cmax and AUC of methadone but does not appear to precipitate opioid withdrawal symptoms or require methadone dosage adjustment and could be useful in treatment of HIV-1-infected patients who are users of illicit intravenous narcotics. Drugs that induce CYP3A-mediated clearance of lopinavir and lower its plasma concentration should be used with caution (corticosteroids) or with dosage adjustment of lopinavir/ritonavir (carbamazepine, phenytoin and barbiturates) when coadministered with it.

No clinically significant interactions were observed during coadministration of norethindrone or pravastatin with lopinavir/ritonavir. Likewise, coadministration of rifabutin or ketoconazole does not require lopinavir/ritonavir dosage adjustment. Clinically significant interactions are not expected between lopinavir/ ritonavir and either fluvastatin, dapsone, cotrimoxazole, azithromycin, erythromycin or fluconazole.

Therapeutic Efficacy

The therapeutic efficacy of lopinavir/ritonavir in combination with other antiretroviral agents has been evaluated in several (both comparative and noncomparative) phase II/III clinical trials in antiretroviral therapy-naive and -experienced adults and children, and in two large (>11 000 participants) prospective, nonblind, noncomparative ‘salvage’ programmes in adults with HIV-1 infection. All trials used decreasing plasma HIV-1 RNA levels (viral load) and increasing CD4+ cell counts as surrogate markers of clinical drug efficacy. The effects of lopinavir/ritonavir on HIV-1- and AIDS-related morbidity and mortality are yet to be established.

Lopinavir coformulated with ritonavir in three different dose combinations (200/100mg, 400/100mg and 400/200mg) administered twice daily in combination with standard dosages of the two commonly used NRTIs (lamivudine and stavudine) induced a rapid decline in plasma HIV-1 RNA levels that was sustained throughout the 48-week study period (the mean reduction from baseline was 2.23 log10 copies/mL) in a phase II trial in 100 antiretroviral therapy-naive patients. In the nonblind extension of this study, lopinavir/ritonavir 400/100mg twice daily produced continued suppression of viral load <50 copies/mL in a substantial proportion of patients (70% and 97% by intent-to-treat and on-treatment analyses), and improved immunological status of patients through week 204 (the mean increase from baseline in CD4+ cell count was 440 cells/μL), regardless of patient’s baseline immune status.

The efficacy of lopinavir/ritonavir 400/100mg twice daily in combination with lamivudine and stavudine compared favourably with that of a nelfinavir (750mg three times daily)-based PI-triple (a PI plus two NRTIs) regimen in a large randomised, double-blind phase III study in 653 antiretroviral therapy-naive adults with HIV-1 infection. Lopinavir/ritonavir demonstrated significantly greater suppression of plasma HIV-1 RNA levels than nelfinavir, starting from week 20 (<400 copies/mL) and week 32 (<50 copies/mL) and persisting through weeks 48 and 60. Significantly more patients receiving lopinavir/ritonavir-based triple therapy maintained viral response at both timepoints than recipients of the nelfinavir-based regimen. Both drugs had similar overall effects on patients’ immune systems; however, in patients with a very poor immune responsiveness at baseline (CD4+ cell count <50 cells/μL), lopinavir/ritonavir induced a significantly greater increase in the mean CD4+ cell count compared with nelfinavir, after 60 weeks of treatment. Lopinavir/ritonavir-based therapy was equally as effective in female as in male patients with HIV-1 infection, with or without hepatitis B and/or C virus (HBV/HCV) co-infection.

In 70 patients experiencing virological failure with treatment regimens comprising a single PI, alone or combined with one or more NRTI, substitution of their prior PI with lopinavir/ritonavir (400/100mg or 400/200mg twice daily) produced rapid (within the first 2 weeks of treatment) viral suppression (viral load <400 copies/mL or >-1 log10 copies/mL reduction from baseline) in 80% of patients and rapid improvement in CD4+ cell count (increase was significant from week 8). These results were maintained at 48 weeks and for the duration of the study in patients who continued lopinavir/ritonavir-based salvage therapy, with no statistically significant differences recorded between the two lopinavir/ritonavir dosage combinations. At week 144, plasma HIV-1 RNA levels were suppressed below 400 copies/mL in at least half and below 50 copies/mL in almost half (49%) of the patients. All patients also received nevirapine and had their baseline NRTI regimen changed to include at least one NRTI they had not received previously.

A smaller randomised, nonblind phase II trial in multiple PI-experienced but non-nucleoside reverse transcriptase inhibitor (NNRTI)-naive HIV-infected adults (n = 57) found two lopinavir/ritonavir dosage combinations (400/100mg vs 533/133mg twice daily) to have similar efficacy at 24 weeks in an antiretroviral regimen containing efavirenz 600mg once daily and NRTIs of the investigators’ choice. In the noncomparative extension of the study, treatment with the lopinavir/ritonavir 533/133mg twice-daily regimen maintained a high level of viral load suppression and continued to improve the CD4+ cell count, throughout week 72. Baseline in vitro phenotypic and genotypic susceptibility to lopinavir of viral isolates had an important influence on virological response throughout the course of study (see Overview of Pharmacodynamic Properties summary).

The efficacy of lopinavir/ritonavir coformulation has also been evaluated in two large (>11 000 participants in 35 countries worldwide) prospective, nonblind, noncomparative ‘salvage’ programmes (the Expanded Access Program [EAP] and the ATU programme [Autorisation Temporaire d’ Utilisation] in HIV-1-infected adults who had failed to respond to and/or were intolerant to combinations of other available antiretroviral agents. Participants in both studies had significant prior exposure to both PIs and NNRTIs, and a large proportion had advanced disease on enrolment. In both studies patients received lopinavir/ ritonavir 400/100mg twice daily with the dosage increase to 533/133mg if concomitant treatment included nevirapine or efavirenz. After the first 24 weeks of treatment with lopinavir/ritonavir-based salvage regimens in the EAP, overall >50% of patients achieved a viral load of <-500 copies/m, with ≈75% of patients attaining at least 1 log10 copies/mL reduction from baseline. In the ATU programme, a similar percentage (≈72%) of patients achieved viral response (defined as plasma HIV-1 RNA level <400 copies/mL or >-1 log10 copies/mL decrease from baseline). An association was observed between the baseline lopinavir mutation score and the virological response to lopinavir/ritonavir-based treatment (see Overview of Pharmacodynamic Properties summary).

Data in children are limited to a nonblind, phase I/II study in antiretroviral therapy-naive (n = 44) and -experienced (n = 56) children (aged between 3 months and 12 years). All patients received regimens based on lopinavir/ritonavir 300/75 mg/m2 twice daily (increased from 230/57.5mg twice daily after 3 weeks). After 72 weeks, lopinavir/ritonavir-based regimens adequately suppressed plasma HIV-1 RNA levels in most patients in both groups, although overall responses tended to be lower in experienced patients. Immune status of patients in each group continually improved throughout the study.

Tolerability

Coformulated lopinavir/ritonavir appeared to be well tolerated in both antiretroviral therapy-naive and -experienced HIV-1-infected adults and children, in comparative and noncomparative clinical trials, which was reflected by the low rates of study drug-related discontinuation of therapy (i.e. 4–7% through 60–204 weeks of therapy across the four comparative phase II/III trials in adults and 1% through 72 weeks of therapy in a single trial in children). This rate of discontinuation was unaffected by baseline HBV/HCV status in a phase III study in adults.

The most frequently reported adverse event in adults, of at least moderate severity, was diarrhoea (12–31% incidence) in phase II/III clinical trials and in both antiretroviral therapy-naive and -experienced patients. Other less common complaints included other gastrointestinal disturbances (nausea, abdominal pain, vomiting), asthenia, headache and skin rash. The incidence of adverse events of at least moderate severity in children was low (11% overall); skin rash was the most common occurring in 2%, and allergic reactions, fever, viral infections, constipation, hepatomegaly, pancreatitis, vomiting, dry skin and taste perversion all occurred in 1% of patients. In the EAP, serious adverse events such as myocardial infarction, pancreatitis, lactic acidosis and hepatic failure were infrequent (<1%) during lopinavir/ritonavir therapy. Adverse events consistent with changes in body fat composition (including lipodystrophy, obesity and abdomen enlargement [2% each] and Cushingoid appearance, multiple lipomas and gynaecomastia [≤1% each]) were observed with equal frequency (7%) in lopinavir/ritonavir- or nelfinavir-treated ‘naive’ patients, through week 60 in the phase III study.

In the only phase III trial in adults, grade 3/4 laboratory abnormalities occurred with similar frequencies in lopinavir/ritonavir- and nelfinavir-treated ‘naive’ patients, except for the elevation in triglyceride levels, which occurred more frequently with lopinavir/ritonavir than with nelfinavir (11% vs 2%; p < 0.001). The incidence of grade 3/4 elevations in total cholesterol and triglycerides levels appears higher in PI-experienced than in antiretroviral therapy-naive patients receiving the coformulation, although evidence from direct comparison is still lacking. Biochemical abnormalities of grade 3/4 severity in children were infrequent (<6%).

Pharmacoeconomic Analyses

Thus far, cost consequences of initiating antiretroviral therapy with lopinavir/ ritonavir versus nelfinavir as the PI component in the triple regimen (in combination with lamivudine and stavudine) have been estimated in two pharmacoeconomic models. Both models analysed the results from a phase III study (see Therapeutic Efficacy summary) in 625 antiretroviral therapy-naive HIV-infected patients. Limited data from these analyses estimate a 60-week, 5-year and lifetime cost savings with coformulated lopinavir/ritonavir in comparison with nelfinavir based on higher treatment response rates achieved with the former drug. The estimated incremental cost effectiveness ratio with lopinavir/ritonavir was comparable to values calculated for generic antihypertensive drugs.

Dosage and Administration

Coformulated lopinavir/ritonavir is approved for use in both antiretroviral therapy-naive and -experienced patients. It is available for oral administration in capsule and liquid formulations. The recommended dosage for adults, in the US, for the treatment of HIV-1 infection is 400/100mg (three capsules or 5mL oral solution) twice daily, and the coformulation should be administered with meals of moderate-to-high fat content in order to improve its oral bioavailability. The drug is indicated for use only in combination with other antiretroviral agents.

A number of clinically important drug interactions have been reported with lopinavir/ritonavir, necessitating dosage adjustments of lopinavir/ritonavir and/or the interacting drugs, and several drugs are contraindicated in patients receiving the coformulation (see Drug Interactions summary). Lopinavir/ritonavir is classified under pregnancy category C in the US. It should be administered with caution in patients with hepatic impairment and with haemophilia A and B.

Keywords

Ritonavir Efavirenz Nevirapine Indinavir Saquinavir 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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  1. 1.Adis International LimitedMairangi Bay, Auckland 10New Zealand

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