Kaletra
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Kaletra - Scientific Information

Manufacture: AbbVie
Country: Canada
Condition: HIV Infection, Nonoccupational Exposure
Class: Protease inhibitors
Form: Tablets
Ingredients: lopinavir, ritonavir, colloidal silicon dioxide, copovidone, polyethylene glycol 3350, polyvinyl alcohol, sodium stearyl fumarate, sorbitan monolaurate, talc, titanium dioxide, yellow ferric oxide E172

Pharmaceutical information

Lopinavir

Proper name: Lopinavir
Chemical name: [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
Molecular formula and molecular mass: C37H48N4O5 628.80
Structural formula:



Physicochemical properties:
Description: Lopinavir is a white to light tan powder.
Solubility: Lopinavir is freely soluble in methanol and ethanol, soluble in isopropanol and practically insoluble in water.

Ritonavir

Proper name: Ritonavir
Chemical name: 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*)]
Molecular formula and molecular mass: C37H48N6O5S2720.95
Structural formula:


Physicochemical properties:
Description: Lopinavir is a white to light tan powder.
Solubility: Ritonavir is freely soluble in methanol and ethanol, soluble in isopropanol and practically insoluble in water.

Clinical Trials

Study Demographics and Trial Design

Table 1. Summary of Patient Demographics for Clinical Trials in Specific Indications
Study # Trial Design Dosage, Route of
Administration and
Duration
Study
Subjects
Mean Age
(Range)1
Gender
Race
(%M/F)
(%C/O)2
Mean
Baseline CD4
Cell Count
(Range)3
Mean Baseline Plasma HIV-1 RNA (Range)4
Patients With Prior Antiretroviral Therapy M98-863 Randomized, Double-blinded, Multicentre KALETRA capsules (400/100 mg b.i.d.) + stavudine + lamivudine
vs.
nelfinavir (750 mg t.i.d.) + stavudine + lamivudine
Oral
48 weeks
653 38
(19-84)
80/20
7/43
259
(2-949)
4.9
(2.6-6.8)
M97-720 (Evaluation KALETRA at 3 dose levels) Randomized, Blinded, Multicentre GRP I - KALETRA capsules (200/100 mg b.i.d.) + stavudine + lamivudine GRP II - KALETRA capsules (400/100 mg b.i.d. & 400/200 mg b.i.d.) + stavudine + lamivudine
Oral
360 weeks
100 35
(21-59)
96/4
70/30
338
(3-918)
4.9
(3.3-6.3)
M02-418 Randomized, Open-label, Multicentre KALETRA capsules daily + tenofovir DF + emitricitabine
vs.
KALETRA capsules b.i.d. + tenofovir DF + emitricitabine
Oral
48 weeks
190 39
(19-75)
78/22
54/46
260
(3-1006)
4.8
(2.6-6.4)
M98-888 Randomized, Open-label, Multicentre KALETRA capsules (400/100 mg b.i.d.) + nevirapine & NRTIs
vs.
investigator-selected PI(s) + nevirapine + NRTIs
Oral
48 weeks
288 40
(18-73)
86/14
68/32
322
(10-1059)
4.1
(2.6-6.0)
M97-765 (Evaluation lopinavir/ ritonavir at 2 dose levels) Randomized, Blinded, Multicentre KALETRA capsules (400/100 mg b.i.d. & 400/200 mg b.i.d.) + nevirapine & 2 NRTIs
Oral
144 weeks
70 40
(22-66)
90/10
73/27
372
(72-807)
4.0
(2.9-5.8)
Pediatric Use M98-940 Open-label, Multicentre Randomized
Oral
72 weeks
KALETRA oral solution (230/57.5 mg per m2) 100
(40% anti-retroviral naïve & 56% experi-enced)
5
(6 months - 12 yrs) (14% < 2 yrs)
43/57
14/86
838 4.7
KALETRA oral solution (300/75 mg per m2)

1: Measured in Years

2: % Male/Female, % Caucasian/Other

3: Measured in cells/mm3

4: Measured in log10 copies/mL

Definitions: b.i.d. = twice daily; t.i.d. = three times a day; NRTI = nucleoside reverse transcriptase inhibitor; PI = protease inhibitor; GRP = Group.

Study Results

Adult Use

Patients Without Prior Antiretroviral Therapy

Study M98-863: KALETRA capsules twice daily + stavudine + lamivudine compared to nelfinavir three times a day + stavudine + lamivudine.

Study M98-863 was a randomized, double-blind, multicentre trial comparing treatment with KALETRA capsules (400/100 mg twice daily) plus stavudine and lamivudine versus nelfinavir (750 mg three times a day) plus stavudine and lamivudine in 653 antiretroviral treatment-naïve patients. Patients had a mean age of 38 years (range: 19 to 84 years), 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).

The percent of patients with HIV RNA < 400 copies/mL and outcomes of patients through 48 weeks are summarized in Table 2.

Table 2. Outcomes of Randomized Treatment Through Week 48 (Study M98-863)
Outcome KALETRA capsules 400/100 mg
b.i.d. + d4T + 3TC
(N=326)
Nelfinavir 750 mg t.i.d.
+ 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 event 4% 4%
Discontinued for other reasons3 10% 8%

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

2: Includes confirmed viral rebound and failure to achieve confirmed less than 400 copies/mL through Week 48.

3: Includes loss to follow-up, patient’s withdrawal, non-compliance, protocol violation, and other reasons.

Definitions: b.i.d. = twice daily; t.i.d. = three times daily; d4T = stavudine; 3TC = lamivudine.

Through 48 weeks of therapy there was a statistically significant higher proportion of patients in the KALETRA arm compared to the nelfinavir arm with HIV RNA less than 400 copies/mL (75 vs. 62%, respectively) and HIV RNA less than 50 copies/mL (67 vs. 52%, respectively). Treatment response by baseline HIV RNA level subgroups is presented in Table 3.

Table 3. Proportion of Responders Through Week 48 by Baseline Viral Load (Study M98-863)
Baseline Viral Load
(HIV-1 RNA copies/mL)
KALETRA capsules 400/100 mg b.i.d.
+ d4T + 3TC
Nelfinavir t.i.d. + d4T + 3TC
< 400
copies/mL1
< 50
copies/mL2
n < 400
copies/mL1
< 50
copies/mL2
n
< 30,000 74% 71% 82 79% 79% 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 RNA < 400 copies/mL through Week 48.

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

Definitions: D4T = stavudine; 3TC = lamivudine.

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 M97-720: KALETRA capsules twice daily + stavudine + lamivudine

Study M97-720 was a randomized, blinded, multicentre trial evaluating treatment with KALETRA capsules at three dose levels (Group I: 200/100 mg twice daily and 400/100 mg twice daily; Group II: 400/100 mg twice daily and 400/200 mg twice daily) plus lamivudine (150 mg twice daily) and stavudine (40 mg twice daily) in 100 antiretroviral-naïve patients. All patients were converted to open-label KALETRA capsules at the 400/100 mg twice daily dose between Weeks 48 and 72 of the study. Patients had a mean age of 35 years (range: 21 to 59 years), 70% were Caucasian, and 96% were male. Mean baseline CD4 cell count was 338 cells/mm3 (range: 3 to 918 cells/mm3) and mean baseline plasma HIV-1 RNA was 4.9 log10 copies/mL (range: 3.3 to 6.3 log10 copies/mL).

Through 360 weeks of treatment, the proportion of patients with HIV RNA < 400 (< 50) copies/mL was 61% (59%) [N=100] (see Table 4), and the corresponding mean increase in CD4 cell count was 501 cells/mm3 (see Table 5). Thirty-nine patients (39%) discontinued the study, including 15 (15%) discontinuations due to adverse events and 1 (1%) death. Eighteen (18%) patients demonstrated loss of virologic response (two consecutive rebound HIV-1 RNA values above 400 copies/mL, one rebound HIV-1 RNA value followed by discontinuation, or failure to achieve HIV-1 RNA < 400 copies/mL). Genotypic analysis of viral isolates was conducted on these patients and an additional 10 patients with isolated HIV-1 RNA values > 400 copies/mL after Week 24. Results from 19 patients confirmed no primary or active site mutations in protease (amino acids at positions 8, 30, 32, 36, 47, 48, 50, 82, 84 and 90) or protease inhibitor (PI) phenotypic resistance.

Table 4. Summary of HIV-1 RNA Results (Study M97-720)
Proportion of Subjects with HIV-1
RNA Levels < 400 Copies/mL
Proportion of Subjects with HIV-1
RNA Levels < 50 Copies/mL
Week On-Treatment ITT (NC=F) On-Treatment ITT (NC=F)
24 87/92 (95%) 90/100 (90%) 71/90 (79%) 74/100 (74%)
48 85/94 (90%) 85/100 (85%) 76/94 (81%) 76/100 (76%)
72 82/84 (98%) 87/100 (87%) 76/84 (91%) 79/100 (79%)
204 71/72 (99%) 71/100 (71%) 70/72 (97%) 70/100 (70%)
360 61/62 (98%) 61/100 (61%) 59/62 (95%) 59/100 (59%)

Definitions: ITT (NC=F): Intent-to-treat (Noncompleter=Failure).

Table 5. Mean Change from Baseline to Week 360 in CD4 Cell Count by Baseline Value (Study M97-720)
Baseline CD4 Cell
Count Value
N1 Baseline Mean
(cells/microliter)
Week 360 Mean
(cells/microliter)
Mean (SE) Change from
Baseline to Week 360
< 50 15 22.8 555.6 532.8 (111.61)
50-199 12 121.8 597.8 476.1 (65.56)
200-349 11 272.0 745.5 473.5 (72.66)
350-499 11 408.7 1010.7 602.0 (84.13)
≥ 500 11 656.2 1065.9 409.7 (75.65)

1: Analysis includes all subjects with CD4 cell count values at both baseline and Week 360; N=60.

Definitions: SE = standard error.

Study M02-418: KALETRA capsules daily + tenofovir DF + emtricitabine compared to lopinavir/ritonavir twice daily + tenofovir DF + emtricitabine

Study M02-418 was a randomized, open-label, multicentre trial comparing treatment with KALETRA capsules 800/200 mg once daily plus tenofovir DF and emtricitabine versus KALETRA capsules 400/100 mg twice daily plus tenofovir DF and emtricitabine in 190 antiretroviral-naïve patients. Patients had a mean age of 39 years (range: 19 to 75 years), 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 responses and outcomes of randomized treatment are presented in Table 6 and Table 7, respectively. Through 48 weeks of treatment, the proportion of patients with HIV-1 RNA < 50 copies/mL was 71% (KALETRA once daily [N=115]) and 65% (KALETRA twice daily [N=75]).

Table 6. Virologic response Through Week 48 (Study M02-418)1,2
Week Proportion of Subjects Responding < 50 Copies/mL ITT (FDA TLOVR)
KALETRA capsules 800/200 mg
daily + TDF + FTC
(N=115)
KALETRA capsules 400/100 mg
b.i.d. + TDF + FTC
(N=75)
4 6% 0%
8 18% 17%
16 40% 45%
24 58% 57%
32 68% 62%
40 72% 65%
48 71% 65%

1: Roche AMPLICOR HIV-1 MONITOR Assay

2: Responders at each visit are patients who had achieved and maintained HIV-1 RNA < 50 copies/mL without discontinuation by that visit.

Definitions: b.i.d. = twice daily; TDF = tenofovir DF; FTC = emtricitabine; ITT (FDA TLOVR) = Intent-to-treat (FDA Time to Loss of Virologic Response).

Table 7. Outcomes of Randomized Treatment Through Week 48 (Study M02-418)
Outcome KALETRA capsules
800/200 mg daily + TDF + FTC
(N=115)
KALETRA capsules
400/100 mg b.i.d. + TDF + FTC
(N=75)
Responder*1 71% 65%
Virologic failure2 10% 9%
Rebound 6% 5%
Never suppressed though 48 Weeks 3% 4%
Death 0% 1%
Discontinued due to adverse event 12% 7%
Discontinued for other reasons3 7% 17%

* Corresponds to rates at Week 48 in Table 6.

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.

Definitions: b.i.d. = twice daily; TDF = tenofovir DF; FTC = emtricitabine.

Through 48 weeks of therapy, 71% of the patients in the KALETRA capsules daily arm and 65% of the patients 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 daily arm and 196 cells/mm3 for the KALETRA twice daily arm.

Study M05-730: KALETRA tablets once daily + tenofovir DF + emtricitabine compared to KALETRA tablets twice daily + tenofovir DF + emtricitabine

Study M05-730 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 8.

Table 8. Outcomes of Randomized Treatment Through Week 48 (Study M05-730)
Outcome1 KALETRA tablets
800/200 mg daily + TDF
+ FTC
(N=333)
KALETRA tablets
400/100 mg b.i.d. + TDF
+ FTC
(N=331)
Responder2 78% 77%
Virologic failure3 10% 9%
Rebound 5% 5%
Never suppressed and on study at 48 Weeks 5% 2%
Discontinued due to insufficient viral response 1% 2%
Death 1% 0%
Discontinued due to adverse event 4% 3%
Discontinued for other reasons4 8% 12%

1: Based on FDA Time to Loss of Virologic Response algorithm, a secondary endpoint for the study.

2: Patients achieved and maintained confirmed HIV RNA <50 copies/mL through Week 48.

3: Includes confirmed viral rebound, failure to suppress and on study at Week 48, and discontinued due to insufficient viral response.

4: 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 per the FDA Time to Loss of Virologic Response algorithm. The difference in response rates between groups was 0.4% (95% confidence interval for the difference, -5.9% to 6.8%); this difference was not statistically significant (p = 0.926). 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.

Patients with Prior Antiretroviral Therapy

Study M98-888: KALETRA capsules twice daily + nevirapine + NRTIs compared to investigator-selected PI(s) + nevirapine + NRTIs

Study M98-888 was a randomized, open-label, multicentre trial comparing treatment with KALETRA capsules (400/100 mg twice daily) plus nevirapine and NRTIs versus investigator-selected PI(s) plus nevirapine and NRTIs in 288 single PI-experienced non-nucleoside reverse transcriptase inhibitor (NNRTI)-naïve patients. Patients had a mean age of 40 years (range: 18 to 73 years), 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 9.

Through 48 weeks of therapy, there was a statistically significant higher proportion of patients in the KALETRA capsules arm compared to the investigator-selected PI(s) arm with HIV 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 capsules arm and 112 cells/mm3 for the investigator-selected PI(s) arm.

Table 9. Outcomes of Randomized Treatment Through Week 48 (Study M98-888)
Outcome KALETRA capsules 400/100 mg
b.i.d. + nevirapine + NRTIs
(N=148)
Investigator-selected PI(s) +
nevirapine + NRTIs
(N=140)
Responder*1 57% 33%
Virologic failure2 24% 41%
Rebound 11% 19%
Never suppressed though Week 48 13% 23%
Death 1% 2%
Discontinued due to adverse event 5% 11%
Discontinued for other reasons3 14% 13%

* Corresponds to responses at Week 48.

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.

Definition: NRTI s= nucleoside reverse transcriptase inhibitors; PI = protease inhibitor.

Study M97-765: KALETRA capsules twice daily + nevirapine + NRTIs

Study M97-765 was a randomized, blinded, multicentre trial evaluating treatment with KALETRA capsules at two dose levels (400/100 mg twice daily and 400/200 mg twice daily) plus nevirapine (200 mg twice daily) and two NRTIs in 70 single PI-experienced, NNRTI-naïve patients. Patients had a mean age of 40 years (range: 22 to 66 years), were 73% Caucasian, and were 90% male. Mean baseline CD4 cell count was 372 cells/mm3 (range: 72 to 807 cells/mm3) and mean baseline plasma HIV-1 RNA was 4.0 log10 copies/mL (range: 2.9 to 5.8 log10 copies/mL).

Through 144 weeks of treatment in Study M97-765, the proportion of patients with 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 9 (13%) discontinuations secondary to adverse events and two (3%) deaths.

Study M06-802: KALETRA tablets 800/200 mg once daily versus 400/100 mg twice daily when co-administered with NRTIs in antiretroviral-experienced, HIV-1 infected subjects

Study 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 subejcts with detectable viral loads while receiving their current antiviral therapy. 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 NRTIs 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 10.

Table 10. Ouctomes of Randomized Treatment Through Week 48 (Study M06-802)
Outcome KALETRA Once Daily + NRTIs
(n=300)
KALETRA Twice Daily +
NRTIs
(n=299)
Responder*1 55% 52%
Virologic failure2 25% 28%
Rebound 12% 14%
Never suppressed though Week 48 13% 15%
Death 1% 1%
Discontinued due to adverse event 1% 1%
Discontinued for other reasons3 15% 14%

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.

Definitions: NRTI = Nucleoside/Nucleotide reverse transcriptase inhibitor.

Pediatric Use

StudyM98-940: KALETRA oral solution twice daily in antiretroviral-naïve and experienced pediatric patients

Study M98-940 was an open-label, multicentre 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 NNRTI-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 NRTIs.

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 72 weeks of therapy, the proportion of patients who achieved and maintained HIV RNA < 400 copies/mL was 75% (33/44) for antiretroviral-naïve patients, 72% (23/32) for NRTI only experienced patients and 50% (12/24) for PI- and NRTI-experienced patients. The mean increase from baseline in CD4 cell count was 387 cells/mm3 for antiretroviral-naïve and 435 cells/mm3 for antiretroviral-experienced patients treated through 72 weeks. Two patients (2%) prematurely discontinued the study due to an adverse event or HIV-related event. One antiretroviral-naïve patient prematurely discontinued secondary to an adverse event attributed to KALETRA. One antiretroviral-experienced patient prematurely discontinued secondary to an HIV-related event.

Dose selection for patients 6 months to 12 years of age was based on the following results. 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).

Pivotal Comparative Bioavailability Studies

Studies M03-616 and M04-703 examined the relative bioavailability of lopinavir and ritonavir following single dose administration of 400/100 mg given as two KALETRA 200/50 mg tablets and three KALETRA 133.3/33.3 mg capsules using randomized, open-label, cross-over designs. Study M03-616 enrolled 63 healthy adults (46 males and 17 females) in a fasting/non-fasting design where one lot of the tablet was compared to one lot of the capsule. Study M04-703 enrolled 48 healthy adults (34 males and 14 females) in a non-fasting design where two production scale lots of the tablet were compared to one lot of the capsule.

Table 11 summarizes the comparative bioavailability of the two formulations from single KALETRA capsule and tablet doses under non-fasting (moderate-fat meal) conditions.

Table 11. Relative Bioavailability and 90% Confidence Intervals for Lopinavir and Ritonavir from Meta-Analysis of Studies M03-616 and M04-703 (Moderate-Fat Meal Conditions) Following a Single 400/100 mg Dose: Tablet to Capsule Comparison
Regimen
Test vs. Reference
Pharmacokinetic
Parameter
Geometric Mean1
Arithmetic Mean (CV%)
Relative Bioavailability
Test Reference Ratio of
Geometric
Means2
90%
Confidence
Interval
Lopinavir
Tablet vs. Capsule Cmax (mcg/mL) 8.0
8.2 (26)
6.5
6.7 (29)
1.235 1.188-1.285
AUCt (mcg•h/mL) 95.8
100.5 (33)
80.9
86.1 (38)
1.184 1.131-1.239
AUC (mcg•h/mL) 96.2
100.9 (33)
81.5
86.8 (38)
1.181 1.129-1.236
Ritonavir
Tablet vs. Capsule Cmax (mcg/mL) 0.6
0.6 (42)
0.4
0.5 (58)
1.349 1.263-1.441
AUCt (mcg•h/mL) 4.3
4.7 (42)
3.6
4.0 (49)
1.202 1.146-1.261
AUC (mcg•h/mL) 4.4
4.8 (41)
3.7
4.1 (48)
1.193 1.139-1.249

1: Antilogarithm of the least squares means for logarithms.

2: Antilogarithm of the difference (test minus reference) of the least squares means for logarithms.

Note: Includes two lots of the tablets and two lots of the capsules administered as a single 400/100 mg dose under moderate-fat meal conditions. KALETRA tablets used in these studies are identical to KALETRA tablets available on the Canadian market. KALETRA capsules are no longer marketed in Canada.

Table 12 summarizes the comparative bioavailability of the two formulations from single KALETRA capsule and tablet doses under fasting and non-fasting conditions in Study M03-616.

Table 12. Relative Bioavailability and 90% Confidence Intervals for Lopinavir and Ritonavir from Study M03-616 Following a Single 400/100 mg Dose: Tablet to Capsule Comparison
Regimen
Test vs. Reference
Pharmacokinetic
Parameter
Geometric Mean1
Arithmetic Mean (CV%)
Relative Bioavailability
Test Reference Ratio of
Geometric
Means2
90%
Confidence
Interval
Lopinavir
Tablet (Fasting) vs. Capsule (Moderate-Fat Meal) Cmax (mcg/mL) 6.95
7.2 (28)
6.3
6.6 (27)
1.101 1.032-1.175
AUCt (mcg•h/mL) 76.2
81.6 (37)
76.0
82.6 (35)
1.002 0.931-1.080
AUC (mcg•h/mL) 76.5
82.0 (37)
76.5
83.1 (35)
1.000 0.929-1.077
Fat Meal) vs. Capsule (Moderate-Fat Meal) Cmax (mcg/mL) 8.2
8.4 (26)
6.3
6.6 (27)
1.295 1.230-1.362
AUCt (mcg•h/mL) 96.7
101.9 (33)
76.0
82.6 (35)
1.272 1.197-1.351
AUC (mcg•h/mL) 97.1
102.3 (33)
76.5
83.1 (35)
1.269 1.195-1.348
Tablet (High-Fat Meal) vs. Capsule (Moderate-Fat Meal) Cmax (mcg/mL) 6.90
7.1 (25)
7.23
7.4 (21)
0.954 0.876-1.040
AUCt (mcg•h/mL) 86.6
88.3 (20)
85.5
88.5 (27)
1.012 0.924-1.108
AUC (mcg•h/mL) 87.1
88.8 (20)
86.0
88.9 (27)
1.013 0.926-1.108
Tablet (Fasting) vs. Capsule (Fasting)# Cmax (mcg/mL) 7.0
7.2 (28)
4.8
5.3 (44)
1.457 1.314-1.615
AUCt (mcg•h/mL) 76.2
81.6 (37)
46.9
56.4 (56)
1.627 1.439-1.839
AUC (mcg•h/mL) 76.5
82.0 (37)
47.4
56.9 (56)
1.616 1.431-1.824
Ritonavir
Tablet (Fasting) vs. Capsule (Moderate-Fat Meal) Cmax (mcg/mL) 0.50
0.57 (49)
0.37
0.44 (56)
1.331 1.183-1.497
AUCt (mcg•h/mL) 3.52
4.08 (48)
3.20
3.80 (50)
1.098 1.006-1.199
AUC (mcg•h/mL) 3.65
4.21 (46)
3.34
3.94 (48)
1.092 1.004-1.188
Tablet (Moderate-Fat Meal) vs. Capsule (Moderate-Fat Meal) Cmax (mcg/mL) 0.5
0.58 (45)
0.4
0.44 (56)
1.396 1.286-1.517
AUCt (mcg•h/mL) 4.1
4.65 (46)
3.2
3.80 (50)
1.270 1.189-1.356
AUC (mcg•h/mL) 4.2
4.78 (45)
3.3
3.94 (48)
1.254 1.177-1.336
Tablet (High-Fat Meal) vs. Capsule (Moderate-Fat Meal) Cmax (mcg/mL) 0.5
30.57 (39)
0.47
0.53 (59)
1.147 0.987-1.333
AUCt (mcg•h/mL) 4.32
4.55 (34)
3.76
4.09 (42)
1.149 1.048-1.258
AUC (mcg•h/mL) 4.4
44.68 (33)
3.91
4.23 (41)
1.136 1.040-1.240
Tablet (Fasting) vs. Capsule (Fasting)3 Cmax (mcg/mL) 0.5
0.57 (49)
0.3
0.38 (67)
1.707 1.495-1.950
AUCt (mcg•h/mL) 3.5
4.08 (48)
2.2
2.86 (64)
1.579 1.402-1.778
AUC (mcg•h/mL) 3.7
4.21 (46)
2.4
2.99 (61)
1.532 1.376-1.706

1: Antilogarithm of the least squares means for logarithms.

2: Antilogarithm of the difference (test minus reference) of the least squares means for logarithms.

3: The relative bioavailability of the tablet administered under fasting conditions with the capsule administered under fasting conditions does not reflect recommended dosing conditions.

Note: All formulations administered as a single 400/100 mg dose. KALETRA tablets used in this study are identical to KALETRA tablets available on the Canadian market. KALETRA capsules are no longer marketed in Canada.

Table 13 summarizes the comparative bioavailability of the two formulations from single KALETRA capsule and tablet doses under non-fasting conditions in Study M04-703.

Table 13. Relative Bioavailability and 90% Confidence Intervals for Lopinavir and Ritonavir from Study M04-703 (Moderate-Fat Meal Conditions) Following a Single 400/100 mg Dose: Tablet to Capsule Comparison
Regimen
Test vs. Reference
Pharmacokinetic
Parameter
Geometric Mean1
Arithmetic Mean (CV%)
Relative Bioavailability
Test Reference Ratio of
Geometric
Means2
90%
Confidence
Interval
Lopinavir
Tablet (Lot 1) vs. Capsule Cmax (mcg/mL) 8.1
8.29 (26)
6.6
6.92 (30)
1.227 1.158-1.300
AUCt (mcg•h/mL) 95.7
100.4 (33)
84.5
91.6 (39)
1.132 1.062-1.208
AUC (mcg•h/mL) 96.2
101.0 (33)
85.2
92.5 (40)
1.129 1.059-1.204
Tablet (Lot 2) vs. Capsule Cmax (mcg/mL) 7.7
7.94 (26)
6.6
6.92 (30)
1.170 1.104-1.241
AUCt (mcg•h/mL) 93.2
98.7 (35)
84.5
91.6 (39)
1.102 1.034-1.176
AUC (mcg•h/mL) 93.6
99.2 (35)
85.2
92.5 (40)
1.099 1.031-1.172
Ritonavir
Tablet (Lot 1) vs. Capsule Cmax (mcg/mL) 0.6
0.63 (38)
0.4
0.51 (59)
1.378 1.242-1.530
AUCt (mcg•h/mL) 4.3
4.59 (37)
3.8
4.23 (48)
1.151 1.075-1.232
AUC (mcg•h/mL) 4.5
4.72 (37)
3.9
4.35 (47)
1.148 1.075-1.226
Tablet (Lot 2) vs. Capsule Cmax (mcg/mL) 0.6
0.60 (43)
0.4
0.51 (59)
1.291 1.163-1.433
AUCt (mcg•h/mL) 4.3
4.64 (40)
3.8
4.23 (48)
1.152 1.076-1.234
AUC (mcg•h/mL) 4.4
4.75 (40)
3.9
4.35 (47)
1.147 1.074-1.225

1: Antilogarithm of the least squares means for logarithms.

2: Antilogarithm of the difference (test minus reference) of the least squares means for logarithms.

Note: All formulations administered as a single 400/100 mg dose. KALETRA tablets used in this study are identical to KALETRA tablets available on the Canadian market. KALETRA capsules are no longer marketed in Canada.

Table 14 summarizes the comparative bioavailability from single tablet doses under fasting and non-fasting conditions in Study M03-616.

Table 14. Relative Bioavailability and 90% Confidence Intervals for Lopinavir and Ritonavir from Study M03-616 Following a Single 400/100 mg Dose: Tablet Food Effect Comparison
Regimen
Test vs. Reference
Pharmacokinetic
Parameter
Geometric Mean1
Arithmetic Mean (CV%)
Relative Bioavailability
Test Reference Ratio of
Geometric
Means2
90%
Confidence
Interval
Lopinavir
Tablet (Moderate-Fat) vs. Tablet (Fasting) Cmax (mcg/mL) 8.2
8.38 (26)
7.0
7.16 (28)
1.176 1.111-1.244
AUCt (mcg•h/mL) 96.7
101.9 (33)
76.2
81.6 (37)
1.269 1.191-1.352
AUC (mcg•h/mL) 97.1
102.3 (33)
76.5
82.0 (37)
1.269 1.191-1.352
Tablet (High-Fat Meal) vs. Tablet (Fasting) Cmax (mcg/mL) 6.9
7.08 (25)
7.0
7.40 (38)
0.993 0.877-1.124
AUCt (mcg•h/mL) 86.6
88.3 (20)
73.0
79.9 (45)
1.187 1.028-1.371
AUC (mcg•h/mL) 87.1
88.8 (20)
73.3
80.2 (44)
1.189 1.029-1.373
Tablet (High-Fat Meal) vs. Tablet (Moderate-Fat Meal) Cmax (mcg/mL) 6.9
7.08 (25)
8.2
8.34 (21)
0.844 0.780-0.913
AUCt (mcg•h/mL) 86.6
88.3 (20)
94.3
96.8 (23)
0.918 0.859-0.982
AUC (mcg•h/mL) 87.1
88.8 (20)
94.7
97.2 (23)
0.919 0.861-0.982
Ritonavir
Tablet (Moderate-Fat) vs. Tablet (Fasting) Cmax (mcg/mL) 0.5
0.58 (45)
0.5
0.57 (49)
1.049 0.943-1.167
AUCt (mcg•h/mL) 4.1
4.65 (46)
3.5
4.08 (48)
1.156 1.066-1.253
AUC (mcg•h/mL) 4.2
4.78 (45)
3.7
4.21 (46)
1.149 1.063-1.241
Tablet (High-Fat Meal) vs. Tablet (Fasting) Cmax (mcg/mL) 0.5
0.57 (39)
0.5
0.57 (59)
1.103 0.920-1.323
AUCt (mcg•h/mL) 4.3
4.55 (34)
3.5
3.99 (55)
1.247 1.071-1.453
AUC (mcg•h/mL) 4.4
4.68 (33)
3.6
4.10 (54)
1.239 1.068-1.436
Tablet (High-Fat Meal) vs. Tablet (Moderate-Fat Meal) Cmax (mcg/mL) 0.5
0.57 (39)
0.6
0.60 (45)
0.973 0.853-1.109
AUCt (mcg•h/mL) 4.3
4.55 (34)
4.1
4.43 (38)
1.042 0.977-1.111
AUC (mcg•h/mL) 4.4
4.68 (33)
4.3
4.56 (37)
1.040 0.977-1.107

1: Antilogarithm of the least squares means for logarithms.

2: Antilogarithm of the difference (test minus reference) of the least squares means for logarithms.

Note: All formulations administered as a single 400/100 mg dose. KALETRA tablets used in this study are identical to KALETRA tablets available on the Canadian market.

The average lopinavir Tmax for the tablet under fasting conditions, following a moderate-fat meal and following a high fat meal were 3.6, 4.0 and 5.4 hours, respectively. The average ritonavir Tmax for the tablet under fasting conditions, following a moderate-fat meal and following a high fat meal were 3.4, 4.0 and 5.4 hours, respectively. The lopinavir terminal phase half-lives were similar for all regimens and ranged, on average, from 2.6 to 2.7 hours. The ritonavir terminal phase half-lives were similar for all regimens and ranged, on average, from 4.2 to 4.7 hours.

Study M06-858 examined the relative bioavailability of lopinavir and ritonavir following single dose administration of 400/100 mg given as four KALETRA 100/25 mg tablets and given as two KALETRA 200/50 mg tablets using a randomized, open-label cross-over design under fasting conditions in 44 healthy adults (35 males, 9 females).

Table 15 summarizes the comparative bioavailability of the two formulations from single KALETRA 100/25 mg tablet and 200/50 mg tablet doses under fasting conditions.

Table 15. Relative Bioavailability and 90% Confidence Intervals for Lopinavir and Ritonavir from Study M06-858 Following a Single 400/100 mg Dose: 100/25 mg Tablet to 200/50 mg Tablet Comparison
Regimen
Test vs. Reference
Parameter Geometric Mean1
Arithmetic Mean (CV%)
Relative Bioavailability
Test Reference Ratio of
Geometric
Means2
Confidence Interval
90%
Lopinavir
100/25 mg tablet vs. 200/50 mg tablet Cmax (mcg/mL) 5.36
5.66 (30%)
5.23
5.47 (31%)
1.03 0.964-1.090
AUCT (mcg•h/mL) 61.02
66.61 (38%)
58.50
62.33 (35%)
1.05 0.975-1.120
AUCI (mcg•h/mL) 61.22
66.89 (38%)
58.68
62.56 (36%)
1.05 0.975-1.120
Tmax (h)# 3.48 (50%) 3.59 (36%)
T1/2 (h)# 2.74 (32%) 2.74 (31%)
Ritonavir
100/25 mg tablet vs. 200/50 mg tablet Cmax (mcg/mL) 0.37
0.42 (52%)
0.36
0.40 (47%)
1.04 0.943-1.139
AUCT (mcg•h/mL) 2.97
3.29 (43%)
2.89
3.14 (39%)
1.03 0.959-1.103
AUCI (mcg•h/mL) 3.01
3.33 (43%)
2.93
3.18 (39%)
1.03 0.959-1.102
Tmax (h)3 3.42 (53%) 3.31 (36%)
T1/2 (h)3 5.08 (19%) 5.05 (18%)

1: Antilogarithm of the least squares means for logarithms.

2: Antilogarithm of the difference (test minus reference) of the least squares means for logarithms.

3: Expressed as arithmetic mean (CV%) only.

Detailed Pharmacology

Pharmacodynamics

A Phase 1, multiple-dose, open-label, placebo and active controlled (moxifloxacin 400 mg once daily), randomized study was conducted according to a four-way crossover design in healthy volunteers. Two dosage regimens of lopinavir/ritonavir were examined, a therapeutic dose of 400/100 mg twice daily and a supratherapeutic dose of 800/200 mg twice daily. Digital electrocardiograms (EKGs/ECGs) were performed in triplicate on study Day 3 and compared to time-matched baseline EKGs. On Day 3, lopinavir concentrations were approximately 1.5- to 3-fold higher than those observed at steady state with the 400/100 mg twice daily or the 800/200 mg once daily dose. At these increased concentrations, the maximum increase in QTcF was 3.6 msec with an upper 95% CI of 6.3 msec for 400/100 mg twice daily, and 13.1 msec with an upper bound 95% CI of 15.8 msec for supratherapeutic dose of 800/200 mg twice daily. Exposure-response analysis were conducted with both lopinavir and ritonavir concentrations as they contributed equally to the QTc effect, the model predicted no effect (the 95% upper CI of QTcF interval less than 10 msec) up to combined lopinavir and ritonavir concentrations approximately 35 to 70% higher than maximum concentrations observed with 400/100 mg twice daily or 800/200 mg once daily dosing. Therefore, lopinavir/ritonavir at approved doses is unlikely to result in clinically significant QTcF prolongation.

The absolute PR interval on Day 3 and change from baseline were also evaluated. Mean change from baseline in PR interval of 11.6 to 31.2 msec was noted in subjects receiving KALETRA up to a supratherapeutic dose of 800/200 mg twice daily on study Day 3. The maximum PR interval was 286 msec and no second or third degree heart block was observed. Exposure-response analysis predicted that the PR effect of lopinavir/ritonavir plateaus around 20 msec, thus lopinavir/ritonavir 400/100 mg twice daily is unlikely to result in clinically significant PR prolongation.

Pharmacokinetics

For details regarding the lopinavir/ritonavir pharmacokinetics refer to the ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics section.

The effects of co-administration of KALETRA on the AUC, Cmax and Cmin are summarized in Table 16 (effect of other drugs on lopinavir) and Table 17 (effect of KALETRA on other drugs).

Effect of Co-Administered Drugs on Lopinavir

Table 16. Drug Interactions: Pharmacokinetic Parameters for Lopinavir in the Presence of the Co-administered Drug
Co-administered
Drug
Dose of
Co-administered Drug (mg),
Duration
Dose of KALETRA
(mg), Duration
n Ratio (with/without co-administered drug) of
Lopinavir Pharmacokinetic Parameters
(90% CI); No Effect = 1.00
Cmax AUC Cmin
Amprenavir1 750 b.i.d., 10 d 400/100 capsule b.i.d.,
21 d
12 0.72
(0.65, 0.79)
0.62
(0.56, 0.70)
0.43
(0.34, 0.56)
Atorvastatin 20 daily, 4 d 400/100 capsule b.i.d.,
14 d
12 0.90
(0.78, 1.06)
0.90
(0.79, 1.02)
0.92
(0.78, 1.10)
Boceprevir 800 mg q8h, 6 d 400/100 tablet b.i.d., 22 d 39 0.70 (0.65, 0.77) 0.66 (0.60, 0.72) 0.57 (0.49, 0.65)
Efavirenz2 600 qHS, 9 d 400/100 capsule b.i.d.,
9 d
11, 7* 0.97
(0.78, 1.22)
0.81
(0.64, 1.03)
0.61
(0.38, 0.97)
600 qHS, 9 d 500/125 tablet b.i.d.,
10 d
19 1.12
(1.02, 1.23)
1.06
(0.96, 1.17)
0.90
(0.78, 1.04)
600 qHS, 9 d 600/150 tablet b.i.d.,
10 d
23 1.36
(1.28, 1.44)
1.36
(1.28, 1.44)
1.32
(1.21, 1.44)
Fosamprenavir8 700 b.i.d. plus ritonavir 100 b.i.d., 14 d 400/100 capsule b.i.d.,
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 b.i.d.,
16 d
12 0.89
(0.80, 0.99)
0.87
(0.75, 1.00)
0.75
(0.55, 1.00)
Nelfinavir 1000 b.i.d., 10 d 400/100 capsule b.i.d.,
21 d
13 0.79
(0.70, 0.89)
0.73
(0.63, 0.85)
0.62
(0.49, 0.78)
Nevirapine 200 b.i.d., steady-state (> 1 yr)3 400/100 capsule b.i.d.,
steady-state (> 1 yr)
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 daily,
2 wk, b.i.d. 1 wk4
300/75 mg/m2 oral
solution b.i.d., 3 wk
12, 15* 0.86
(0.64, 1.16)
0.78
(0.56, 1.09)
0.45
(0.25, 0.81)
Omeprazole 40 daily, 5 d 400/100 tablet b.i.d.,
10 d
11 1.08
(0.99, 1.17)
1.07
(0.99, 1.15)
1.03
(0.90, 1.18)
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)
Pravastatin 20 daily, 4 d 400/100 capsule b.i.d.,
14 d
12 0.98
(0.89, 1.08)
0.95
(0.85, 1.05)
0.88
(0.77, 1.02)
Ranitidine 150 single dose 400/100 tablet b.i.d.,
10 d
12 0.98
(0.95, 1.02)
0.98
(0.94, 1.01)
0.93
(0.89, 0.98)
800/200 tablet once daily, 10 d 11 0.98
(0.95, 1.01)
0.96
(0.90, 1.02)
0.85
(0.67, 1.08)
Rifabutin 150 daily, 10 d 400/100 capsule b.i.d.,
20 d
14 1.08
(0.97, 1.19)
1.17
(1.04, 1.31)
1.20
(0.96, 1.65)
Rifampin 600 daily, 10 d 400/100 capsule b.i.d.,
20 d
22 0.45
(0.40, 0.51)
0.25
(0.21, 0.29)
0.01
(0.01, 0.02)
600 daily, 14 d7 800/200 capsule b.i.d.,
9 d5
10 1.02
(0.85, 1.23)
0.84
(0.64, 1.10)
0.43
(0.19, 0.96)
400/400 capsule b.i.d.,
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 contraindicated [see (CONTRAINDICATIONS) and (DRUG INTERACTIONS)].
Ritonavir2 100 b.i.d.,
3 to 4 wk3
400/100 capsule b.i.d.,
3 to 4 wk
8, 21* 1.28
(0.94, 1.76)
1.46
(1.04, 2.06)
2.16
(1.29, 3.62)
Telaprevir 750 mg, q8h, 10 d 400/100 b.i.d., 20 d 12 0.96 (0.87, 1.05) 1.06 (0.96, 1.17) 1.14 (0.96, 1.36)
Tenofovir9 300 mg daily, 14 d 400/100 capsule b.i.d., 14 d 24 NC† NC† NC†
Tipranavir/ ritonavir3 500/200 mg b.i.d.,
(28 doses)
400/100 capsule b.i.d.,
(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-negative subjects unless otherwise indicated. Drug interaction studies were not performed with the once daily regimen of KALETRA, except for omeprazole and ranitidine.

1: KALETRA at dosage of 400/100 mg should not be used with amprenavir.

2: The pharmacokinetics of ritonavir are unaffected by concurrent efavirenz.

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 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.

6: 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.

7: 28% ≥ Grade 2 transaminases were noted in this study.

8: Data extracted from the fosamprenavir labelling.

9: Data extracted from the tenofovir labelling.

10: Intensive pharmacokinetic analysis.

11: Drug levels obtained at 8 to 16 hrs post-dose.

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

† No Change

Definitions: b.i.d. = twice daily; d = day; wk = week; yr = year; qHS = every night.

Effect of KALETRA on Co-Administered Drugs

Table 17. Drug Interactions: Pharmacokinetic Parameters for Co-administered Drug in the Presence of KALETRA
Co-administered Drug Dose of Co-administered Drug (mg), Duration Dose of KALETRA (mg), Duration n Ratio (with/without KALETRA) of Co-administered Drug Pharmacokinetic Parameters (90% CI);
No Effect = 1.00
Cmax AUC Cmin
Amprenavir1 1200 b.i.d., 14 d alone vs. 750 b.i.d., 10 d combo 400/100 capsule b.i.d.,
21 d
11 1.12
(0.91, 1.39)
1.72
(1.41, 2.09)
4.57
(3.51, 5.95)
Atorvastatin 20 daily, 4 d 400/100 capsule b.i.d.,
14 d
12 4.67
(3.35, 6.51)
5.88
(4.69, 7.37)
2.28
(1.91, 2.71)
Boceprevir 800 mg q8h, 6 d 400/100 tablet b.i.d., 22 d 39 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
b.i.d., 10 d
15 0.91
(0.84, 0.97)
1.05
(0.96, 1.16)
N/A
Efavirenz 600 qHS, 9 d 400/100 capsule b.i.d.,
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 mcg daily, 21 d
(norethindrone-mestranol)
400/100 capsule
b.i.d., 14 d
12 0.59
(0.52, 0.66)
0.58
(0.54, 0.62)
0.42
(0.36, 0.49)
Fosamprenavir5 700 b.i.d. plus ritonavir 100 b.i.d., 14 d 400/100 capsule b.i.d.,
14 d
18 0.42
(0.30, 0.58)
0.37
(0.28, 0.49)
0.35
(0.27, 0.46)
Indinavir1 800 t.i.d., 5 d alone fasting vs. 600 b.i.d., 10 d with KALETRA nonfasting 400/100 capsule
b.i.d., 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 b.i.d.,
16 d
12 1.13
(0.91, 1.40)
3.04
(2.44, 3.79)
NA
Lamotrigine 100 b.i.d., 12 d vs. 100 b.i.d., 8 d alone 400/100 capsule b.i.d., 12 d 18 0.54 (0.49, 0.58) 0.5 (0.47, 0.54) 0.44 (0.40, 0.47)
200 b.i.d., 9 d vs. 100 b.i.d., 8 d alone 400/100 capsule b.i.d., 9 d 15 1.03 (0.90, 1.17) 0.91 (0.82, 1.02) 0.79 (0.69, 0.90)
Maraviroc 300 mg b.i.d 400/100 capsule b.i.d. 11 1.97 (1.66, 2.34) 3.95 (3.43, 4.56) 9.24 (7.98, 10.7)
Methadone 5 single dose 400/100 capsule
b.i.d., 10 d
11 0.55
(0.48, 0.64)
0.47
(0.42, 0.53)
NA
Nelfinavir1


M8 metabolite
1250 b.i.d., 14 d alone vs. 1000 b.i.d., 10 d combo 400/100 capsule b.i.d.,
21 d
13 0.93
(0.82, 1.05)
2.36
(1.91, 2.91)
1.07
(0.95, 1.19)
3.46
(2.78, 4.31)
1.86
(1.57, 2.22)
7.49
(5.85, 9.58)
Nevirapine 200 b.i.d., steady-state (> 1 yr)3 400/100 capsule
b.i.d., 20 d
5, 6* 1.05
(0.72, 1.52)
1.08
(0.72, 1.64)
1.15
(0.71, 1.86)
Norethindrone 1 daily, 21 d
(norethindrone-mestranol)
400/100 capsule
b.i.d., 14 d
12 0.84
(0.75, 0.94)
0.83
(0.73, 0.94)
0.68
(0.54, 0.85)
Pravastatin 20 daily, 4 d 400/100 capsule b.i.d.,
14 d
12 1.26
(0.87, 1.83)
1.33
(0.91, 1.94)
N/A
Rifabutin

25-O-desacetyl rifabutin

Rifabutin + 25-O-desacetyl rifabutin3
300 daily, 10 d alone vs. 150 daily, 10 d combo 400/100 capsule b.i.d.,
10 d
12 2.12
(1.89, 2.38)
23.6
(13.7, 25.3)
3.46
(3.07, 3.91)
3.03
(2.79, 3.30)
47.5
(29.3, 51.8)
5.73
(5.08, 6.46)
4.90
(3.18, 5.76)
94.9
(74.0, 122)
9.53
(7.56, 12.01)
Saquinavir1 1200 t.i.d., 5 d alone vs. 800 b.i.d., 10 d with KALETRA 400/100 capsule b.i.d.,
15 d
14 6.34
(5.32, 7.55)
9.62
(8.05, 11.49)
16.74
(13.73, 20.42)
800 b.i.d., 10 d with KALETRA vs. 1200 b.i.d., 5 d with KALETRA 0.984
(0.74, 1.30)
0.974
(0.73, 1.28)
0.954
(0.70, 1.29)
Rosuvastatin620 mg daily, 7 d400/100 tablet
b.i.d., 7 d
154.66
(3.4, 6.4)
2.08
(1.66, 2.6)
1.04
(0.9, 1.2)
Telaprevir 750 mg, q8h, 10 d 400/100 b.i.d., 20 d 12 0.47 (0.41, 0.52) 0.46 (0.41, 0.52) 0.48 (0.40, 0.56)
Tenofovir7 300 mg daily, 14 d 400/100 capsule b.i.d., 14 d 24 NC† 1.32
(1.26, 1.38)
1.51
(1.32, 1.66)

All interaction studies conducted in healthy, HIV-negative subjects unless otherwise indicated. Drug interaction studies were not performed with the once daily regimen of KALETRA.

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

4: Ratios are for saquinavir 1200 twice daily + KALETRA vs. saquinavir 800 twice daily + KALETRA.

5: Data extracted from the fosamprenavir labeling.

6: Data extracted from the rosuvastatin package insert and results presented at the 2007 Conference on Retroviruses and Opportunistic Infection (Hoody, et al., abstract L-107, poster # 564).

7: Data extracted from the tenofovir labelling.

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

† No Change

Definitions: b.i.d. = twice daily; d = day; wk = week; yr = year; qHS = every night; N/A = Not Available.

Toxicology

The toxicology of lopinavir has been assessed in mice, rats, dogs and rabbits in studies ranging in duration from a single dose to nine months of oral administration. The most significant target organ for toxicity in the preclinical toxicity studies has been the liver.

Acute Toxicity

Lopinavir alone or in combination with ritonavir at a 2:1 ratio has a low order of acute toxicity in rodents by the oral route but is more toxic when administered as an intravenous injection. The acute oral approximate lethal dose (ALD) of lopinavir when given alone was > 2500 mg/kg for rats. Toxic signs were limited to rales and labored/noisy respiration in those rats that received 500 mg/kg or higher. The oral ALD of the lopinavir/ritonavir combination was >1250/625 mg/kg for both mice and rats. Toxic signs for both species included decreased activity, ataxia, dyspnea and squinting. In addition, increased salivation was observed in rats.

When administered intravenously, the ALD was > 62.5/31.3 mg/kg for mice and 31.3/15.6 mg/kg for rats. Signs of toxicity for mice included squinting and red or greenish urine. Signs of toxicity for rats included red urine and ataxia. In addition, death was observed in those rats given a dose of 31.3/15.6.mg/kg or higher.

Long-Term Toxicity

Repeated dose toxicity studies in rodent and dogs have identified liver, thyroid, blood, spleen and kidney as the target organs.

Due to hepatic toxicity (rats) and gastrointestinal toxicity (dogs), the 6-month rat study and the 6- and 9-month dog studies were carried out at systemic exposures lower than exposures of humans at the recommended dose of treatment. Based on the exposures achieved in the long-term toxicity studies in rats and dogs, the clinical relevance of the animal data is unknown. The typical human exposure to lopinavir/ritonavir is approximately 160/10 mcg•h/mL.

Effects on the Liver

Mouse

A three-month oral maximum-tolerated dosage study was conducted in mice at dosages of 0, 20/10, 60/30 and 200/100 mg/kg/day. Hepatic toxicity observed in mice given 200/100 mg/kg/day (458/62 mcg•h/mL) was characterized by increased hepatic enzymes [alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyl transpeptidase (GGT)] and liver weights and histopathological changes (cytoplasmic vacuolation, necrosis, subacute inflammation and hepatocytomegaly). Elevations of cholesterol and triglyceride levels were also noted at this dosage level. Increased liver weights and cholesterol levels occurred at a dosage of 60/30 mg/kg/day. No signs of toxicity were seen in the dosage group of 20/10 mg/kg/day with corresponding mean AUC values of 43/3 mcg•h/mL.

Rat

A lopinavir/ritonavir combination was administered to adult rats by oral gavage for a period of two weeks to six months. Hepatic changes observed in rats included increased cholesterol levels and elevated liver enzyme activities [ALT, alkaline phosphatase (ALP), GGT] and histopathologic lesions such as multinucleated hepatocytes, hepatocytomegaly, single cell necrosis and histiocytosis. These changes were observed at 50/25 mg/kg/day (mean AUC values of 73/8 mcg•h/mL) for six months. Ultrastructural evaluation of the liver revealed lysosomal inclusions in hepatocytes and minimal increase in smooth endoplasmic reticulum. Histopathologic alterations had not resolved in rats during the one-month of recovery. Due to an increase in serum ALT levels in male rats receiving 10/5 mg/kg/day, the no-hepatotoxic-effect dosage level in rats when administered for six months was considered to be less than 10/5 mg/kg/day (lopinavir/ritonavir), resulting in mean AUC values of approximately 18/1 mcg•h/mL.

A lopinavir/ritonavir combination was administered to neonatal rats (3 to 4 days old at the start of treatment) at dosages of 0, 10/5, 20/10 and 40/20 mg/kg/day for two weeks and to juvenile rats (16 days old at the start of treatment) at dosages of 0, 10/5, 30/15 and 100/50 mg/kg/day for four weeks. Changes in the liver (hepatocytomegaly) along with increases in liver weights, cholesterol levels and liver enzymes (ALT, GGT) of juvenile rats at dosages of 100/50 mg/kg/day which attained group mean AUC values of approximately 172/10 mcg•h/mL were generally similar to those observed in adult rats at the same dosages and similar drug exposures. However, significantly higher drug exposures (AUC values) were evident in neonates compared with adult rats at similar dosage levels. Less toxicity was seen in neonates relative to adults at similar drug exposures. A dosage level of 40/20 mg/kg/day (group mean AUC values of 140/13 mcg•h/mL) for two weeks in neonates produced only increased liver weights, but no microscopic findings in the liver or any other organs.

Dog

A lopinavir/ritonavir combination was administered by oral capsules to dogs for a period of two weeks to nine months. Dogs appeared to be less sensitive than rats to the hepatotoxic effects of the lopinavir/ritonavir combination. Although elevated liver enzyme activities (ALT, AST, ALP) and hepatocellular changes were seen in dogs, such changes were only observed in dogs receiving dosages of 70/35 to 100/50 mg/kg/day (mean AUC values of 189/65 mcg•h/mL) for three months or dosages of 45/15 mg/kg/day or greater for six months and achieving plasma exposures of approximately 206/53 mcg•h/mL. An increase in liver enzyme activities (ALP, ALT) and cell swelling in the liver occurred in dogs receiving 25/8 mg/kg/day (mean AUC values of 76/11 mcg•h/mL) for six months. The hepatocellular changes seen in dogs appeared to be reversible after a one-month recovery period. A dosage of 10/3 mg/kg/day (mean AUC values of 25/3 mcg•h/mL) for the lopinavir/ritonavir combination did not produce liver toxicity in dogs when treated for six months. In a nine-month study, only elevations in ALP and increased relative liver weights, but without any histopathologic changes were seen in dogs receiving dosages up to 50/20 mg/kg/day (mean AUC values of 78/39 mcg•h/mL).

Elevated GGT observed in repeated dose studies was limited to rodents only, and no increases in total bilirubin or urobilinogen were noted in rodents or dogs.

Cholestatic disease, with and without accompanying inflammation of the liver developed in anorectic, clinically compromised, high-dose dogs (AUC24 = 189/65 mcg•h/mL) in the three-month study.

Effects on the Thyroid

Mild but dose-related hypertrophy of follicular cells in the thyroid gland along with decreased serum thyroxine (T4) levels and elevated serum thyroid stimulating hormone (TSH) were observed in adult rats that received lopinavir/ritonavir combination for two to 26 weeks at dosages of 50/25 mg/kg/day or greater (mean AUC values of 65/14 mcg•h/mL or more). Neonatal and juvenile rats appeared to be less sensitive to the thyroid change produced by lopinavir/ritonavir than adult rats. No thyroid change was seen in neonatal rats receiving 40/20 mg/kg/day (mean AUC values of 140/13 mcg•h/mL) for two weeks, and thyroid change occurred in juvenile rats only when the dosage was up to 100/50 mg/kg/day (mean AUC values of 172/10 mcg•h/mL) for four weeks. All changes were reversible following a one-month recovery period. No effects on the thyroid gland were observed in any of the mouse (up to three months of treatment) or dog studies (up to nine months of treatment).

Effects on the Blood

Decreases in erythrocytic variables (erythrocyte count, hematocrit, hemoglobin) along with an increased incidence and/or severity of anisocytosis (erythrocytes of variable size) and poikilocytosis (erythrocytes with abnormal shapes) were observed in adult rats treated with lopinavir/ritonavir combination at 50/25 mg/kg/day or higher (mean AUC values of approximately 65/14 mcg•h/mL or more) for three to six months. Erythrocyte morphological changes in rats persisted through the one-month recovery period. Similar erythrocytic changes also occurred in one female dog that received dosages of 45/15 to 60/20 mg/kg/day (mean AUC values of approximately 205/53 mcg•h/mL) for six months. Erythrocytic changes were not detected in mice that received the drug combination at dosages up to 200/100 mg/kg/day (mean AUCs = 458/62 mcg•h/mL) for three months or in dogs given the drug combination at dosages up to 50/25 mg/kg/day (mean AUCs = 78/39 mcg•h/mL) for nine months. Elevations of clotting times (APTT) were observed in rats in the three-month study at systemic exposure of 161/13 mcg•h/mL and in male rats in the six-month study at systemic exposure 56/5.2 mcg•h/mL.

Effects on the Kidney and Spleen

No kidney changes were observed in rat or dog studies with durations through six months or in dogs treated for nine months. Changes in kidney (microvesicular cytoplasmic vacuolation) occurred only in mice that received a combination dosage of 200/100 mg/kg/day (mean AUCs = 458/62 mcg•h/mL) for three months. Changes in spleen (histiocytosis and increased spleen weight) were limited to rats receiving combination dosages of 50/25 mg/kg/day or higher (mean AUCs of 73/8 mcg•h/mL or greater) for six months.

Effects on the Gastrointestinal Tract and Associated ECG Changes

The most sensitive indication of toxicity in dogs that received lopinavir/ritonavir combination was gastrointestinal (GI) distress consisting of emesis, diarrhea and/or loose stools. Dosage-related GI distress occurred generally within 1 to 2 hours after dosing at all dosages tested in the repeated dose studies. In the three-month toxicity study, moderate to severe GI distress occurred in dogs receiving the high dosages of 70/35 to 100/50 mg/kg/day (mean AUCs = 189/65 mcg•h/mL), subsequently hypokalemia, hyponatremia, hypochloridemia and variable blood acid-base imbalances were observed in the affected dogs.

ECG changes occurred in dogs at systemic exposure approximately equal and higher than exposure of humans at the recommended dose for three months. Prominent U waves were the primary ECG changes seen in the affected dogs. These changes are considered to be related to hypokalemia rather that direct cardiac toxicity.

Effects on the Testis

Testicular degeneration, generally classified as minimal or mild, was observed in dogs that received the drug combination at dosages of 10/3 to 60/20 mg/kg/day (mean AUC values of 20/2 to 206/53 mcg•h/mL) for six months. Features of the degeneration included loss of germ cells, germ cell degeneration and tubular vacuolization. The incidence and severity of testicular degeneration did not appear to be related to dosage or to correlate with the systemic drug exposures. In addition, no testicular changes were seen in dogs receiving the drug combination for nine months at dosages up to 50/25 mg/kg/day (mean AUC values of 78/39 mcg•h/mL). Bilateral testicular degeneration was also noted in male dogs receiving ritonavir alone at dosages of 50 mg/kg/day (mean AUCs = 64 mcg•h/mL) or greater, for six months or longer.

Effects on Serum Cholesterol and Triglycerides

Elevations in serum cholesterol levels were seen in mice and rats, and an increase in triglyceride levels was limited to mice that received the drug combination. No effects on cholesterol or triglycerides occurred in dogs receiving the drug combination for up to nine months. Increases in cholesterol and triglycerides occurred in mice receiving a combination dosage of 100/50 mg/kg/day (mean AUCs = 292/29 mcg•h/mL) for two weeks or dosages of ≥ 60/30 mg/kg/day (mean AUCs = 121/12 mcg•h/mL) for three months. Increased cholesterol levels were evident in juvenile rats receiving dosages of ≥ 30/15 mg/kg/day (mean AUCs = 62/3 mcg•h/mL) for four weeks and in adult rats given dosages of ≥ 50/25 mg/kg/day (mean AUCs of 65/7 to 73/8 mcg•h/mL) for three or six months. The elevations of cholesterol levels were considered possibly secondary to hepatic effects.

Mutagenicity and Carcinogenicity

Long-term carcinogenicity studies of up to two years duration in mice and rats were conducted for lopinavir/ritonavir at a ratio of 2/1 at maximum tolerated dosages. In mice, dosages of lopinavir/ritonavir of 0/0, 20/10, 60/30, and 120/60 mg/kg/day achieved plasma exposures of up to 2 times (lopinavir) and 5 times (ritonavir) the human therapeutic concentrations. The findings revealed a non-genotoxic, mutagenic induction of hepatocellular adenomas and carcinomas. The relevance to human risk is unknown. In rats, dosages of lopinavir/ritonavir were 0/0, 10/5, 20/10, and 50/25 mg/kg/day and resulted in maximum plasma exposures that were slightly subtherapeutic (0.6 and 0.8 times the therapeutic plasma concentrations for lopinavir and ritonavir, respectively). There was no evidence of carcinogenicity in rats. However, neither lopinavir nor ritonavir, nor lopinavir/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.

Reproduction and Teratology

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).

Reproduction

No treatment-related malformations were observed when lopinavir in combination with ritonavir was administered to pregnant rats or rabbits. Embryonic and fetal developmental toxicities (early resorption, decreased fetal viability, decreased fetal body weight, increased incidence of skeletal variations and skeletal ossification delays) occurred in rats at a maternally toxic dosage (100/50 mg/kg/day). Based on AUC measurements, the drug exposures in rats at 100/50mg/kg/day were approximately 0.7-fold for lopinavir and 1.8-fold for ritonavir for males and females that of the exposures in humans at the recommended therapeutic dose (400/100 mg twice daily). In a peri- and post-natal study in rats, a developmental toxicity (a decrease in survival in pups between birth and postnatal day 21) occurred at 40/20 mg/kg/day and greater.

No embryonic and fetal developmental toxicities were observed in rabbits at a maternally toxic dosage (80/40 mg/kg/day). Based on AUC measurements, the drug exposures in rabbits at 80/40 mg/kg/day were approximately 0.6-fold for lopinavir and 1.0-fold for ritonavir that of the exposures in humans at the recommended therapeutic dose (400/100 mg twice daily).

Maternal and Fetal Tissue Distribution

Single oral administration of [14C]-lopinavir in combination with ritonavir to pregnant rats showed that [14C]-lopinavir-derived radioactivity was widely distributed throughout the tissues analyzed, traversed the placental barrier and was detected in the fetuses of pregnant rats. Maternal and fetal liver had the highest concentration of radioactivity; penetration into the brain was minimal.

Lacteal Excretion

Substantial amounts of radioactivity were observed in the milk following administration of a single oral dose of [14C]-lopinavir (10 mg/kg) given in combination with ritonavir (5 mg/kg). The milk to plasma ratio of radioactivity ranged from 0.084 to 1.53 during 24 hours after dosing. Radioactivity derived from [14C]-lopinavir was detectable in the milk at the first sampling time point, 0.5 hour postdose. The maximum mean concentration of radioactivity in the milk was 1.93 mcg equivalents [14C]-lopinavir/g at 5 hours post dose. The concentrations declined with time after 5 hours postdose to a mean value of 0.026 mcg equivalents [14C]-lopinavir/g at 24 hours postdose.