Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061 Ludwigshafen, Germany
Pharmaco-therapeutic group: antivirals for systemic use, antivirals for treatment of HIV infections, combinations
ATC code: J05AR10
Lopinavir provides the antiviral activity of Kaletra. Lopinavir is an inhibitor of the HIV-1 and HIV-2 proteases. Inhibition of HIV protease prevents cleavage of the gag-pol polyprotein resulting in the production of immature, non-infectious virus.
QTcF interval was evaluated in a randomised, placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 39 healthy adults, with 10 measurements over 12 hours on Day 3. The maximum mean (95% upper confidence bound) differences in QTcF from placebo were 3.6 (6.3) and 13.1(15.8) for 400/100 mg twice daily and supratherapeutic 800/200 mg twice daily LPV/r, respectively. The induced QRS interval prolongation from 6 ms to 9.5 ms with high dose lopinavir/ritonavir (800/200 mg twice daily) contributes to QT prolongation. The two regimens resulted in exposures on Day 3 which were approximately 1.5 and 3-fold higher than those observed with recommended once daily or twice daily LPV/r doses at steady state. No subject experienced an increase in QTcF of ≥60 ms from baseline or a QTcF interval exceeding the potentially clinically relevant threshold of 500 ms.
Modest prolongation of the PR interval was also noted in subjects receiving lopinavir/ritonavir in the same study on Day 3. The mean changes from baseline in PR interval ranged from 11.6 ms to 24.4 ms in the 12 hour interval post dose. Maximum PR interval was 286 ms and no second or third degree heart block was observed (see section 4.4).
The in vitro antiviral activity of lopinavir against laboratory and clinical HIV strains was evaluated in acutely infected lymphoblastic cell lines and peripheral blood lymphocytes, respectively. In the absence of human serum, the mean IC50 of lopinavir against five different HIV-1 laboratory strains was 19 nM. In the absence and presence of 50% human serum, the mean IC50 of lopinavir against HIV-1IIIB in MT4 cells was 17 nM and 102 nM, respectively. In the absence of human serum, the mean IC50 of lopinavir was 6.5 nM against several HIV-1 clinical isolates.
HIV-1 isolates with reduced susceptibility to lopinavir have been selected in vitro. HIV-1 has been passaged in vitro with lopinavir alone and with lopinavir plus ritonavir at concentration ratios representing the range of plasma concentration ratios observed during Kaletra therapy. Genotypic and phenotypic analysis of viruses selected in these passages suggest that the presence of ritonavir, at these concentration ratios, does not measurably influence the selection of lopinavir-resistant viruses. Overall, the in vitro characterisation of phenotypic cross-resistance between lopinavir and other protease inhibitors suggest that decreased susceptibility to lopinavir correlated closely with decreased susceptibility to ritonavir and indinavir, but did not correlate closely with decreased susceptibility to amprenavir, saquinavir, and nelfinavir.
In clinical studies with a limited number of isolates analysed, the selection of resistance to lopinavir has not been observed in naïve patients without significant protease inhibitor resistance at baseline. See further the detailed description of the clinical studies.
The selection of resistance to lopinavir in patients having failed prior protease inhibitor therapy was characterised by analysing the longitudinal isolates from 19 protease inhibitor-experienced subjects in 2 Phase II and one Phase III studies who either experienced incomplete virologic suppression or viral rebound subsequent to initial response to Kaletra and who demonstrated incremental in vitro resistance between baseline and rebound (defined as emergence of new mutations or 2-fold change in phenotypic susceptibility to lopinavir). Incremental resistance was most common in subjects whose baseline isolates had several protease inhibitor-associated mutations, but <40-fold reduced susceptibility to lopinavir at baseline. Mutations V82A, I54V and M46I emerged most frequently. Mutations L33F, I50V and V32I combined with I47V/A were also observed. The 19 isolates demonstrated a 4.3-fold increase in IC50 compared to baseline isolates (from 6.2- to 43-fold, compared to wild-type virus).
Genotypic correlates of reduced phenotypic susceptibility to lopinavir in viruses selected by other protease inhibitors. The in vitro antiviral activity of lopinavir against 112 clinical isolates taken from patients failing therapy with one or more protease inhibitors was assessed. Within this panel, the following mutations in HIV protease were associated with reduced in vitro susceptibility to lopinavir: L10F/I/R/V, K20M/R, L24I, M46I/L, F53L, I54L/T/V, L63P, A71I/L/T/V, V82A/F/T, I84V and L90M. The median EC50 of lopinavir against isolates with 0−3, 4−5, 6−7 and 8−10 mutations at the above amino acid positions was 0.8, 2.7 13.5 and 44.0-fold higher than the EC50 against wild type HIV, respectively. The 16 viruses that displayed >20-fold change in susceptibility all contained mutations at positions 10, 54, 63 plus 82 and/or 84. In addition, they contained a median of 3 mutations at amino acid positions 20, 24, 46, 53, 71 and 90. In addition to the mutations described above, mutations V32I and I47A have been observed in rebound isolates with reduced lopinavir susceptibility from protease inhibitor experienced patients receiving Kaletra therapy, and mutations I47A and L76V have been observed in rebound isolates with reduced lopinavir susceptibility from patients receiving Kaletra therapy.
Conclusions regarding the relevance of particular mutations or mutational patterns are subject to change with additional data, and it is recommended to always consult current interpretation systems for analysing resistance test results.
The clinical relevance of reduced in vitro susceptibility to lopinavir has been examined by assessing the virologic response to Kaletra therapy, with respect to baseline viral genotype and phenotype, in 56 patients previous failing therapy with multiple protease inhibitors. The EC50 of lopinavir against the 56 baseline viral isolates ranged from 0.6 to 96-fold higher than the EC50 against wild type HIV. After 48 weeks of treatment with Kaletra, efavirenz and nucleoside reverse transcriptase inhibitors, plasma HIV RNA ≤400 copies/ml was observed in 93% (25/27), 73% (11/15), and 25% (2/8) of patients with <10-fold, 10 to 40-fold, and >40-fold reduced susceptibility to lopinavir at baseline, respectively. In addition, virologic response was observed in 91% (21/23), 71% (15/21) and 33% (2/6) patients with 0−5, 6−7, and 8−10 mutations of the above mutations in HIV protease associated with reduced in vitro susceptibility to lopinavir. Since these patients had not previously been exposed to either Kaletra or efavirenz, part of the response may be attributed to the antiviral activity of efavirenz, particularly in patients harbouring highly lopinavir resistant virus. The study did not contain a control arm of patients not receiving Kaletra.
Activity of other protease inhibitors against isolates that developed incremental resistance to lopinavir after Kaletra therapy in protease inhibitor experienced patients: The presence of cross resistance to other protease inhibitors was analysed in 18 rebound isolates that had demonstrated evolution of resistance to lopinavir during 3 Phase II and one Phase III studies of Kaletra in protease inhibitorexperienced patients. The median fold IC50 of lopinavir for these 18 isolates at baseline and rebound was 6.9- and 63-fold, respectively, compared to wild type virus. In general, rebound isolates either retained (if cross-resistant at baseline) or developed significant cross-resistance to indinavir, saquinavir and atazanavir. Modest decreases in amprenavir activity were noted with a median increase of IC50 from 3.7- to 8-fold in the baseline and rebound isolates, respectively. Isolates retained susceptibility to tipranavir with a median increase of IC50 in baseline and rebound isolates of 1.9- and 1.8–fold, respectively, compared to wild type virus. Please refer to the Aptivus Summary of Product Characteristics for additional information on the use of tipranavir, including genotypic predictors of response, in treatment of lopinavir-resistant HIV-1 infection.
The effects of Kaletra (in combination with other antiretroviral agents) on biological markers (plasma HIV RNA levels and CD4+ T-cell counts) have been investigated in controlled studies of Kaletra of 48 to 360 weeks duration.
Study M98-863 was a randomised, double-blind trial of 653 antiretroviral treatment naïve patients investigating Kaletra (400/100 mg twice daily) compared to nelfinavir (750 mg three times daily) plus stavudine and lamivudine. Mean baseline CD4+ T-cell count was 259 cells/mm³ (range: 2 to 949 cells/mm³) and mean baseline plasma HIV-1 RNA was 4.9 log10 copies/ml (range: 2.6 to 6.8 log10 copies/ml).
Table 1:
| Outcomes at Week 48: Study M98-863 | ||
|---|---|---|
| Kaletra (N=326) | Nelfinavir (N=327) | |
| HIV RNA <400 copies/ml* | 75% | 63% |
| HIV RNA <50 copies/ml†* | 67% | 52% |
| Mean increase from baseline in CD4+ T-cell count (cells/mm³) | 207 | 195 |
* intent to treat analysis where patients with missing values are considered virologic failures
† p<0.001
One-hundred thirteen nelfinavir-treated patients and 74 lopinavir/ritonavir-treated patients had an HIV RNA above 400 copies/ml while on treatment from Week 24 through Week 96. Of these, isolates from 96 nelfinavir-treated patients and 51 lopinavir/ritonavir-treated patients could be amplified for resistance testing. Resistance to nelfinavir, defined as the presence of the D30N or L90M mutation in protease, was observed in 41/96 (43%) patients. Resistance to lopinavir, defined as the presence of any primary or active site mutations in protease (see above), was observed in 0/51 (0%) patients. Lack of resistance to lopinavir was confirmed by phenotypic analysis.
Sustained virological response to Kaletra (in combination with nucleoside/nucleotide reverse transcriptase inhibitors) has been also observed in a small Phase II study (M97-720) through 360 weeks of treatment. One hundred patients were originally treated with Kaletra in the study (including 51 patients receiving 400/100 mg twice daily and 49 patients at either 200/100 mg twice daily or 400/200 mg twice daily). All patients converted to open-label Kaletra at the 400/100 mg twice daily dose between week 48 and week 72. Thirty-nine patients (39%) discontinued the study, including 16 (16%) discontinuations due to adverse events, one of which was associated with a death. Sixty-one patients completed the study (35 patients received the recommended 400/100 mg twice daily dose throughout the study).
Table 2:
| Outcomes at Week 360: Study M97-720 | |
|---|---|
| Kaletra (N=100) | |
| HIV RNA <400 copies/ml | 61% |
| HIV RNA <50 copies/ml | 59% |
| Mean increase from baseline in CD4+ T-cell count (cells/mm³) | 501 |
Through 360 weeks of treatment, genotypic analysis of viral isolates was successfully conducted in 19 of 28 patients with confirmed HIV RNA above 400 copies/ml revealed no primary or active site mutations in protease (amino acids at positions 8, 30, 32, 46, 47, 48, 50, 82, 84 and 90) or protease inhibitor phenotypic resistance.
Patients with prior antiretroviral therapy:
M97-765 is a randomised, double-blind trial evaluating Kaletra at two dose levels (400/100 mg and 400/200 mg, both twice daily) plus nevirapine (200 mg twice daily) and two nucleoside reverse transcriptase inhibitors in 70 single protease inhibitor experienced, non-nucleoside reverse transcriptase inhibitor naïve patients. Median baseline CD4 cell count was 349 cells/mm³ (range 72 to 807 cells/mm³) and median baseline plasma HIV-1 RNA was 4.0 log10 copies/ml (range 2.9 to 5.8 log10 copies/ml).
Table 3:
| Outcomes at Week 24: Study M97-765 | |
|---|---|
| Kaletra 400/100 mg (N=36) | |
| HIV RNA <400 copies/ml (ITT)* | 75% |
| HIV RNA <50 copies/ml (ITT)* | 58% |
| Mean increase from baseline in CD4+ T-cell count (cells/mm³) | 174 |
* intent to treat analysis where patients with missing values are considered virologic failures
M98-957 is a randomised, open-label study evaluating Kaletra treatment at two dose levels (400/100 mg and 533/133 mg, both twice daily) plus efavirenz (600 mg once daily) and nucleoside reverse transcriptase inhibitors in 57 multiple protease inhibitor experienced, non-nucleoside reverse transcriptase inhibitor naïve patients. Between week 24 and 48, patients randomised to a dose of 400/100 mg were converted to a dose of 533/133 mg. Median baseline CD4 cell count was 220 cells/mm³ (range13 to 1030 cells/mm³).
Table 4:
| Outcomes at Week 48: Study M98-957 | |
|---|---|
| Kaletra 400/100 mg (N=57) | |
| HIV RNA <400 copies/ml* | 65% |
| Mean increase from baseline in CD4+ T-cell count (cells/mm³) | 94 |
* intent to treat analysis where patients with missing values are considered virologic failures
M98-940 was an open-label study of a liquid formulation of Kaletra in 100 antiretroviral naïve (44%) and experienced (56%) paediatric patients. All patients were non-nucleoside reverse transcriptase inhibitor naïve. Patients were randomised to either 230 mg lopinavir/57.5 mg ritonavir per m² or 300 mg lopinavir/75 mg ritonavir per m². Naïve patients also received nucleoside reverse transcriptase inhibitors. Experienced patients received nevirapine plus up to two nucleoside reverse transcriptase inhibitors. Safety, efficacy and pharmacokinetic profiles of the two dose regimens were assessed after 3 weeks of therapy in each patient. Subsequently, all patients were continued on the 300/75 mg per m² dose. Patients had a mean age of 5 years (range 6 months to 12 years) with 14 patients less than 2 years old and 6 patients one year or less. Mean baseline CD4+ T-cell count was 838 cells/mm³ and mean baseline plasma HIV-1 RNA was 4.7 log10 copies/ml.
Table 5:
| Outcomes at Week 48: Study M98-940* | ||
|---|---|---|
| Antiretroviral Naïve (N=44) | Antiretroviral Experienced (N=56) | |
| HIV RNA <400 copies/ml | 84% | 75% |
| Mean increase from baseline in CD4+ T-cell count (cells/mm³) | 404 | 284 |
* intent to treat analysis where patients with missing values are considered virologic failures
Study P1030 was an open-label, dose-finding trial evaluating the pharmacokinetic profile, tolerability, safety and efficacy of Kaletra oral solution at a dose of 300 mg lopinavir/75 mg ritonavir per m² twice daily plus 2 NRTIs in HIV-1 infected infants ≥14 days and <6 months of age. At entry, median (range) HIV-1 RNA was 6.0 (4.7-7.2) log10 copies/ml and median (range) CD4+T-cell percentage was 41 (16-59).
Table 6:
| Outcomes at Week 24: Study P1030 | ||
|---|---|---|
| Age: ≥14 days and <6 weeks (N=10) | Age: ≥6 weeks and <6 months (N=21) | |
| HIV RNA <400 copies/ml* | 70% | 48% |
| Median change from baseline in CD4+ T-cell count (cells/mm³) | -1% (95% CI: -10, 18) (n=6) | +4% (95% CI: -1, 9) (n=19) |
* Proportion of subjects who had HIV-1 <400 copies/ml and had remained on study treatment
Study P1060 was a randomised controlled trial of nevirapine versus lopinavir/ritonavir-based therapy in subjects 2 to 36 months of age infected with HIV-1 who had (Cohort I) and had not (Cohort II) been exposed to nevirapine during pregnancy for prevention of mother-to-child transmission. Lopinavir/ritonavir was administered twice daily at 16/4 mg/kg for subjects 2 months to <6 months, 12/3 mg/kg for subjects ≥6 months and <15 kg, 10/2.5 mg/kg for subjects ≥6 months and ≥15 kg to <40 kg, or 400/100 mg for subjects ≥40 kg. The nevirapine-based regimen was 160-200 mg/m² once daily for 14 days, then 160-200 mg/m² every 12 hours. Both treatment arms included zidovudine 180 mg/m² every 12 hours and lamivudine 4 mg/kg every 12 hours. The median follow-up was 48 weeks in Cohort I and 72 weeks in Cohort II. At entry, median age was 0.7 years, median CD4 T-cell count was 1147 cells/mm³, median CD4 T-cell was 19%, and median HIV-1 RNA was >750,000 copies/ml. Among 13 subjects with viral failure in the lopinavir/ritonavir group with resistance data available no resistance to lopinavir/ritonavir was found.
Table 7:
| Outcomes at Week 24: Study P1060 | ||||
|---|---|---|---|---|
| Cohort I | Cohort II | |||
| lopinavir/ritonavir (N=82) | nevirapine (N=82) | lopinavir/ritonavir (N=140) | nevirapine (N=147) | |
| Virologic failure* | 21.7% | 39.6% | 19.3% | 40.8% |
* Defined as confirmed plasma HIV-1 RNA level >400 copies/ml at 24 weeks or viral rebound >4000 copies/ml after Week 24. Overall failure rate combining the treatment differences across age strata, weighted by the precision of the estimate within each age stratum
p=0.015 (Cohort I); p<0.001 (Cohort II)
The CHER study was a randomized, open-label study comparing 3 treatment strategies (deferred treatment, early treatment for 40 weeks, or early treatment for 96 weeks) in children with perinatally acquired HIV-1 infection. The treatment regimen was zidovudine plus lamivudine plus 300 mg lopinavir/75 mg ritonavir per m² twice daily until 6 months of age, then 230 mg lopinavir/57.5 mg ritonavir per m² twice daily. There were no reported events of failure attributed to therapy limiting toxicity.
Table 8:
| Hazard Ratio for Death or Failure of First-line Therapy Relative to ART Deferred Treatment: CHER Study | ||
|---|---|---|
| 40 week arm (N=13) | 96 week arm (N=13) | |
| Hazard ratio for death or failure of therapy* | 0.319 | 0.332 |
* Failure defined as clinical, immunological disease progression, virological failure or regimen limiting ART toxicity
p=0.0005 (40 week arm); p<0.0008 (96 week arm)
The pharmacokinetic properties of lopinavir co-administered with ritonavir have been evaluated in healthy adult volunteers and in HIV-infected patients; no substantial differences were observed between the two groups. Lopinavir is essentially completely metabolised by CYP3A. Ritonavir inhibits the metabolism of lopinavir, thereby increasing the plasma levels of lopinavir. Across studies, administration of Kaletra 400/100 mg twice daily yields mean steady-state lopinavir plasma concentrations 15 to 20-fold higher than those of ritonavir in HIV-infected patients. The plasma levels of ritonavir are less than 7% of those obtained after the ritonavir dose of 600 mg twice daily. The in vitro antiviral EC50 of lopinavir is approximately 10-fold lower than that of ritonavir. Therefore, the antiviral activity of Kaletra is due to lopinavir.
Multiple dosing with 400/100 mg Kaletra twice daily for 2 weeks and without meal restriction produced a mean ± SD lopinavir peak plasma concentration (Cmax) of 12.3 5.4 g/ml, occurring approximately 4 hours after administration. The mean steady-state trough concentration prior to the morning dose was 8.1 ± 5.7 μg/ml. Lopinavir AUC over a 12 hour dosing interval averaged 113.2 ± 60.5 μg∙h/ml. The absolute bioavailability of lopinavir co-formulated with ritonavir in humans has not been established.
Kaletra soft capsules and liquid have been shown to be bioequivalent under nonfasting conditions (moderate fat meal). Administration of a single 400/100 mg dose of Kaletra soft capsules with a moderate fat meal (500–682 kcal, 22.7 –25.1% from fat) was associated with a mean increase of 48% and 23% in lopinavir AUC and Cmax, respectively, relative to fasting. For Kaletra oral solution, the corresponding increases in lopinavir AUC and Cmax were 80% and 54%, respectively. Administration of Kaletra with a high fat meal (872 kcal, 55.8% from fat) increased lopinavir AUC and Cmax by 96% and 43%, respectively, for soft capsules, and 130% and 56%, respectively, for oral solution. To enhance bioavailability and minimise variability Kaletra is to be taken with food.
At steady state, lopinavir is approximately 98−99% bound to serum proteins. Lopinavir binds to both alpha-1-acid glycoprotein (AAG) and albumin however, it has a higher affinity for AAG. At steady state, lopinavir protein binding remains constant over the range of observed concentrations after 400/100 mg Kaletra twice daily, and is similar between healthy volunteers and HIV-positive patients.
In vitro experiments with human hepatic microsomes indicate that lopinavir primarily undergoes oxidative metabolism. Lopinavir is extensively metabolised by the hepatic cytochrome P450 system, almost exclusively by isozyme CYP3A. Ritonavir is a potent CYP3A inhibitor which inhibits the metabolism of lopinavir and therefore, increases plasma levels of lopinavir. A 14C-lopinavir study in humans showed that 89% of the plasma radioactivity after a single 400/100 mg Kaletra dose was due to parent active substance. At least 13 lopinavir oxidative metabolites have been identified in man. The 4-oxo and 4-hydroxymetabolite epimeric pair are the major metabolites with antiviral activity, but comprise only minute amounts of total plasma radioactivity. Ritonavir has been shown to induce metabolic enzymes, resulting in the induction of its own metabolism, and likely the induction of lopinavir metabolism. Pre-dose lopinavir concentrations decline with time during multiple dosing, stabilising after approximately 10 days to 2 weeks.
After a 400/100 mg 14C-lopinavir/ritonavir dose, approximately 10.4 ± 2.3% and 82.6 ± 2.5% of an administered dose of 14C-lopinavir can be accounted for in urine and faeces, respectively. Unchanged lopinavir accounted for approximately 2.2% and 19.8% of the administered dose in urine and faeces, respectively. After multiple dosing, less than 3% of the lopinavir dose is excreted unchanged in the urine. The effective (peak to trough) half-life of lopinavir over a 12 hour dosing interval averaged 5−6 hours, and the apparent oral clearance (CL/F) of lopinavir is 6 to 7 l/h.
Data from clinical trials in children below 2 years of age include the pharmacokinetics of Kaletra 300/75 mg/m² twice daily studied in a total of 31 paediatric patients, ranging in age from 14 days to 6 months. The pharmacokinetics of Kaletra 300/75 mg/m² twice daily with nevirapine and 230/57.5 mg/m² twice daily alone have been studied in 53 paediatric patients ranging in age from 6 months to 12 years. The mean (SD) for the studies are reported in the table below. The 230/57.5 mg/m² twice daily regimen without nevirapine and the 300/75 mg/m² twice daily regimen with nevirapine provided lopinavir plasma concentrations similar to those obtained in adult patients receiving the 400/100 mg twice daily regimen without nevirapine.
| Cmax (μg/ml) | Cmin (μg/ml) | AUC12 (μg∙h/ml) |
|---|---|---|
| Age ≥14 days to <6 weeks cohort (N=9): | ||
| 5.17 (1.84) | 1.40 (0.48) | 43.39 (14.80) |
| Age ≥6 weeks to <6 months cohort (N=18): | ||
| 9.39 (4.91) | 1.95 (1.80) | 74.50 (37.87) |
| Age ≥6 months to <12 years cohort (N=53): | ||
| 8.2 (2.9)a | 3.4 (2.1)a | 72.6 (31.1)a |
| 10.0 (3.3)b | 3.6 (3.5)b | 85.8 (36.9)b |
| Adultc | ||
| 12.3 (5.4) | 8.1 (5.7) | 113.2 (60.5) |
a Kaletra oral solution 230/57.5 mg/m² twice daily regimen without nevirapine
b Kaletra oral solution 300/75 mg/m² twice daily regimen with nevirapine
c Kaletra film-coated tablets 400/100 mg twice daily at steady state
Kaletra pharmacokinetics have not been studied in older people. No age or gender related pharmacokinetic differences have been observed in adult patients. Pharmacokinetic differences due to race have not been identified.
Kaletra pharmacokinetics have not been studied in patients with renal insufficiency; however, since the renal clearance of lopinavir is negligible, a decrease in total body clearance is not expected in patients with renal insufficiency.
The steady state pharmacokinetic parameters of lopinavir in HIV-infected patients with mild to moderate hepatic impairment were compared with those of HIV-infected patients with normal hepatic function in a multiple dose study with lopinavir/ritonavir 400/100 mg twice daily. A limited increase in total lopinavir concentrations of approximately 30% has been observed which is not expected to be of clinical relevance (see section 4.2).
Repeat-dose toxicity studies in rodents and dogs identified major target organs as the liver, kidney, thyroid, spleen and circulating red blood cells. Hepatic changes indicated cellular swelling with focal degeneration. While exposure eliciting these changes were comparable to or below human clinical exposure, dosages in animals were over 6-fold the recommended clinical dose. Mild renal tubular degeneration was confined to mice exposed with at least twice the recommended human exposure; the kidney was unaffected in rats and dogs. Reduced serum thyroxin led to an increased release of TSH with resultant follicular cell hypertrophy in the thyroid glands of rats. These changes were reversible with withdrawal of the active substance and were absent in mice and dogs. Coombs-negative anisocytosis and poikilocytosis were observed in rats, but not in mice or dogs. Enlarged spleens with histiocytosis were seen in rats but not other species. Serum cholesterol was elevated in rodents but not dogs, while triglycerides were elevated only in mice.
During in vitro studies, cloned human cardiac potassium channels (HERG) were inhibited by 30% at the highest concentrations of lopinavir/ritonavir tested, corresponding to a lopinavir exposure 7-fold total and 15-fold free peak plasma levels achieved in humans at the maximum recommended therapeutic dose. In contrast, similar concentrations of lopinavir/ritonavir demonstrated no repolarisation delay in the canine cardiac Purkinje fibres. Lower concentrations of lopinavir/ritonavir did not produce significant potassium (HERG) current blockade. Tissue distribution studies conducted in the rat did not suggest significant cardiac retention of the active substance; 72-hour AUC in heart was approximately 50% of measured plasma AUC. Therefore, it is reasonable to expect that cardiac lopinavir levels would not be significantly higher than plasma levels.
In dogs, prominent U waves on the electrocardiogram have been observed associated with prolonged PR interval and bradycardia. These effects have been assumed to be caused by electrolyte disturbance.
The clinical relevance of these preclinical data is unknown, however, the potential cardiac effects of this product in humans cannot be ruled out (see also sections 4.4 and 4.8).
In rats, embryofoetotoxicity (pregnancy loss, decreased foetal viability, decreased foetal body weights, increased frequency of skeletal variations) and postnatal developmental toxicity (decreased survival of pups) was observed at maternally toxic dosages. The systemic exposure to lopinavir/ritonavir at the maternal and developmental toxic dosages was lower than the intended therapeutic exposure in humans.
Long-term carcinogenicity studies of lopinavir/ritonavir in mice revealed a nongenotoxic, mitogenic induction of liver tumours, generally considered to have little relevance to human risk. Carcinogenicity studies in rats revealed no tumourigenic findings. Lopinavir/ritonavir was not found to be mutagenic or clastogenic in a battery of in vitro and in vivo assays including the Ames bacterial reverse mutation assay, the mouse lymphoma assay, the mouse micronucleus test and chromosomal aberration assays in human lymphocytes.
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