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All about: Kaletra

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Generic Name: lopinavir and ritonavir
Dosage Form: Capsules and oral solution

Kaletra Description

Kaletra (lopinavir/ritonavir) is a co-formulation of lopinavir and ritonavir. Lopinavir is an inhibitor of the HIV protease. As co-formulated in Kaletra, ritonavir inhibits the CYP3A-mediated metabolism of lopinavir, thereby providing increased plasma levels of lopinavir.

Lopinavir is chemically designated as [1S-[1R*,(R*), 3R*, 4R*]] - N - [4 - [[(2,6 - dimethylphenoxy)acetyl]amino] - 3 - hydroxy - 5 - phenyl - 1 - (phenylmethyl)pentyl]tetrahydro - alpha - (1 - methylethyl) - 2 - oxo - 1(2H) - pyrimidineacetamide. Its molecular formula is C37H48N4O5, and its molecular weight is 628.80. Lopinavir has the following structural formula:

Ritonavir is chemically designated as 10-Hydroxy-2-methyl-5-(1-methylethyl)-1- [2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester, [5S-(5R*,8R*,10R*,11R*)]. Its molecular formula is C37H48N6O5S2, and its molecular weight is 720.95. Ritonavir has the following structural formula:

Lopinavir is a white to light tan powder. It is freely soluble in methanol and ethanol, soluble in isopropanol and practically insoluble in water.

Kaletra capsules are available for oral administration in a strength of 133.3 mg lopinavir and 33.3 mg ritonavir with the following inactive ingredients: FD&C Yellow No. 6, gelatin, glycerin, oleic acid, polyoxyl 35 castor oil, propylene glycol, sorbitol special, titanium dioxide, and water.

Kaletra oral solution is available for oral administration as 80 mg lopinavir and 20 mg ritonavir per milliliter with the following inactive ingredients: Acesulfame potassium, alcohol, artificial cotton candy flavor, citric acid, glycerin, high fructose corn syrup, Magnasweet-110 flavor, menthol, natural& artificial vanilla flavor, peppermint oil, polyoxyl 40 hydrogenated castor oil, povidone, propylene glycol, saccharin sodium, sodium chloride, sodium citrate, and water.

Kaletra oral solution contains 42.4% alcohol (v/v).

Kaletra - Clinical Pharmacology

Microbiology

Mechanism of Action

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

Antiviral Activity In Vitro

The in vitro antiviral activity of lopinavir against laboratory HIV strains and clinical HIV 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) of lopinavir against five different HIV-1 laboratory strains ranged from 10-27 nM (0.006-0.017 µg/mL, 1 µg/mL = 1.6 µM) and ranged from 4-11 nM (0.003-0.007 µg/mL) against several HIV-1 clinical isolates (n = 6). In the presence of 50% human serum, the mean EC50 of lopinavir against these five laboratory strains ranged from 65-289 nM (0.04-0.18 µg/mL), representing a 7- to 11-fold attenuation. Combination drug activity studies with lopinavir and other protease inhibitors or reverse transcriptase inhibitors have not been completed.

Resistance

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

The selection of resistance to Kaletra in antiretroviral treatment naive patients has not yet been characterized. In a Phase III study of 653 antiretroviral treatment naive patients (Study 863), plasma viral isolates from each patient on treatment with plasma HIV > 400 copies/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 mutation in HIV protease, was observed in 25/76 (33%) of evaluable nelfinavir-treated patients. The selection of resistance to Kaletra in antiretroviral treatment naive 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 Phase II studies of 227 antiretroviral treatment naive and protease inhibitor experienced patients, isolates from 4 of 23 patients with quantifiable (> 400 copies/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 (nelfinavir, indinavir, or saquinavir) and one patient had received treatment with multiple protease inhibitors (indinavir, saquinavir and ritonavir). All four of these patients had at least 4 mutations associated with protease inhibitor resistance immediately prior to Kaletra therapy. Following viral rebound, isolates from these patients all contained additional mutations, some of which are recognized to be associated with protease inhibitor resistance. However, there are insufficient data at this time to identify lopinavir-associated mutational patterns in isolates from patients on Kaletra therapy. The assessment of these mutational patterns is under study.

Cross-resistance – Preclinical Studies

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

The in vitro activity of lopinavir against clinical isolates from patients previously treated with a single protease inhibitor was determined. Isolates that displayed > 4-fold reduced susceptibility to nelfinavir (n = 13) and saquinavir (n = 4), displayed < 4-fold reduced susceptibility to lopinavir. Isolates with > 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 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 NNRTI-naive patients with HIV RNA > 1000 copies/mL despite previous therapy with at least two protease inhibitors selected from nelfinavir, indinavir, saquinavir and ritonavir (Study 957). In this study, patients were initially randomized to receive one of two doses of Kaletra in combination with efavirenz and nucleoside reverse transcriptase inhibitors. The EC50 values of lopinavir against the 56 baseline viral isolates ranged from 0.5- to 96-fold higher than the wild-type EC50. Fifty-five percent (31/56) of these baseline isolates displayed a > 4-fold reduced susceptibility to lopinavir. These 31 isolates had a mean reduction in lopinavir susceptibility of 27.9-fold. Table 1 shows the 48 week virologic response (HIV RNA < 400 and < 50 copies) according to susceptibility and number of genotypic mutations at baseline in 50 evaluable patients enrolled in the study (957) described above. Because this was a select patient population and the sample size was small, the data depicted in Table 1 do not constitute definitive clinical susceptibility breakpoints. Additional data are needed to determine clinically significant breakpoints for Kaletra.

Table 1. HIV RNA Response at Week 48 by Baseline Kaletra Susceptibility and by Number of Protease Inhibitor-associated Mutations1
Lopinavir susceptibility2 at baseline HIV RNA < 400 copies/mL (%) HIV RNA < 50 copies/mL (%)

1 Lopinavir susceptibility was determined by recombinant phenotypic technology performed by Virologic; genotype also performed by Virologic.

2 Fold change in susceptibility from wild type.

3 Thirteen of the 23 patient isolates contained PI mutations at positions 82, 84, and/or 90.

< 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%)
Number of protease inhibitor mutations at baseline
Up to 5 21/23 (91%)3 19/23 (83%)
> 5 17/27 (63%) 14/27 (52%)

There are insufficient data at this time to identify lopinavir-associated mutational patterns in isolates from patients on Kaletra therapy. Further studies are needed to assess the association between specific mutational patterns and virologic response rates.

Pharmacokinetics

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 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-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-infected adult subjects (n = 19).

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

Absorption

In a pharmacokinetic study in HIV-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/mL, occurring approximately 4 hours after administration. The mean steady-state trough concentration prior to the morning dose was 7.1 ± 2.9 µg/mL and minimum concentration within a dosing interval was 5.5 ± 2.7 µg/mL. Lopinavir AUC over a 12 hour dosing interval averaged 92.6 ± 36.7 µg•h/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 liquid. When administered under fasting conditions, both the mean AUC and Cmax of lopinavir were 22% lower for the Kaletra liquid 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. For Kaletra oral solution, the corresponding increases in lopinavir AUC and Cmax were 80 and 54%, respectively. Relative to fasting, administration of Kaletra with a high fat meal (872 kcal, 56% from fat) increased lopinavir AUC and Cmax by 97 and 43%, respectively, for capsules, and 130 and 56%, respectively, for oral solution. To enhance bioavailability and minimize pharmacokinetic variability Kaletra 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-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 14C-lopinavir 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/hr (mean ± SD, n = 19).

Once Daily Dosing

The pharmacokinetics of once daily Kaletra have been evaluated in HIV-infected subjects naïve 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/mL, occurring approximately 6 hours after administration. The mean steady-state trough concentration prior to the morning dose was 3.2 ± 2.1 µg/mL and minimum concentration within a dosing interval was 1.7 ± 1/6 µg/mL. Lopinavir AUC over a 24 hour dosing interval averaged 154.1 ± 61.4 µg•h/mL.

Special Populations

Gender, Race and Age

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

Pediatric Patients

The pharmacokinetics of Kaletra 300/75 mg/m2 twice-daily and 230/57.5 mg/m2 twice-daily have been studied in a total of 53 pediatric patients, ranging in age from 6 months to 12 years. 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). Kaletra once-daily has not been evaluated in pediatric patients.

The mean steady-state lopinavir AUC, Cmax, and Cmin were 72.6 ± 31.1 µg•h/mL, 8.2 ± 2.9 and 3.4± 2.1 µg/mL, respectively after Kaletra 230/57.5 mg/m2 twice-daily without nevirapine (n = 12), and were 85.8 ± 36.9 µg•h/mL, 10.0 ± 3.3 and 3.6 ± 3.5 µg/mL, respectively, after 300/75 mg/m2 twice-daily with nevirapine (n = 12). The nevirapine regimen was 7 mg/kg twice-daily (6 months to 8 years) or 4 mg/kg twice-daily (> 8 years).

Renal Insufficiency

Lopinavir 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.

Hepatic Impairment

Lopinavir is principally metabolized and eliminated by the liver. Multiple dosing of Kaletra 400/100 mg twice-daily to HIV 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-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 PRECAUTIONS).

Drug-drug Interactions

See also CONTRAINDICATIONS, WARNINGS and PRECAUTIONS– 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).

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 co-administered 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 2 (effect of other drugs on lopinavir) and Table 3 (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 10 in PRECAUTIONS.

Table 2. Drug Interactions: Pharmacokinetic Parameters for Lopinavir in the Presence of the Co-administered Drug (See PRECAUTIONS – Table 10 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 Co-administered drug-/alone) of Lopinavir Pharmacokinetic Parameters (90% CI); No Effect = 1.00
Cmax AUC Cmin

All interaction studies conducted in healthy, HIV-negative subjects unless otherwise indicated.

1   The pharmacokinetics of ritonavir are unaffected by concurrent efavirenz.

2   Data extracted from the fosamprenavir package insert.

3  Study conducted in HIV-positive adult subjects.

4   Study conducted in HIV-positive pediatric subjects ranging in age from 6 months to 12 years.

5   Titrated to 800/200 BID as 533/133 BID x 1 d, 667/167 BID x 1 d, then 800/200 BID x 7 d, compared to 400/100 BID x 10 days alone.

6   Titrated to 400/400 BID as 400/200 BID x 1 d, 400/300 BID x 1 d, then 400/400 BID x 7 d, compared to 400/100 BID x 10 days alone.

7  Data extracted from the tenofovir package insert.

*   Parallel group design; n for Kaletra + co-administered drug, n for Kaletra alone.

†   NC = No change.

Amprenavir 750 BID, 10 d 400/100 BID, 21 d 12 0.72
(0.65, 0.79)
0.62
(0.56, 0.70)
0.43
(0.34, 0.56)
Atorvastatin 20 QD, 4 d 400/100 BID, 14 d 12 0.90
(0.78, 1.06)
0.90
(0.79, 1.02)
0.92
(0.78, 1.10)
Efavirenz1 600 QHS, 9 d 400/100 BID, 9 d 11, 7* 0.97
(0.78, 1.22)
0.81
(0.64, 1.03)
0.61
(0.38, 0.97)
Fosamprenavir2 700 BID plus ritonavir 100 BID, 14 d 400/100 BID, 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 BID, 16 d 12 0.89
(0.80, 0.99)
0.87
(0.75, 1.00)
0.75
(0.55, 1.00)
Nelfinavir 1000 BID, 10 d 400/100 BID, 21 d 13 0.79
(0.70, 0.89)
0.73
(0.63, 0.85)
0.62
(0.49, 0.78)
Nevirapine 200 BID, steady-state (> 1 yr)3 400/100 BID, 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 QD, 2 wk; BID 1 wk4 (> 1 yr) 300/75 mg/m2 BID, 3 wk 12, 15* 0.86
(0.64, 1.16)
0.78
(0.56, 1.09)
0.45
(0.25, 0.81)
Pravastatin 20 QD, 4 d 400/100 BID, 14 d 12 0.98
(0.89, 1.08)
0.95
(0.85, 1.05)
0.88
(0.77, 1.02)
Rifabutin 150 QD, 10 d 400/100 BID, 20 d 14 1.08
(0.97, 1.19)
1.17
(1.04, 1.31)
1.20
(0.96, 1.65)
Rifampin 600 QD,
10 d
400/100 BID, 20 d 22 0.45
(0.40, 0.51)
0.25
(0.21, 0.29)
0.01
(0.01, 0.02)
600 QD,
14 d
800/200 BID, 9 d5 10 1.02
(0.85, 1.23)
0.84
(0.64, 1.10)
0.43
(0.19, 0.96)
600 QD,
14 d
400/400 BID, 9 d6 9 0.93
(0.81, 1.07)
0.98
(0.81, 1.17)
1.03
(0.68, 1.56)
Co-administration of Kaletra and rifampin is not recommended.
(See PRECAUTIONS–
Table 9 and Table 10)
Ritonavir3 100 BID,
3-4 wk
400/100 BID,
3-4 wk
8, 21* 1.28
(0.94, 1.76)
1.46
(1.04, 2.06)
2.16
(1.29, 3.62)
Tenofovir7 300 mg QD, 14 d 400/100 BID, 14 d 24 NC NC NC
Table 3. Drug Interactions: Pharmacokinetic Parameters for Co-administered Drug in the Presence of Kaletra (See PRECAUTIONS – Table 10 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

All interaction studies conducted in healthy, HIV-negative subjects unless otherwise indicated.

1  Ratio of parameters for amprenavir, indinavir, nelfinavir, and saquinavir are not normalized for dose.

2  Desipramine is a probe substrate for assessing effects on CYP2D6-mediated metabolism.

3   Data extracted from the fosamprenavir package insert.

4  Effect on the dose-normalized sum of rifabutin parent and 25-O-desacetyl rifabutin active metabolite.

5   Data extracted from the tenofovir package insert.

*   Parallel group design; n for Kaletra + co-administered drug, n for co-administered drug alone.

N/A = Not available.

†   NC = No change.

Amprenavir1 750 BID, 10 d combo vs. 1200 BID, 14 d alone 400/100 BID, 21 d 11 1.12
(0.91, 1.39)
1.72
(1.41, 2.09)
4.57
(3.51, 5.95)
Atorvastatin 20 QD, 4 d 400/100 BID, 14 d 12 4.67
(3.35, 6.51)
5.88
(4.69, 7.37)
2.28
(1.91, 2.71)
Desipramine2 100 single dose 400/100 BID, 10 d 15 0.91
(0.84, 0.97)
1.05
(0.96, 1.16)
N/A
Efavirenz 600 QHS, 9 d 400/100 BID, 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 µg QD, 21 d (Ortho Novum®) 400/100 BID, 14 d 12 0.59
(0.52, 0.66)
0.58
(0.54, 0.62)
0.42
(0.36, 0.49)
Fosamprenavir3 700 BID plus ritonavir 100 BID, 14 d 400/100 BID, 14 d 18 0.42
(0.30, 0.58)
0.37
(0.28, 0.49)
0.35
(0.27, 0.46)
Indinavir1 600 BID, 10 d combo nonfasting vs. 800 TID, 5 d alone fasting 400/100 BID, 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 BID, 16 d 12 1.13
(0.91, 1.40)
3.04
(2.44, 3.79)
N/A
Methadone 5 single dose 400/100 BID, 10 d 11 0.55
(0.48, 0.64)
0.47
(0.42, 0.53)
N/A
Nelfinavir1 1000 BID, 10 d combo vs. 1250 BID, 14 d alone 400/100 BID, 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 200 QD, 14 d; BID, 6 d 400/100 BID, 20 d 5, 6* 1.05
(0.72, 1.52)
1.08
(0.72, 1.64)
1.15
(0.71, 1.86)
Norethindrone 1 QD, 21 d (Ortho Novum®) 400/100 BID, 14 d 12 0.84
(0.75, 0.94)
0.83
(0.73, 0.94)
0.68
(0.54, 0.85)
Pravastatin 20 QD, 4 d 400/100 BID, 14 d 12 1.26
(0.87, 1.83)
1.33
(0.91, 1.94)
N/A
Rifabutin 150 QD, 10 d; combo vs. 300 QD, 10 d; alone 400/100 BID, 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-O-desacetyl rifabutin4 3.46
(3.07, 3.91)
5.73
(5.08, 6.46)
9.53
(7.56, 12.01)
Saquinavir1 800 BID, 10 d combo vs. 1200 TID, 5 d alone, 400/100 BID, 15 d 14 6.34
(5.32, 7.55)
9.62
(8.05, 11.49)
16.74
(13.73, 20.42)
1200 BID, 5 d combo vs. 1200 TID, 5 d alone 400/100 BID, 20 d 10 6.44
(5.59, 7.41)
9.91
(8.28, 11.86)
16.54
(10.91, 25.08)
Tenofovir5 300 mg QD, 14 d 400/100 BID, 14 d 24 NC 1.32
(1.26, 1.38)
1.51
(1.32, 1.66)

Indications and Usage for Kaletra

Kaletra is indicated in combination with other antiretroviral agents for the treatment of HIV-infection. This indication is based on analyses of plasma HIV RNA levels and CD4 cell counts in controlled studies of Kaletra of 48 weeks duration and in smaller uncontrolled dose-ranging studies of Kaletra of 144-204 weeks duration.

Once-daily administration of Kaletra is not recommended in therapy-experienced patients.

When initiating treatment with Kaletra in therapy-naïve patients, it should be noted that the incidence of diarrhea was greater for Kaletra once-daily compared to Kaletra twice-daily in Study 418 (57% vs. 35% - events of all grades and probably or possibly related to drug; 16% vs. 5% - events of at least moderate severity and probably or possibly related to drug) (see CLINICAL PHARMACOLOGY, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION).

Description of Clinical Studies

Patients Without Prior Antiretroviral Therapy

Study 863: Kaletra twice-daily + stavudine + lamivudine compared to nelfinavir three-times-daily + stavudine + lamivudine

Study 863 is an ongoing, randomized, double-blind, multicenter trial comparing treatment with Kaletra (400/100 mg twice-daily) plus stavudine and lamivudine versus nelfinavir (750 mg three-times-daily) plus stavudine and lamivudine in 653 antiretroviral treatment naïve 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/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).

Treatment response and outcomes of randomized treatment are presented in Table 4.

Table 4. Outcomes of Randomized Treatment Through Week 48 (Study 863)
Outcome Kaletra+d4T+3TC
(N = 326)
Nelfinavir+d4T+3TC
(N = 327)

1   Patients achieved and maintained confirmed HIV 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.

Responder1 75% 62%
Virologic failure2
   Rebound
   Never suppressed through Week 48
9%
7%
2%
25%
15%
9%
Death 2% 1%
Discontinued due to adverse event 4% 4%
Discontinued for other reasons3 10% 8%

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 RNA < 400 copies/mL (75% vs. 62%, respectively) and HIV RNA < 50 copies/mL (67% vs. 52%, respectively). Treatment response by baseline HIV RNA level subgroups is presented in Table 5.

Table 5. 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

1   Patients achieved and maintained confirmed HIV RNA < 400 copies/mL through Week 48.

2   Patients achieved HIV RNA < 50 copies/mL at Week 48.

< 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

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

Study 418: Kaletra once-daily + tenofovir DF + emtricitabine compared to Kaletra twice-daily + tenofovir DF + 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 naïve 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/mm3 (range: 3 to 1006 cells/mm3) and mean baseline plasma HIV-1 RNA was 4.8 log10 copies/mL (range: 2.6 to 6.4 log10 copies/mL).

Treatment response and outcomes of randomized treatment are presented in Table 6.

Table 6. Outcomes of Randomized Treatment Through Week 48 (Study 418)
Outcome Kaletra QD
+ TDF + FTC
(n = 115)
Kaletra BID
+ TDF + FTC
(n = 75)

1   Patients achieved and maintained confirmed HIV 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.

Responder1 71% 65%
Virologic failure2
Rebound
Never suppressed through Week 48
10%
6%
3%
9%
5%
4%
Death 0% 1%
Discontinued due to an adverse event 12% 7%
Discontinued for other reasons3 7% 17%

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

Patients with Prior Antiretroviral Therapy

Study 888: Kaletra twice-daily + nevirapine + NRTIs compared to investigator-selected protease inhibitor(s) + nevirapine + NRTIs

Study 888 is a randomized, open-label, multicenter trial comparing treatment with Kaletra (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)-naïve 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/mm3 (range: 10 to 1059 cells/mm3) and mean baseline plasma HIV-1 RNA was 4.1 log10 copies/mL (range: 2.6 to 6.0 log10 copies/mL).

Treatment response and outcomes of randomized treatment through Week 48 are presented in Table 7.

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Table 7. Outcomes of Randomized Treatment Through Week 48 (Study 888)
Outcome Kaletra + nevirapine + NRTIs
(n = 148)
Investigator-Selected Protease Inhibitor(s) + nevirapine + NRTIs
(n = 140)

1   Patients achieved and maintained confirmed HIV 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.

Responder1 57% 33%
Virologic Failure2 24% 41%