DrugLib.com — Drug Information Portal

Rx drug information, pharmaceutical research, clinical trials, news, and more

Kaletra (Lopinavir / Ritonavir) - Description and Clinical Pharmacology

 
 



DESCRIPTION

KALETRA (lopinavir/ritonavir) is a co-formulation of lopinavir and ritonavir. Lopinavir is an inhibitor of the HIV-1 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 is a white to light tan powder. It is freely soluble in methanol and ethanol, soluble in isopropanol and practically insoluble in water. 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 is a white to light tan powder. It is freely soluble in methanol and ethanol, soluble in isopropanol and practically insoluble in water. Ritonavir has the following structural formula:

KALETRA film-coated tablets are available for oral administration in two strengths:

  • Yellow tablets containing 200 mg of lopinavir and 50 mg of ritonavir
  • Pale yellow tablets containing 100 mg of lopinavir and 25 mg of ritonavir.

The yellow, 200 mg lopinavir/50 mg ritonavir, tablets contain the following inactive ingredients: copovidone, sorbitan monolaurate, colloidal silicon dioxide, and sodium stearyl fumarate. The following are the ingredients in the film coating: hypromellose, titanium dioxide, polyethylene glycol 400, hydroxypropyl cellulose, talc, colloidal silicon dioxide, polyethylene glycol 3350, yellow ferric oxide E172, and polysorbate 80.

The pale yellow, 100 mg lopinavir/25 mg ritonavir, tablets contain the following inactive ingredients: copovidone, sorbitan monolaurate, colloidal silicon dioxide, and sodium stearyl fumarate. The following are the ingredients in the film coating: polyvinyl alcohol, titanium dioxide, talc, polyethylene glycol 3350, and yellow ferric oxide E172.

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).

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)

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/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 µgh/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.

Plasma concentrations of lopinavir and ritonavir after administration of two 200/50 mg KALETRA tablets are similar to three 133.3/33.3 mg KALETRA capsules under fed conditions with less pharmacokinetic variability.

Effects of Food on Oral Absorption
KALETRA Tablets
No clinically significant changes in Cmax and AUC were observed following administration of KALETRA tablets under fed conditions compared to fasted conditions. Relative to fasting, administration of KALETRA tablets with a moderate fat meal (500 - 682 Kcal, 23 to 25% calories from fat) increased lopinavir AUC and Cmax by 26.9% and 17.6%, respectively. Relative to fasting, administration of KALETRA tablets with a high fat meal (872 Kcal, 56% from fat) increased lopinavir AUC by 18.9% but not Cmax. Therefore, KALETRA tablets may be taken with or without food.
KALETRA Oral Solution
Relative to fasting, administration of KALETRA oral solution with a moderate fat meal (500 - 682 Kcal, 23 to 25% calories from fat) increased lopinavir AUC and Cmax by 80 and 54%, respectively. Relative to fasting, administration of KALETRA oral solution with a high fat meal (872 Kcal, 56% from fat) increased lopinavir AUC and Cmax by 130% and 56%, respectively. To enhance bioavailability and minimize pharmacokinetic variability KALETRA oral solution 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 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-1 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 lopinavir 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.

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 naïve 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 and 15.2 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 (5.5, 5.6)].

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 oral solution 300/75 mg/m2 twice daily and 230/57.5 mg/m2 twice daily have been studied in a total of 53 pediatric patients in Study 940, ranging in age from 6 months to 12 years [see Clinical Studies]. 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).

The mean steady-state lopinavir AUC, Cmax, and Cmin were 72.6 ± 31.1 µgh/mL, 8.2 ± 2.9 and 3.4 ± 2.1 µg/mL, respectively after KALETRA oral solution 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).

The pharmacokinetics of KALETRA oral solution at approximately 300/75 mg/m2 twice daily have also been evaluated in infants at approximately 6 weeks of age (n = 9) and between 6 weeks and 6 months of age (n = 18) in Study 1030. The mean steady-state lopinavir AUC12, Cmax, and C12 were 43.4 ± 14.8 µg• h/mL, 5.2 ± 1.8 µg/mL and 1.9 ± 1.1 µg/mL, respectively, in infants at approximately 6 weeks of age, and 74.5 ± 37.9 µg• h/mL, 9.4 ± 4.9 and 3.1 ± 1.8 µg/mL, respectively, in infants between 6 weeks and 6 months of age after KALETRA oral solution was administered at approximately 300/75 mg/m2 twice daily without concomitant NNRTI therapy.

The pharmacokinetics of KALETRA soft gelatin capsule and oral solution (Group 1: 400/100 mg/m2 twice daily + 2 NRTIs; Group 2: 480/120 mg/m2 twice daily + ≥ 1 NRTI + 1 NNRTI) have been evaluated in children and adolescents age ≥ 2 years to < 18 years of age who had failed prior therapy (n=26) in Study 1038. KALETRA doses of 400/100 and 480/120 mg/m2 resulted in high lopinavir exposure, as almost all subjects had lopinavir AUC12 above 100 µg•h/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 and Drug Interactions (7)].

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 10 (effect of other drugs on lopinavir) and Table 11 (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 9 in Drug Interactions (7).

Table 10. Drug Interactions: Pharmacokinetic Parameters for Lopinavir in the Presence of the Co-administered Drug 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
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
12, 15* 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
8, 21* 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.
† 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 11. 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)
Desipramine2 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 µg 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)
Fosamprenavir3 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)
Indinavir1 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
Nelfinavir1 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 200 once daily, 14 d; twice daily, 6 d 400/100 
capsule twice daily, 20 d
5, 6* 1.05
(0.72, 1.52)
1.08
(0.72, 1.64)
1.15
(0.71, 1.86)
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-O-desacetyl 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   Ratio of parameters for indinavir, and nelfinavir, 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  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/mL, 1 µg/mL = 1.6 µM) and ranged from 4-11 nM (0.003-0.007 µg/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/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/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 naïve patients has not yet been characterized. In a study of 653 antiretroviral treatment naïve patients (Study 863), plasma viral isolates from each patient on treatment with plasma HIV-1 RNA > 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 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 naïve 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 naïve 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 (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 > 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 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 12 shows the 48-week virologic response (HIV-1 RNA <400 copies/mL) according to the number of the above protease inhibitor resistance-associated substitutions at baseline in studies 888 and 765 [see Clinical Studies and] 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 12. 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-naïve) n=130 Study 765 (Single protease inhibitor-experienced3, NNRTI-naïve) n=56 Study 957 (Multiple protease inhibitor-experienced4, NNRTI-naïve) 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-naïve patients with HIV-1 RNA >1,000 copies/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 >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 13.

Table 13. 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.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Lopinavir/ritonavir combination was evaluated for carcinogenic potential by oral gavage administration to mice and rats for up to 104 weeks. Results showed an increase in the incidence of benign hepatocellular adenomas and an increase in the combined incidence of hepatocellular adenomas plus carcinoma in both males and females in mice and males in rats at doses that produced approximately 1.6-2.2 times (mice) and 0.5 times (rats) the human exposure (based on AUC0-24hr measurement) at the recommended dose of 400/100 mg KALETRA twice daily. Administration of lopinavir/ritonavir did not cause a statistically significant increase in the incidence of any other benign or malignant neoplasm in mice or rats.

Carcinogenicity studies in mice and rats have been carried out on ritonavir. In male mice, there was a dose dependent increase in the incidence of both adenomas and combined adenomas and carcinomas in the liver. Based on AUC measurements, the exposure at the high dose was approximately 4-fold for males that of the exposure in humans with the recommended therapeutic dose (400/100 mg KALETRA twice daily). There were no carcinogenic effects seen in females at the dosages tested. The exposure at the high dose was approximately 9-fold for the females that of the exposure in humans. There were no carcinogenic effects in rats. In this study, the exposure at the high dose was approximately 0.7-fold that of the exposure in humans with the 400/100 mg KALETRA twice daily regimen. Based on the exposures achieved in the animal studies, the significance of the observed effects is not known.

Mutagenesis

Neither lopinavir nor ritonavir was found to be mutagenic or clastogenic in a battery of in vitro and in vivo assays including the Ames bacterial reverse mutation assay using S. typhimurium and E. coli, the mouse lymphoma assay, the mouse micronucleus test and chromosomal aberration assays in human lymphocytes.

Impairment of Fertility

Lopinavir in combination with ritonavir at a 2:1 ratio produced no effects on fertility in male and female rats at levels of 10/5, 30/15 or 100/50 mg/kg/day. Based on AUC measurements, the exposures in rats at the high doses were approximately 0.7-fold for lopinavir and 1.8-fold for ritonavir of the exposures in humans at the recommended therapeutic dose (400/100 mg twice daily).

CLINICAL STUDIES

Adult Patients without Prior Antiretroviral Therapy

Study 863: KALETRA Capsules twice daily + stavudine + lamivudine compared to nelfinavir three times daily + stavudine + 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 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 14.

Table 14. Outcomes of Randomized Treatment Through Week 48 (Study 863)
Outcome KALETRA+d4T+3TC
(N = 326)
Nelfinavir+d4T+3TC
(N = 327)
Responder1 75% 62%
Virologic failure2
     Rebound
     Never suppressed through Week 48
9%
7%
2%
25%
15%
9%
Death 2% 1%
Discontinued due to adverse events 4% 4%
Discontinued for other reasons3 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 < 400 copies/mL (75% vs. 62%, respectively) and HIV-1 RNA < 50 copies/mL (67% vs. 52%, respectively). Treatment response by baseline HIV-1 RNA level subgroups is presented in Table 15.

Table 15. 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/mL 1 <50 copies/mL 2 n <400 copies/mL 1 <50 copies/mL 2 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/mm3 for the KALETRA arm and 195 cells/mm3 for the nelfinavir arm.

Study 730: KALETRA Tablets once daily + tenofovir DF + emtricitabine compared to KALETRA Tablets twice daily + tenofovir DF + 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-naïve 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/mm3 (range: 20 to 775 cells/mm3) and mean baseline plasma HIV-1 RNA was 5.0 log10 copies/mL (range: 1.7 to 7.0 log10 copies/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 730)
Outcome KALETRA Once Daily + TDF + FTC
(n = 333)
KALETRA Twice Daily + TDF + FTC
(n = 331)
Responder1 78% 77%
Virologic failure2
     Rebound
     Never suppressed through Week 48
10%
5%
5%
8%
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 < 50 copies/mL (95% confidence interval for the difference, -5.9% to 6.8%). Mean CD4+ cell count increases at Week 48 were 186 cells/mm3 for the KALETRA once daily arm and 198 cells/mm3 for the KALETRA twice daily arm.

Adult Patients with Prior Antiretroviral Therapy

Study 888: KALETRA Capsules twice daily + nevirapine + NRTIs compared to investigator-selected protease inhibitor(s) + nevirapine + 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)-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 17.

Table 17. 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
     Rebound
     Never suppressed through Week 48
24%
11%
13%
41%
19%
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 HIV-1 RNA < 400 copies/mL (57% vs. 33%, respectively).

Through 48 weeks of therapy, the mean increase from baseline in CD4+ cell count was 111 cells/mm3 for the KALETRA arm and 112 cells/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 Co-administered 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/mm3 (range: 4 to 952 cells/mm3) and mean baseline plasma HIV-1 RNA was 4.3 log10 copies/mL (range: 1.7 to 6.6 log10 copies/mL).

Treatment response and outcomes of randomized treatment through Week 48 are presented in Table 18.

Table 18. 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/mm3 for the once daily group and 122 cells/mm3 for the twice daily group.

Other Studies Supporting Approval in Adult Patients

Study 720: KALETRA twice daily + stavudine + lamivudine
Study 765: KALETRA twice daily + nevirapine + 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/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/mL, respectively.

Through 360 weeks of treatment in study 720, the proportion of patients with HIV-1 RNA < 400 (< 50) copies/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/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 < 400 (< 50) copies/mL was 54% (50%) [n = 70], and the corresponding mean increase in CD4+ cell count was 212 cells/mm3. Twenty-seven patients (39%) discontinued the study, including 5 (7%) discontinuations secondary to adverse reactions and 2 (3%) deaths.

Pediatric Studies

Study 1030 was an open-label, multicenter, dose-finding trial evaluating the pharmacokinetic profile, tolerability, safety and efficacy of KALETRA oral solution containing lopinavir 80 mg/mL and ritonavir 20 mg/mL at a dose of 300/75 mg/m2 twice daily plus 2 NRTIs in HIV-1 infected infants ≥14 days and <6 months of age.

Ten infants, ≥14 days and <6 wks of age, were enrolled at a median (range) age of 5.7 (3.6-6.0) weeks and all completed 24 weeks. At entry, median (range) HIV-1 RNA was 6.0 (4.7-7.2) log10 copies/mL. Seven of 10 infants had HIV-1 RNA <400 copies/mL at Week 24. At entry, median (range) CD4+ percentage was 41 (16-59) with a median decrease of 1% (95% CI: -10, 18) from baseline to week 24 in 6 infants with available data.

Twenty-one infants, between 6 weeks and 6 months of age, were enrolled at a median (range) age of 14.7 (6.9-25.7) weeks and 19 of 21 infants completed 24 weeks. At entry, median (range) HIV RNA level was 5.8 (3.7-6.9) log10 copies/mL. Ten of 21 infants had HIV RNA <400 copies/mL at Week 24. At entry, the median (range) CD4+ percentage was 32 (11-54) with a median increase of 4% (95% CI: -1, 9) from baseline to week 24 in 19 infants with available data.

See Clinical Pharmacology (12.3) 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/mL and ritonavir 20 mg/mL in 100 antiretroviral naïve (44%) and experienced (56%) pediatric patients. All patients were non-nucleoside reverse transcriptase inhibitor naïve. Patients were randomized to either 230 mg lopinavir/57.5 mg ritonavir per m2 or 300 mg lopinavir/75 mg ritonavir per m2. Naïve 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/mm3 and mean baseline plasma HIV-1 RNA was 4.7 log10 copies/mL.

Through 48 weeks of therapy, the proportion of patients who achieved and sustained an HIV-1 RNA < 400 copies/mL was 80% for antiretroviral naïve patients and 71% for antiretroviral experienced patients. The mean increase from baseline in CD4+ cell count was 404 cells/mm3 for antiretroviral naïve and 284 cells/mm3 for antiretroviral experienced patients treated through 48 weeks. At 48 weeks, two patients (2%) had prematurely discontinued the study. One antiretroviral naïve 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 14 days to 6 months of age receiving 300/75 mg/m2 twice daily without nevirapine, plasma concentrations were lower than those observed in adults or in older children. This dose resulted in HIV-1 RNA < 400 copies/mL in 55% of patients (70% in those initiating treatment at <6 weeks of age).
  • Among patients 6 months to 12 years of age, the 230/57.5 mg/m2 oral solution twice daily regimen without nevirapine and the 300/75 mg/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 < 400 copies/mL) similar to that seen in the adult clinical trials.
  • Among patients 12 to 18 years of age receiving 400/100 mg/m2 or 480/120 mg/m2 (with efavirenz) twice daily, plasma concentrations were 60-100% higher than among 6 to 12 year old patients receiving 230/57.5 mg/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.

-- advertisement -- The American Red Cross
 
Home | About Us | Contact Us | Site usage policy | Privacy policy

All Rights reserved - Copyright DrugLib.com, 2006-2017