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Kaletra Capsules

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Kaletra Capsules

Kaletra Capsules

CLINICAL PHARMACOLOGY

Mechanism of Action

Lopinavir is an antiviral drug [see Microbiology].

Pharmacokinetics

The pharmacokinetic properties of lopinavir co-administered with ritonavir have been evaluated in healthy adult volunteers and in HIV-1 infected patients; no substantial differences were observed between the two groups. Lopinavir is essentially completely metabolized 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-1 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.

Figure 1 displays the mean steady-state plasma concentrations of lopinavir and ritonavir after KALETRA 400/100 mg twice daily with food for 3 weeks from a pharmacokinetic study in HIV-1 infected adult subjects (n = 19).

Figure 1: Mean Steady-State Plasma Concentrations with 95% Confidence Intervals (CI) for HIV-1 Infected Adult Subjects (N = 19)

Mean Steady-State Plasma Concentrations with 95% Confidence Intervals - Illustration

Absorption

In a pharmacokinetic study in HIV-1 positive subjects (n = 19), multiple dosing with 400/100 mg KALETRA twice daily with food for 3 weeks produced a mean ± SD lopinavir peak plasma concentration (Cmax) of 9.8 ± 3.7 μg per mL, occurring approximately 4 hours after administration. The mean steady-state trough concentration prior to the morning dose was 7.1 ± 2.9 μg per mL and minimum concentration within a dosing interval was 5.5 ± 2.7 μg per mL. Lopinavir AUC over a 12 hour dosing interval averaged 92.6 ± 36.7 μg•h per mL. The absolute bioavailability of lopinavir co-formulated with ritonavir in humans has not been established. Under nonfasting conditions (500 kcal, 25% from fat), lopinavir concentrations were similar following administration of KALETRA co-formulated capsules and oral solution. When administered under fasting conditions, both the mean AUC and Cmax of lopinavir were 22% lower for the KALETRA oral solution relative to the capsule formulation.

Effects of Food on Oral Absorption

Administration of a single 400/100 mg dose of KALETRA capsules with a moderate fat meal (500-682 kcal, 23 to 25% calories from fat) was associated with a mean increase of 48 and 23% in lopinavir AUC and Cmax, respectively, relative to fasting. Relative to fasting, administration of KALETRA capsules with a high fat meal (872 kcal, 56% from fat) increased lopinavir AUC and Cmax by 97 and 43%, respectively. To enhance bioavailability and minimize pharmacokinetic variability KALETRA capsules should be taken with food.

Distribution

At steady state, lopinavir is approximately 98-99% bound to plasma 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-1 positive patients.

Metabolism

In vitro experiments with human hepatic microsomes indicate that lopinavir primarily undergoes oxidative metabolism. Lopinavir is extensively metabolized by the hepatic cytochrome P450 system, almost exclusively by the CYP3A isozyme. Ritonavir is a potent CYP3A inhibitor which inhibits the metabolism of lopinavir, and therefore increases plasma levels of lopinavir. A 14Clopinavir study in humans showed that 89% of the plasma radioactivity after a single 400/100 mg KALETRA dose was due to parent drug. At least 13 lopinavir oxidative metabolites have been identified in man. Ritonavir has been shown to induce metabolic enzymes, resulting in the induction of its own metabolism. Pre-dose lopinavir concentrations decline with time during multiple dosing, stabilizing after approximately 10 to 16 days.

Elimination

Following 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 feces, respectively, after 8 days. Unchanged lopinavir accounted for approximately 2.2 and 19.8% of the administered dose in urine and feces, respectively. After multiple dosing, less than 3% of the lopinavir dose is excreted unchanged in the urine. The apparent oral clearance (CL/F) of lopinavir is 5.98 ± 5.75 L per hr (mean ± SD, n = 19).

Once Daily Dosing

The pharmacokinetics of once daily KALETRA have been evaluated in HIV-1 infected subjects na´ve to antiretroviral treatment. KALETRA 800/200 mg was administered in combination with emtricitabine 200 mg and tenofovir DF 300 mg as part of a once daily regimen. Multiple dosing of 800/200 mg KALETRA once daily for 4 weeks with food (n = 24) produced a mean ± SD lopinavir peak plasma concentration (Cmax) of 11.8 ± 3.7 μg per mL, occurring approximately 6 hours after administration. The mean steady-state lopinavir trough concentration prior to the morning dose was 3.2 ± 2.1 μg per mL and minimum concentration within a dosing interval was 1.7 ± 1.6 μg per mL. Lopinavir AUC over a 24 hour dosing interval averaged 154.1 ± 61.4 μg•h per mL.

The pharmacokinetics of once daily KALETRA has also been evaluated in treatment experienced HIV-1 infected subjects. Lopinavir exposure (Cmax, AUC[0-24h], Ctrough) with once daily KALETRA administration in treatment experienced subjects is comparable to the once daily lopinavir exposure in treatment na´ve subjects.

Effects on Electrocardiogram

QTcF interval was evaluated in a randomized, 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 time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline-correction were 5.3 (8.1) and 15.2 (18.0) mseconds (msec) for 400/100 mg twice daily and supratherapeutic 800/200 mg twice daily KALETRA, respectively. KALETRA 800/200 mg twice daily resulted in a Day 3 mean Cmax approximately 2-fold higher than the mean Cmax observed with the approved once daily and twice daily KALETRA doses at steady state.

PR interval prolongation was also noted in subjects receiving KALETRA in the same study on Day 3. The maximum mean (95% upper confidence bound) difference from placebo in the PR interval after baseline-correction were 24.9 (21.5, 28.3) and 31.9 (28.5, 35.3) msec for 400/100 mg twice daily and supratherapeutic 800/200 mg twice daily KALETRA, respectively [see WARNINGS AND PRECAUTIONS].

Special Populations

Gender, Race and Age

No gender related pharmacokinetic differences have been observed in adult patients. No clinically important pharmacokinetic differences due to race have been identified. Lopinavir pharmacokinetics have not been studied in elderly patients.

Pediatric Patients

The pharmacokinetics of KALETRA soft gelatin capsule and oral solution (Group 1: 400/100 mg per m² twice daily plus 2 NRTIs; Group 2: 480/120 mg per m² twice daily plus at least 1 NRTI plus 1 NNRTI) have been evaluated in children and adolescents at least 2 years to less than 18 years of age who had failed prior therapy (n=26) in Study 1038. KALETRA doses of 400/100 and 480/120 mg per m² resulted in high lopinavir exposure, as almost all subjects had lopinavir AUC12 above 100 μg•h per mL. Both groups of subjects also achieved relatively high average minimum lopinavir concentrations.

KALETRA once daily has not been evaluated in pediatric patients.

Renal Impairment

Lopinavir pharmacokinetics have not been studied in patients with renal impairment; however, since the renal clearance of lopinavir is negligible, a decrease in total body clearance is not expected in patients with renal impairment.

Hepatic Impairment

Lopinavir is principally metabolized and eliminated by the liver. Multiple dosing of KALETRA 400/100 mg twice daily to HIV-1 and HCV co-infected patients with mild to moderate hepatic impairment (n = 12) resulted in a 30% increase in lopinavir AUC and 20% increase in Cmax compared to HIV-1 infected subjects with normal hepatic function (n = 12). Additionally, the plasma protein binding of lopinavir was statistically significantly lower in both mild and moderate hepatic impairment compared to controls (99.09 vs. 99.31%, respectively). Caution should be exercised when administering KALETRA to subjects with hepatic impairment.

KALETRA has not been studied in patients with severe hepatic impairment [see WARNINGS AND PRECAUTIONS and Use in Specific Populations].

Drug Interactions

KALETRA is an inhibitor of the P450 isoform CYP3A in vitro. Co-administration of KALETRA and drugs primarily metabolized by CYP3A may result in increased plasma concentrations of the other drug, which could increase or prolong its therapeutic and adverse effects [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].

KALETRA does not inhibit CYP2D6, CYP2C9, CYP2C19, CYP2E1, CYP2B6 or CYP1A2 at clinically relevant concentrations.

KALETRA has been shown in vivo to induce its own metabolism and to increase the biotransformation of some drugs metabolized by cytochrome P450 enzymes and by glucuronidation.

KALETRA is metabolized by CYP3A. Drugs that induce CYP3A activity would be expected to increase the clearance of lopinavir, resulting in lowered plasma concentrations of lopinavir. Although not noted with concurrent ketoconazole, co-administration of KALETRA and other drugs that inhibit CYP3A may increase lopinavir plasma concentrations.

Drug interaction studies were performed with KALETRA and other drugs likely to be coadministered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of co-administration of KALETRA on the AUC, Cmax and Cmin are summarized in Table 8 (effect of other drugs on lopinavir) and Table 9 (effect of KALETRA on other drugs). The effects of other drugs on ritonavir are not shown since they generally correlate with those observed with lopinavir (if lopinavir concentrations are decreased, ritonavir concentrations are decreased) unless otherwise indicated in the table footnotes. For information regarding clinical recommendations, see Table 7 in DRUG INTERACTIONS.

Table 8: Drug Interactions: Pharmacokinetic Parameters for Lopinavir in the Presence of the Coadministered Drug for Recommended Alterations in Dose or Regimen

Co-administered Drug Dose of Coadministered Drug (mg) Dose of KALETRA (mg) n Ratio (in combination with coadministered drug/alone) of Lopinavir Pharmacokinetic Parameters (90% CI); No Effect = 1.00
C max AUC Cmin
Boceprevir 800 q8h, 6 d 400/100 tablet twice daily, 22 d 13 0.70 (0.65, 0.77) 0.6612 (0.60, 0.72) 0.57 (0.49, 0.65)
Efavirenz1,2 600 at bedtime, 9 d 400/100 capsule twice daily, 9 d 11, 7* 0.97 (0.78, 1.22) 0.81 (0.64, 1.03) 0.61 (0.38, 0.97)
600 at bedtime, 9 d 500/125 tablet twice daily, 10 d 19 1.12 (1.02, 1.23) 1.06 (0.96, 1.17) 0.90 (0.78, 1.04)
600 at bedtime, 9 d 600/150 tablet twice daily, 10 d 23 1.36 (1.28, 1.44) 1.36 (1.28, 1.44) 1.32 (1.21, 1.44)
Fosamprenavir3 700 twice daily plus ritonavir 100 twice daily, 14 d 400/100 capsule twice daily, 14 d 18 1.30 (0.85, 1.47) 1.37 (0.80, 1.55) 1.52 (0.72, 1.82)
Ketoconazole 200 single dose 400/100 capsule twice daily, 16 d 12 0.89 (0.80, 0.99) 0.87 (0.75, 1.00) 0.75 (0.55, 1.00)
Nelfinavir 1000 twice daily, 10 d 400/100 capsule twice daily, 21 d 13 0.79 (0.70, 0.89) 0.73 (0.63, 0.85) 0.62 (0.49, 0.78)
Nevirapine 200 twice daily, steady-state (> 1 yr)4# 400/100 capsule twice daily, steady-state 22, 19* 0.81 (0.62, 1.05) 0.73 (0.53, 0.98) 0.49 (0.28, 0.74)
7 mg/kg or 4 mg/kg once daily, 2 wk; twice daily 1 wk5 (> 1 yr) 300/75 mg/m² oral solution twice daily, 3 wk , * 0.86 (0.64, 1.16) 0.78 (0.56, 1.09) 0.45 (0.25, 0.81)
Omeprazole 40 once daily, 5 d 400/100 tablet twice daily, 10 d 12 1.08 (0.99, 1.17) 1.07 (0.99, 1.15) 1.03 (0.90, 1.18)
40 once daily, 5 d 800/200 tablet once daily, 10 d 12 0.94 (0.88, 1.00) 0.92 (0.86, 0.99) 0.71 (0.57, 0.89)
Pitavastatin6 4 mg once daily, 5 d 400/100 tablet twice daily, 16 d 23 0.93 (0.88, 0.98) 0.91 (0.86, 0.97) NA
Pravastatin 20 once daily, 4 d 400/100 capsule twice daily, 14 d 12 0.98 (0.89, 1.08) 0.95 (0.85, 1.05) 0.88 (0.77, 1.02)
Rifabutin 150 once daily, 10 d 400/100 capsule twice daily, 20 d 14 1.08 (0.97, 1.19) 1.17 (1.04, 1.31) 1.20 (0.96, 1.65)
Ranitidine 150 single dose 400/100 tablet twice daily, 10 d 12 0.99 (0.95, 1.03) 0.97 (0.93, 1.01) 0.90 (0.85, 0.95)
150 single dose 800/200 tablet once daily, 10 d 10 0.97 (0.95, 1.00) 0.95 (0.91, 0.99) 0.82 (0.74, 0.91)
Rifampin 600 once daily, 10 d 400/100 capsule twice daily, 20 d 22 0.45 (0.40, 0.51) 0.25 (0.21, 0.29) 0.01 (0.01, 0.02)
600 once daily, 14 d 800/200 capsule twice daily, 9 d7 10 1.02 (0.85, 1.23) 0.84 (0.64, 1.10) 0.43 (0.19, 0.96)
600 once daily, 14 d 400/400 capsule twice daily, 9 d8 9 0.93 (0.81, 1.07) 0.98 (0.81, 1.17) 1.03 (0.68, 1.56)
Ritonavir4 100 twice daily, 3-4 wk# 400/100 capsule twice daily, 3-4 wk , * 00 S 1.28 (0.94, 1.76) 1.46 (1.04, 2.06) 2.16 (1.29, 3.62)
Telaprevir 750 q8h, 10 days 400/100 tablet twice daily, 20 days 1213 0.96 (0.87, 1.05) 1.06 (0.96, 1.17) 1.14 (0.96, 1.36)
Tenofovir9 300 mg once daily, 14 d 400/100 capsule twice daily, 14 d 24 NC† NC† NC†
Tipranavir/ritonavir4 500/200 mg twice daily (28 doses) # 400/100 capsule twice daily (27 doses) 21, 69 0.53 (0.40, 0.69)10 0.45 (0.32, 0.63)10 0.30 (0.17, 0.51)10 0.48 (0.40, 0.58)11
All interaction studies conducted in healthy, HIV-1 negative subjects unless otherwise indicated.
1 The pharmacokinetics of ritonavir are unaffected by concurrent efavirenz.
2 Reference for comparison is lopinavir/ritonavir 400/100 mg twice daily without efavirenz.
3 Data extracted from the fosamprenavir package insert.
4 Study conducted in HIV-1 positive adult subjects.
5 Study conducted in HIV-1 positive pediatric subjects ranging in age from 6 months to 12 years.
6 Data extracted from the pitavastatin package insert and results presented at the 2011 International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (Morgan, et al, poster #MOPE170).
7 Titrated to 800/200 twice daily as 533/133 twice daily x 1 d, 667/167 twice daily x 1 d, then 800/200 twice daily x 7 d, compared to 400/100 twice daily x 10 days alone.
8 Titrated to 400/400 twice daily as 400/200 twice daily x 1 d, 400/300 twice daily x 1 d, then 400/400 twice daily x 7 d, compared to 400/100 twice daily x 10 days alone.
9 Data extracted from the tenofovir package insert.
10 Intensive PK analysis.
11 Drug levels obtained at 8-16 hrs post-dose.
12 AUC parameter is AUC(0-last)
13 N=12 for test arm, 19 for reference arm
* Parallel group design; n for KALETRA + co-administered drug, n for KALETRA alone. N/A = Not available.
† NC = No change.
# For the nevirapine 200 mg twice daily study, ritonavir, and tipranavir/ritonavir studies, KALETRA was administered with or without food. For all other studies, KALETRA was administered with food.

Table 9: Drug Interactions: Pharmacokinetic Parameters for Co-administered Drug in the Presence of KALETRA for Recommended Alterations in Dose or Regimen

Co-administered Drug Dose of Co-administered Drug (mg) Dose of KALETRA (mg) n Ratio (in combination with KALETRA/alone) of Co-administered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00
Cmax AUC Cmin
Boceprevir 800 q8h, 6 d 400/100 tablet twice daily, 22 d 138 0.50 (0.45, 0.55) 0.55 (0.49, 0.61) 0.43 (0.36, 0.53)
Desipramine1 100 single dose 400/100 capsule twice daily, 10 d 15 0.91 (0.84, 0.97) 1.05 (0.96, 1.16) N/A
Efavirenz 600 at bedtime, 9 d 400/100 capsule twice daily, 9 d 11, 12* 0.91 (0.72, 1.15) 0.84 (0.62, 1.15) 0.84 (0.58, 1.20)
Ethinyl Estradiol 35 ?g once daily, 21 d (Ortho Novum®) 400/100 capsule twice daily, 14 d 12 0.59 (0.52, 0.66) 0.58 (0.54, 0.62) 0.42 (0.36, 0.49)
Fosamprenavir2 700 twice daily plus ritonavir 100 twice daily, 14 d 400/100 capsule twice daily, 14 d 18 0.42 (0.30, 0.58) 0.37 (0.28, 0.49) 0.35 (0.27, 0.46)
Indinavir3 600 twice daily, 10 d combo nonfasting vs. 800 three times daily, 5 d alone fasting 400/100 capsule twice daily, 15 d 13 0.71 (0.63, 0.81) 0.91 (0.75, 1.10) 3.47 (2.60, 4.64)
Ketoconazole 200 single dose 400/100 capsule twice daily, 16 d 12 1.13 (0.91, 1.40) 3.04 (2.44, 3.79) N/A
Methadone 5 single dose 400/100 capsule twice daily, 10 d 11 0.55 (0.48, 0.64) 0.47 (0.42, 0.53) N/A
Nelfinavir3 1000 twice daily, 10 d combo vs. 1250 twice daily 14 d alone 400/100 capsule twice daily, 21 d 13 0.93 (0.82, 1.05) 1.07 (0.95, 1.19) 1.86 (1.57, 2.22)
M8 metabolite 2.36 (1.91, 2.91) 3.46 (2.78, 4.31) 7.49 (5.85, 9.58)
Nevirapine twice daily, 6 d 200 once daily, 14 d; twice daily, 20 d 400/100 capsule 5, 1.05(0.72, 1.52) 1.08 1.15(0.71, 1.86)
6* (0.72, 1.64)
Norethindrone 1 once daily, 21 d (Ortho Novum®) 400/100 capsule twice daily, 14 d 12 0.84 (0.75, 0.94) 0.83 (0.73, 0.94) 0.68 (0.54, 0.85)
Pitavastatin4 4 mg once daily, 5 d 400/100 tablet twice daily, 16 d 23 0.96 (0.84, 1.10) 0.80 (0.73, 0.87) N/A
Pravastatin 20 once daily, 4 d 400/100 capsule twice daily, 14 d 12 1.26 (0.87, 1.83) 1.33 (0.91, 1.94) N/A
Rifabutin 150 once daily, 10 d; combo vs. 300 once daily, 10 d; alone 400/100 capsule twice daily, 10 d 12 2.12 (1.89, 2.38) 3.03 (2.79, 3.30) 4.90 (3.18, 5.76)
25-O-desacetyl rifabutin 23.6 (13.7, 25.3) 47.5 (29.3, 51.8) 94.9 (74.0, 122)
Rifabutin + 25-Odesacetyl rifabutin5 3.46 (3.07, 3.91) 5.73 (5.08, 6.46) 9.53 (7.56, 12.01)
Rosuvastatin6 20 mg once daily, 7 d 400/100 tablet twice daily, 7 d 15 4.66 (3.4, 6.4) 2.08 (1.66, 2.6) 1.04 (0.9, 1.2)
Telaprevir 750 q8h, 10 days 400/100 tablet twice daily, 20 days 129 0.47 (0.41, 0.52) 0.46 (0.41, 0.52) 0.48 (0.40, 0.56)
Tenofovir7 300 mg once daily, 14 d 400/100 capsule twice daily, 14 d 24 NC† 1.32 (1.26, 1.38) 1.51 (1.32, 1.66)
All interaction studies conducted in healthy, HIV-1 negative subjects unless otherwise indicated.
1 Desipramine is a probe substrate for assessing effects on CYP2D6-mediated metabolism.
2 Data extracted from the fosamprenavir package insert.
3 Ratio of parameters for indinavir, and nelfinavir are not normalized for dose.
4 Data extracted from the pitavastatin package insert and results presented at the 2011 International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (Morgan, et al, poster #MOPE170).
5 Effect on the dose-normalized sum of rifabutin parent and 25-O-desacetyl rifabutin active metabolite.
6 Kiser, et al. J Acquir Immune Defic Syndr. 2008 Apr 15;47(5):570-8.
7 Data extracted from the tenofovir package insert.
8 N=12 for Cmin (test arm)
9 N=12 for the test arm, 14 for reference arm
* Parallel group design; n for KALETRA + co-administered drug, n for co-administered drug alone.
N/A = Not available.
† NC = No change.

Microbiology

Mechanism of Action

Lopinavir, an inhibitor of the HIV-1 protease, prevents cleavage of the Gag-Pol polyprotein, resulting in the production of immature, non-infectious viral particles.

Antiviral Activity

The antiviral activity of lopinavir against laboratory HIV strains and clinical HIV-1 isolates was evaluated in acutely infected lymphoblastic cell lines and peripheral blood lymphocytes, respectively. In the absence of human serum, the mean 50% effective concentration (EC50) values of lopinavir against five different HIV-1 subtype B laboratory strains ranged from 10-27 nM (0.006-0.017 μg per mL, 1 μg per mL = 1.6 μM) and ranged from 4-11 nM (0.003-0.007 μg per mL) against several HIV-1 subtype B clinical isolates (n = 6). In the presence of 50% human serum, the mean EC50 values of lopinavir against these five HIV-1 laboratory strains ranged from 65-289 nM (0.04-0.18 μg per mL), representing a 7 to 11-fold attenuation. Combination antiviral drug activity studies with lopinavir in cell cultures demonstrated additive to antagonistic activity with nelfinavir and additive to synergistic activity with amprenavir, atazanavir, indinavir, saquinavir and tipranavir. The EC50 values of lopinavir against three different HIV-2 strains ranged from 12-180 nM (0.008-113 μg per mL).

Resistance

HIV-1 isolates with reduced susceptibility to lopinavir have been selected in cell culture. The presence of ritonavir does not appear to influence the selection of lopinavir-resistant viruses in cell culture.

The selection of resistance to KALETRA in antiretroviral treatment na´ve patients has not yet been characterized. In a study of 653 antiretroviral treatment na´ve patients (Study 863), plasma viral isolates from each patient on treatment with plasma HIV-1 RNA greater than 400 copies per mL at Week 24, 32, 40 and/or 48 were analyzed. No evidence of resistance to KALETRA was observed in 37 evaluable KALETRA-treated patients (0%). Evidence of genotypic resistance to nelfinavir, defined as the presence of the D30N and/or L90M substitution in HIV-1 protease, was observed in 25/76 (33%) of evaluable nelfinavir-treated patients. The selection of resistance to KALETRA in antiretroviral treatment na´ve pediatric patients (Study 940) appears to be consistent with that seen in adult patients (Study 863).

Resistance to KALETRA has been noted to emerge in patients treated with other protease inhibitors prior to KALETRA therapy. In studies of 227 antiretroviral treatment na´ve (100) and protease inhibitor experienced (127) patients, isolates from 4 of 23 patients with quantifiable (greater than 400 copies per mL) viral RNA following treatment with KALETRA for 12 to 100 weeks displayed significantly reduced susceptibility to lopinavir compared to the corresponding baseline viral isolates. Three of these patients had previously received treatment with a single protease inhibitor (indinavir, nelfinavir, or saquinavir) and one patient had received treatment with multiple protease inhibitors (indinavir, ritonavir, and saquinavir). All four of these patients had at least 4 substitutions associated with protease inhibitor resistance immediately prior to KALETRA therapy. Following viral rebound, isolates from these patients all contained additional substitutions, some of which are recognized to be associated with protease inhibitor resistance. However, there are insufficient data at this time to identify patterns of lopinavir resistance-associated substitutions in isolates from patients on KALETRA therapy. The assessment of these patterns is under study.

Cross-resistance - Preclinical Studies

Varying degrees of cross-resistance have been observed among HIV-1 protease inhibitors. Little information is available on the cross-resistance of viruses that developed decreased susceptibility to lopinavir during KALETRA therapy.

The antiviral activity in cell culture of lopinavir against clinical isolates from patients previously treated with a single protease inhibitor was determined. Isolates that displayed greater than 4-fold reduced susceptibility to nelfinavir (n = 13) and saquinavir (n = 4), displayed less than 4-fold reduced susceptibility to lopinavir. Isolates with greater than 4-fold reduced susceptibility to indinavir (n = 16) and ritonavir (n = 3) displayed a mean of 5.7- and 8.3-fold reduced susceptibility to lopinavir, respectively. Isolates from patients previously treated with two or more protease inhibitors showed greater reductions in susceptibility to lopinavir, as described in the following paragraph.

Clinical Studies - Antiviral Activity of KALETRA in Patients with Previous Protease Inhibitor Therapies

The clinical relevance of reduced susceptibility in cell culture to lopinavir has been examined by assessing the virologic response to KALETRA therapy in treatment-experienced patients, with respect to baseline viral genotype in three studies and baseline viral phenotype in one study.

Virologic response to KALETRA has been shown to be affected by the presence of three or more of the following amino acid substitutions in protease at baseline: L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, and I84V. Table 10 shows the 48-week virologic response (HIV-1 RNA less than 400 copies per mL) according to the number of the above protease inhibitor resistance-associated substitutions at baseline in studies 888 and 765 [see Clinical Studies] and study 957 (see below). Once daily administration of KALETRA for adult patients with three or more of the above substitutions is not recommended.

Table 10: Virologic Response (HIV-1 RNA < 400 copies/mL) at Week 48 by Baseline KALETRA Susceptibility and by Number of Protease Substitutions Associated with Reduced Response to KALETRA1

Number of protease inhibitor substitutions at baseline1 Study 888 (Single protease inhibitor-experienced2, NNRTI-naive)
n=130
Study 765 (Single protease inhibitor-experienced3, NNRTI-naive)
n=56
Study 957 (Multiple protease inhibitor-experienced4, NNRTI-naive)
n=50
0-2 76/103 (74%) 34/45 (76%) 19/20 (95%)
3-5 13/26 (50%) 8/11 (73%) 18/26 (69%)
6 or more 0/1 (0%) N/A 1/4 (25%)
1 Substitutions considered in the analysis included L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, and I84V.
2 43% indinavir, 42% nelfinavir, 10% ritonavir, 15% saquinavir.
3 41% indinavir, 38% nelfinavir, 4% ritonavir, 16% saquinavir.
4 86% indinavir, 54% nelfinavir, 80% ritonavir, 70% saquinavir.

Virologic response to KALETRA therapy with respect to phenotypic susceptibility to lopinavir at baseline was examined in Study 957. In this study 56 NNRTI-na´ve patients with HIV-1 RNA greater than 1,000 copies per mL despite previous therapy with at least two protease inhibitors selected from indinavir, nelfinavir, ritonavir, and saquinavir were randomized to receive one of two doses of KALETRA in combination with efavirenz and nucleoside reverse transcriptase inhibitors (NRTIs). The EC50 values of lopinavir against the 56 baseline viral isolates ranged from 0.5- to 96-fold the wild-type EC50 value. Fifty-five percent (31/56) of these baseline isolates displayed greater than 4-fold reduced susceptibility to lopinavir. These 31 isolates had a median reduction in lopinavir susceptibility of 18-fold. Response to therapy by baseline lopinavir susceptibility is shown in Table 11.

Table 11: HIV-1 RNA Response at Week 48 by Baseline Lopinavir Susceptibility1

Lopinavir susceptibility2 at baseline HIV-1 RNA < 400 copies/mL (%) HIV-1 RNA < 50 copies/mL (%)
< 10 fold 25/27 (93%) 22/27 (81%)
> 10 and < 40 fold 11/15 (73%) 9/15 (60%)
> 40 fold 2/8 (25%) 2/8 (25%)
1 Lopinavir susceptibility was determined by recombinant phenotypic technology performed by Virologic.
2 Fold change in susceptibility from wild type.

Clinical Studies

Adult Patients without Prior Antiretroviral Therapy

Study 863: KALETRA Capsules twice daily plus stavudine plus lamivudine compared to nelfinavir three times daily plus stavudine plus lamivudine

Study 863 was a randomized, double-blind, multicenter trial comparing treatment with KALETRA capsules (400/100 mg twice daily) plus stavudine and lamivudine versus nelfinavir (750 mg three times daily) plus stavudine and lamivudine in 653 antiretroviral treatment na´ve patients. Patients had a mean age of 38 years (range: 19 to 84), 57% were Caucasian, and 80% were male. Mean baseline CD4+ cell count was 259 cells per mm³ (range: 2 to 949 cells per mm³) and mean baseline plasma HIV-1 RNA was 4.9 log10 copies per mL (range: 2.6 to 6.8 log10 copies per mL).

Treatment response and outcomes of randomized treatment are presented in Table 12.

Table 12: Outcomes of Randomized Treatment Through Week 48 (Study 863)

Outcome KALETRA+d4T+3TC
(N = 326)
Nelfinavir+d4T+3TC
(N = 327)
Responder 1 75% 62%
Virologic failure2 9% 25%
  Rebound 7% 15%
  Never suppressed through Week 48 2% 9%
Death 2% 1%
Discontinued due to adverse events 4% 4%
3Discontinued for other reasons 10% 8%
1 Patients achieved and maintained confirmed HIV-1 RNA < 400 copies/mL through Week 48.
2 Includes confirmed viral rebound and failure to achieve confirmed < 400 copies/mL through Week 48.
3 Includes lost to follow-up, patient' s withdrawal, non-compliance, protocol violation and other reasons. Overall discontinuation through Week 48, including patients who discontinued subsequent to virologic failure, was 17% in the KALETRA arm and 24% in the nelfinavir arm.

Through 48 weeks of therapy, there was a statistically significantly higher proportion of patients in the KALETRA arm compared to the nelfinavir arm with HIV-1 RNA less than 400 copies per mL (75% vs. 62%, respectively) and HIV-1 RNA less than 50 copies per mL (67% vs. 52%, respectively). Treatment response by baseline HIV-1 RNA level subgroups is presented in Table 13.

Table 13: Proportion of Responders Through Week 48 by Baseline Viral Load (Study 863)

Baseline Viral Load (HIV-1 RNA copies/mL) KALETRA +d4T+3TC Nelfinavir +d4T+3TC
< 400 copies/mL1 < 50 copies/mL2 n < 400 copies/mL1 < 50 copies/mL2 n
< 30,000 74% 71% 82 79% 72% 87
≥ 30,000 to < 100,000 81% 73% 79 67% 54% 79
≥ 100,000 to < 250,000 75% 64% 83 60% 47% 72
≥ 250,000 72% 60% 82 44% 33% 89
1 Patients achieved and maintained confirmed HIV-1 RNA < 400 copies/mL through Week 48.
2 Patients achieved HIV-1 RNA < 50 copies/mL at Week 48.

Through 48 weeks of therapy, the mean increase from baseline in CD4+ cell count was 207 cells per mm³ for the KALETRA arm and 195 cells per mm³ for the nelfinavir arm.

Study 418: KALETRA Capsules once-daily plus tenofovir DF plus emtricitabine compared to KALETRA Capsules twice-daily plus tenofovir DF plus emtricitabine

Study 418 is an ongoing, randomized, open-label, multicenter trial comparing treatment with KALETRA 800/200 mg once-daily plus tenofovir DF and emtricitabine versus KALETRA 400/100 mg twice-daily plus tenofovir DF and emtricitabine in 190 antiretroviral treatment-na´ve patients. Patients had a mean age of 39 years (range: 19 to 75), 54% were Caucasian, and 78% were male. Mean baseline CD4 cell count was 260 cells per mm³ (range: 3 to 1006 cells per mm³) and mean baseline plasma HIV-1 RNA was 4.8 log10 copies per mL (range: 2.6 to 6.4 log10 copies per mL).

Treatment response and outcomes of randomized treatment are presented in Table 14.

Table 14: Outcomes of Randomized Treatment Through Week 48 (Study 418)

Outcome KALETRA Once Daily + TDF + FTC
(n = 115)
KALETRA Twice Daily + TDF + FTC
(n = 75)
Responder 1 71% 65%
Virologic failure2 10% 9%
Rebound 6% 5%
Never suppressed through Week 48 3% 4%
Death 0% 1%
Discontinued due to an adverse event 12% 7%
Discontinued for other reasons3 7% 17%
1 Patients achieved and maintained confirmed HIV-1 RNA < 50 copies/mL through Week 48.
2 Includes confirmed viral rebound and failure to achieve confirmed < 50 copies/mL through Week 48.
3 Includes lost to follow-up, patient's withdrawal, non-compliance, protocol violation and other reasons.

Through 48 weeks of therapy, 71% in the KALETRA once-daily arm and 65% in the KALETRA twice-daily arm achieved and maintained HIV-1 RNA less than 50 copies per mL (95% confidence interval for the difference, -7.6% to 19.5%). Mean CD4 cell count increases at Week 48 were 185 cells per mm³ for the KALETRA once-daily arm and 196 cells per mm³ for the KALETRA twice-daily arm.

Study 730: KALETRA Tablets once daily plus tenofovir DF plus emtricitabine compared to KALETRA Tablets twice daily plus tenofovir DF plus emtricitabine

Study 730 was a randomized, open-label, multicenter trial comparing treatment with KALETRA 800/200 mg once daily plus tenofovir DF and emtricitabine versus KALETRA 400/100 mg twice daily plus tenofovir DF and emtricitabine in 664 antiretroviral treatment-na´ve patients. Patients were randomized in a 1:1 ratio to receive either KALETRA 800/200 mg once daily (n = 333) or KALETRA 400/100 mg twice daily (n = 331). Further stratification within each group was 1:1 (tablet vs. capsule). Patients administered the capsule were switched to the tablet formulation at Week 8 and maintained on their randomized dosing schedule. Patients were administered emtricitabine 200 mg once daily and tenofovir DF 300 mg once daily. Mean age of patients enrolled was 39 years (range: 19 to 71); 75% were Caucasian, and 78% were male. Mean baseline CD4+ cell count was 216 cells per mm³ (range: 20 to 775 cells per mm³) and mean baseline plasma HIV-1 RNA was 5.0 log10 copies per mL (range: 1.7 to 7.0 log10 copies per mL).

Treatment response and outcomes of randomized treatment through Week 48 are presented in Table 15.

Table 15: Outcomes of Randomized Treatment Through Week 48 (Study 730)

Outcome KALETRA Once Daily + TDF + FTC
(n = 333)
KALETRA Twice Daily + TDF + FTC
(n = 331)
Responder1 78% 77%
Virologic failure2 10% 8%
  Rebound 5% 5%
  Never suppressed through Week 48 5% 3%
Death 1% < 1%
Discontinued due to adverse events 4% 3%
Discontinued for other reasons3 8% 11%
1 Patients achieved and maintained confirmed HIV-1 RNA < 50 copies/mL through Week 48.
2 Includes confirmed viral rebound and failure to achieve confirmed < 50 copies/mL through Week 48.
3 Includes lost to follow-up, patient's withdrawal, non-compliance, protocol violation and other reasons.

Through 48 weeks of therapy, 78% in the KALETRA once daily arm and 77% in the KALETRA twice daily arm achieved and maintained HIV-1 RNA less than 50 copies per mL (95% confidence interval for the difference, -5.9% to 6.8%). Mean CD4+ cell count increases at Week 48 were 186 cells per mm³ for the KALETRA once daily arm and 198 cells per mm³ for the KALETRA twice daily arm.

Adult Patients with Prior Antiretroviral Therapy

Study 888: KALETRA Capsules twice daily plus nevirapine plus NRTIs compared to investigator-selected protease inhibitor(s) plus nevirapine plus NRTIs

Study 888 was a randomized, open-label, multicenter trial comparing treatment with KALETRA capsules (400/100 mg twice daily) plus nevirapine and nucleoside reverse transcriptase inhibitors versus investigator-selected protease inhibitor(s) plus nevirapine and nucleoside reverse transcriptase inhibitors in 288 single protease inhibitor-experienced, non-nucleoside reverse transcriptase inhibitor (NNRTI)-na´ve patients. Patients had a mean age of 40 years (range: 18 to 74), 68% were Caucasian, and 86% were male. Mean baseline CD4+ cell count was 322 cells per mm³ (range: 10 to 1059 cells per mm³) and mean baseline plasma HIV-1 RNA was 4.1 log10 copies per mL (range: 2.6 to 6.0 log10 copies per mL).

Treatment response and outcomes of randomized treatment through Week 48 are presented in Table 16.

Table 16: Outcomes of Randomized Treatment Through Week 48 (Study 888)

Outcome KALETRA + nevirapine + NRTIs
(n = 148)
Investigator-Selected Protease Inhibitor(s) + nevirapine + NRTIs
(n = 140)
Responder1 57% 33%
Virologic failure2 24% 41%
  Rebound 11% 19%
  Never suppressed through Week 48 13% 23%
Death 1% 2%
Discontinued due to adverse events 5% 11%
Discontinued for other reasons3 14% 13%
1 Patients achieved and maintained confirmed HIV-1 RNA < 400 copies/mL through Week 48.
2 Includes confirmed viral rebound and failure to achieve confirmed < 400 copies/mL through Week 48.
3 Includes lost to follow-up, patient's withdrawal, non-compliance, protocol violation and other reasons.

Through 48 weeks of therapy, there was a statistically significantly higher proportion of patients in the KALETRA arm compared to the investigator-selected protease inhibitor(s) arm with HIV1 RNA less than 400 copies per mL (57% vs. 33%, respectively).

Through 48 weeks of therapy, the mean increase from baseline in CD4+ cell count was 111 cells per mm³ for the KALETRA arm and 112 cells per mm³ for the investigator-selected protease inhibitor(s) arm.

Study 802: KALETRA Tablets 800/200 mg Once Daily Versus 400/100 mg Twice Daily when Coşadministered with Nucleoside/Nucleotide Reverse Transcriptase Inhibitors in Antiretroviral-Experienced, HIV-1 Infected Subjects

M06-802 was a randomized open-label study comparing the safety, tolerability, and antiviral activity of once daily and twice daily dosing of KALETRA tablets in 599 subjects with detectable viral loads while receiving their current antiviral therapy. Of the enrolled subjects, 55% on both treatment arms had not been previously treated with a protease inhibitor and 81 – 88% had received prior NNRTIs as part of their anti-HIV treatment regimen. Patients were randomized in a 1:1 ratio to receive either KALETRA 800/200 mg once daily (n = 300) or KALETRA 400/100 mg twice daily (n = 299). Patients were administered at least two nucleoside/nucleotide reverse transcriptase inhibitors selected by the investigator. Mean age of patients enrolled was 41 years (range: 21 to 73); 51% were Caucasian, and 66% were male. Mean baseline CD4+ cell count was 254 cells per mm³ (range: 4 to 952 cells per mm³) and mean baseline plasma HIV-1 RNA was 4.3 log10 copies per mL (range: 1.7 to 6.6 log10 copies per mL).

Treatment response and outcomes of randomized treatment through Week 48 are presented in Table 17.

Table 17: Outcomes of Randomized Treatment Through Week 48 (Study 802)

Outcome KALETRA Once Daily + NRTIs
(n = 300)
KALETRA Twice Daily + NRTIs
(n = 299)
Virologic Success (HIV-1 RNA < 50 copies/mL) 57% 54%
Virologic failure1 22% 24%
No virologic data in Week 48 window
Discontinued study due to adverse event or death2 5% 7%
Discontinued study for other reasons3 13% 12%
Missing data during window but on study 3% 3%
1 Includes patients who discontinued prior to Week 48 for lack or loss of efficacy and patients with HIV-1 RNA ≥ 50 copies/mL at Week 48.
2 Includes patients who discontinued due to adverse events or death at any time from Day 1 through Week 48 if this resulted in no virologic data on treatment at Week 48.
3 Includes withdrawal of consent, loss to follow-up, non-compliance, protocol violation and other reasons.

Through 48 weeks of treatment, the mean change from baseline for CD4+ cell count was 135 cells per mm³ for the once daily group and 122 cells per mm³ for the twice daily group.

Other Studies Supporting Approval in Adult Patients

Study 720: KALETRA twice daily plus stavudine plus lamivudine
Study 765: KALETRA twice daily plus nevirapine plus NRTIs

Study 720 (patients without prior antiretroviral therapy) and study 765 (patients with prior protease inhibitor therapy) were randomized, blinded, multi-center trials evaluating treatment with KALETRA at up to three dose levels (200/100 mg twice daily [720 only], 400/100 mg twice daily, and 400/200 mg twice daily). In Study 720, all patients switched to 400/100 mg twice daily between Weeks 48-72. Patients in study 720 had a mean age of 35 years, 70% were Caucasian, and 96% were male, while patients in study 765 had a mean age of 40 years, 73% were Caucasian, and 90% were male. Mean (range) baseline CD4+ cell counts for patients in study 720 and study 765 were 338 (3-918) and 372 (72-807) cells per mm³, respectively. Mean (range) baseline plasma HIV-1 RNA levels for patients in study 720 and study 765 were 4.9 (3.3 to 6.3) and 4.0 (2.9 to 5.8) log10 copies per mL, respectively.

Through 360 weeks of treatment in study 720, the proportion of patients with HIV-1 RNA less than 400 (less than 50) copies per mL was 61% (59%) [n = 100]. Among patients completing 360 weeks of treatment with CD4+ cell count measurements [n=60], the mean (median) increase in CD4+ cell count was 501 (457) cells per mm³. Thirty-nine patients (39%) discontinued the study, including 13 (13%) discontinuations due to adverse reactions and 1 (1%) death.

Through 144 weeks of treatment in study 765, the proportion of patients with HIV-1 RNA less than 400 (less than 50) copies per mL was 54% (50%) [n = 70], and the corresponding mean increase in CD4+ cell count was 212 cells per mm³. Twenty-seven patients (39%) discontinued the study, including 5 (7%) discontinuations secondary to adverse reactions and 2 (3%) deaths.

Pediatric Studies

See CLINICAL PHARMACOLOGY for pharmacokinetic results.

Study 940 was an open-label, multicenter trial evaluating the pharmacokinetic profile, tolerability, safety and efficacy of KALETRA oral solution containing lopinavir 80 mg per mL and ritonavir 20 mg per mL in 100 antiretroviral na´ve (44%) and experienced (56%) pediatric patients. All patients were non-nucleoside reverse transcriptase inhibitor na´ve. Patients were randomized to either 230 mg lopinavir/57.5 mg ritonavir per m² or 300 mg lopinavir/75 mg ritonavir per m². Na´ve patients also received lamivudine and stavudine. 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 three weeks of therapy in each patient. After analysis of these data, all patients were continued on the 300 mg lopinavir/75 mg ritonavir per m² dose. Patients had a mean age of 5 years (range 6 months to 12 years) with 14% less than 2 years. Mean baseline CD4+ cell count was 838 cells per mm³ and mean baseline plasma HIV-1 RNA was 4.7 log10 copies per mL.

Through 48 weeks of therapy, the proportion of patients who achieved and sustained an HIV-1 RNA less than 400 copies per mL was 80% for antiretroviral na´ve patients and 71% for antiretroviral experienced patients. The mean increase from baseline in CD4+ cell count was 404 cells per mm³ for antiretroviral na´ve and 284 cells per mm³ for antiretroviral experienced patients treated through 48 weeks. At 48 weeks, two patients (2%) had prematurely discontinued the study. One antiretroviral na´ve patient prematurely discontinued secondary to an adverse reaction, while one antiretroviral experienced patient prematurely discontinued secondary to an HIV-1 related event.

Dose selection in pediatric patients was based on the following:

  • Among patients 6 months to 12 years of age, the 230/57.5 mg per m² oral solution twice daily regimen without nevirapine and the 300/75 mg per m² oral solution 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). These doses resulted in treatment benefit (proportion of patients with HIV-1 RNA less than 400 copies per mL) similar to that seen in the adult clinical trials.
  • Among patients 12 to 18 years of age receiving 400/100 mg per m² or 480/120 mg per m² (with efavirenz) twice daily, plasma concentrations were 60-100% higher than among 6 to 12 year old patients receiving 230/57.5 mg per m². Mean apparent clearance was similar to that observed in adult patients receiving standard dose and in patients 6 to 12 years of age. Although changes in HIV-1 RNA in patients with prior treatment failure were less than anticipated, the pharmacokinetic data supports use of similar dosing as in patients 6 to 12 years of age, not to exceed the recommended adult dose.
  • For all age groups, the body surface area dosing was converted to body weight dosing using the patient's prescribed lopinavir dose.

Last reviewed on RxList: 2/6/2013
This monograph has been modified to include the generic and brand name in many instances.

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