Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

11.2 Pharmacodynamics
Cardiac Electrophysiology
The effect of KALETRA on QTcF interval was evaluated in a placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 39 healthy adults. The maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline-correction were 5.3 (8.1) and 15.2 (18.0) mseconds (msec) for 400/100 mg twice daily and supratherapeutic 800/200 mg twice daily KALETRA, respectively. KALETRA 800/200 mg twice daily resulted in a Day 3 mean Cmax approximately 2-fold higher than the mean Cmax observed with the approved once daily and twice daily KALETRA doses at steady state. 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)].

Pharmacokinetic Properties

11.3 Pharmacokinetics
The pharmacokinetic properties of lopinavir are summarized in Table 13. The steady-state pharmacokinetic parameters of lopinavir are summarized in Table 14. Under fed conditions, lopinavir concentrations were similar following administration of KALETRA tablets to capsules with less pharmacokinetic variability.
Under fed conditions (500 kcal, 25% from fat), lopinavir concentrations were similar following administration of KALETRA capsules and oral solution.


Table 13. Pharmacokinetic Properties of Lopinavir
Absorption
Tmax (hr)a                 4.4 ± 0.8
Effect of meal
(relative to fasting)
Tablet                   ↑ 19%b
Oral solution                ↑ 130%b
Distribution
% Bound to human plasma proteins            > 98
Vd/Fa (L)                   16.9
Metabolism
Metabolism                  CYP3A
Elimination
Major route of elimination           hepatic
a
t1/2 (h)                 6.9 ± 2.2
% of dose excreted in urine        10.4 ± 2.3
% of dose excreted in feces        82.6 ± 2.5
a. Kaletra tablet
b. Changes in AUC values


Table 14. Steady-State Pharmacokinetic Parameters of Lopinavir, Mean ± SD Pharmacokinetic Parameter                           Twice Dailya         Once Dailyb Cmax (µg/mL)                                          9.8 ± 3.7           11.8 ± 3.7 Cmin (µg/mL)                                          5.5 ± 2.7            1.7 ± 1.6 AUCtau (µg•h/mL)                                     92.6 ± 36.7         154.1 ± 61.4 a. 19 HIV-1 subjects, Kaletra 400/100 mg twice daily
b. 24 HIV-1 subjects, Kaletra 800/200 mg + emtricitabine 200 mg + tenofovir DF 300 mg 

Specific Populations


Gender, Race and Age
No gender or race related pharmacokinetic differences have been observed in adult patients. Lopinavir pharmacokinetics have not been studied in elderly patients.


Pediatric Patients
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.
Table 15. Lopinavir Pharmacokinetic Data from Pediatric Clinical Trials, Mean ± SD Cmax (μg/mL)             Cmin (μg/mL)                AUC12 (μg•hr/m) Age ≥ 6 Months to ≤ 12 years Cohort (N = 24):
8.2 ± 2.9a                   3.4 ± 2.1a                      72.6 ± 31.1a 10.0 ± 3.3b                   3.6 ± 3.5b                      85.8 ± 36.9b a. KALETRA oral solution 230/57.5 mg/m2 twice daily without nevirapine (n=12) b. KALETRA oral solution 300/75 mg/m2 twice daily with nevirapine (n=12) 

Pregnancy
The C12h values of lopinavir were lower during the second and third trimester by approximately 40% as compared to post-partum in 12 HIV-infected pregnant women received KALETRA 400 mg/100 mg twice daily. Yet this decrease is not considered clinically relevant in patients with no documented KALETRA- associated resistance substitutions receiving 400 mg/100 mg twice daily. [see Use in Specific Populations (8.1)].


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
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). KALETRA has not been studied in patients with severe hepatic impairment [see Warnings and Precautions (5.4) and Use in Specific Populations (8.6)].

Drug Interactions
KALETRA is an inhibitor of the P450 isoform CYP3A in vitro.
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.
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). For information regarding clinical recommendations, see Table 12 in Drug Interactions (7).


Table 16. Drug Interactions: Pharmacokinetic Parameters for Lopinavir in the Presence of the Co- administered Drug for Recommended Alterations in Dose or Regimen
Co-administered           Dose of Co-           Dose of       n   Ratio (in combination with Co- Drug                       administered Drug        KALETRA                  administered drug/alone) of (mg)                  (mg)                 Lopinavir Pharmacokinetic
Parameters (90% CI); No Effect
= 1.00
Cmax        AUC         Cmin
Efavirenz1                   600 at bedtime       400/100 capsule   11,      0.97        0.81        0.61 3
twice daily    7        (0.78,   (0.64, 1.03)   (0.38,
1.22)                   0.97)
600 at bedtime        500/125 tablet   19       1.12        1.06        0.90 twice daily             (1.02,   (0.96, 1.17)   (0.78,
1.23)                   1.04)
600 at bedtime        600/150 tablet   23       1.36        1.36        1.32 twice daily             (1.28,   (1.28, 1.44)   (1.21,
1.44)                   1.44)
Etravirine                   200 twice daily        400/100 mg      16       0.89        0.87        0.80 twice day           (0.82-0.96) (0.83-0.92) (0.73-0.88)
(tablets)
Fosamprenavir2             700 twice daily plus   400/100 capsule   18       1.30        1.37        1.52 ritonavir 100 twice daily      twice daily             (0.85,   (0.80, 1.55)   (0.72, 1.47)                   1.82)
Ketoconazole                 200 single dose      400/100 capsule   12       0.89        0.87        0.75 

twice daily              (0.80,   (0.75, 1.00)   (0.55,
0.99)                    1.00)
Nelfinavir              1000 twice daily        400/100 capsule     13       0.79        0.73        0.62 twice daily              (0.70,   (0.63, 0.85)   (0.49,
0.89)                    0.78)
Nevirapine          200 twice daily, steady- 400/100 capsule        22,      0.81        0.73        0.49 state                twice daily      193     (0.62,   (0.53, 0.98)   (0.28, 1.05)                    0.74)
7 mg/kg or 4 mg/kg             (> 1 yr)       12,      0.86        0.78        0.45 once daily; twice daily 1    300/75 mg/m2       153     (0.64,   (0.56, 1.09)   (0.25, wk                  oral solution             1.16)                    0.81) twice daily
Ombitasvir/          25/150/100 + dasabuvir      400/100 tablet     6     0.87 (0.76, 0.94 (0.81, 1.15 (0.93, paritaprevir/                 400                 twice daily
0.99)       1.10)        1.42)
ritonavir+dasabuvir2
Omeprazole             40 once daily, 5 d        400/100 tablet     12       1.08        1.07        1.03 twice daily, 10 d           (0.99,   (0.99, 1.15)   (0.90,
1.17)                    1.18)
40 once daily, 5 d        800/200 tablet     12       0.94        0.92        0.71 once daily, 10 d            (0.88,   (0.86, 0.99)   (0.57,
1.00)                    0.89)
Pravastatin            20 once daily, 4 d       400/100 capsule     12       0.98        0.95        0.88 twice daily, 14 d           (0.89,   (0.85, 1.05)   (0.77,
1.08)                    1.02)
Ranitidine              150 single dose          400/100 tablet     12       0.99        0.97        0.90 twice daily, 10 d           (0.95,   (0.93, 1.01)   (0.85,
1.03)                    0.95)
150 single dose          800/200 tablet     10       0.97        0.95        0.82 once daily, 10 d            (0.95,   (0.91, 0.99)   (0.74,
1.00)                    0.91)
Rifabutin                150 once daily         400/100 capsule     14       1.08        1.17        1.20 twice daily              (0.97,   (1.04, 1.31)   (0.96,
1.19)                    1.65)
Rifampin                 600 once daily         400/100 capsule     22       0.45        0.25        0.01 twice daily              (0.40,   (0.21, 0.29)   (0.01,

0.51)                       0.02)
600 once daily        800/200 capsule        10      1.02          0.84          0.43 twice daily                (0.85,     (0.64, 1.10)     (0.19,
1.23)                       0.96)
600 once daily        400/400 capsule        9       0.93          0.98          1.03 twice daily                (0.81,     (0.81, 1.17)     (0.68,
1.07)                       1.56)
Rilpivirine                 150 once daily         400/100 twice         15      0.96          0.99          0.89 daily (capsules)            (0.88-1.05) (0.89-1.10) (0.73-1.08)
Ritonavir                  100 twice daily,       400/100 capsule        8,      1.28          1.46          2.16 twice daily     213        (0.94,     (1.04, 2.06)     (1.29,
1.76)                       3.62)


Tipranavir/ritonavir      500/200 twice daily     400/100 capsule        21      0.53          0.45       0.30 (0.17, twice daily     693        (0.40,     (0.32, 0.63)     0.51)
0.69)                       0.484
(0.40,
0.58)
1 Reference for comparison is lopinavir/ritonavir 400/100 mg twice daily without efavirenz 2 Data extracted from the U.S. prescribing information of co-administered drugs.
3 Parallel group design
4 Drug levels obtained at 8-16 hours post-dose.
N/A = Not available.


Table 17. 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-    Dose of     n       Ratio (in combination with administered KALETRA                            KALETRA/alone) of Co- Drug             (mg)                           administered Drug
(mg)                                      Pharmacokinetic Parameters
(90% CI); No Effect = 1.00
Cmax          AUC             Cmin
Bedaquiline1                    400 single dose     400/100        N/A         N/A          1.22            N/A twice daily                           (1.11, 1.34)


Efavirenz                600 at bedtime,      400/100       11, 123      0.91          0.84            0.84 capsule twice               (0.72,      (0.62, 1.15) (0.58, 1.20)
daily                   1.15)
Elbasvir/ grazoprevir1    50 once daily                       10      2.87 (2.29, 3.71 (3.05,       4.58 (3.72, 3.58)          4.53)          5.64)
400/100
200 once daily                       13      7.31 (5.65,      12.86       21.70 (12.99, twice daily
9.45)         (10.25,         36.25)
16.13)
Ethinyl Estradiol        35 µg once daily     400/100         12         0.59          0.58            0.42 (Ortho Novum®) capsule twice                   (0.52,      (0.54, 0.62) (0.36, 0.49) daily                   0.66)
Etravirine               200 twice daily      400/100         16         0.70          0.65            0.55 tablet twice              (0.64-0.78) (0.59-0.71) (0.49-0.62)
day
Fosamprenavir1           700 twice daily      400/100         18         0.42          0.37            0.35 plus ritonavir capsule twice                  (0.30,      (0.28, 0.49) (0.27, 0.46) 100 twice daily        daily                   0.58)
Indinavir                600 twice daily      400/100         13         0.71          0.91            3.47 combo          capsule twice               (0.63,      (0.75, 1.10) (2.60, 4.64) nonfasting vs.        daily                   0.81)
800 three times
daily alone
fasting
Ketoconazole             200 single dose      400/100         12         1.13          3.04            N/A capsule twice               (0.91,      (2.44, 3.79)
daily                   1.40)
Maraviroc1               300 twice daily      400/100         11      1.97 (1.66, 3.95 (3.43,       9.24 (7.98, twice daily                2.34)          4.56)          10.7)
Methadone                 5 single dose       400/100         11         0.55          0.47            N/A capsule twice               (0.48,      (0.42, 0.53)
daily                   0.64)
Nelfinavir               1000 twice daily     400/100         13         0.93          1.07            1.86 combo vs.       capsule twice               (0.82,      (0.95, 1.19) (1.57, 2.22) 1250 twice daily       daily                   1.05)


alone
M8 metabolite                                                                2.36        3.46          7.49 (1.91,   (2.78, 4.31) (5.85, 9.58)
2.91)
Nevirapine                   200 once daily         400/100       5, 63      1.05        1.08          1.15 twice daily        capsule twice             (0.72,   (0.72, 1.64) (0.71, 1.86) daily                 1.52)
Norethindrone                  1 once daily         400/100        12        0.84        0.83          0.68 ®
(Ortho Novum ) capsule twice                   (0.75,   (0.73, 0.94) (0.54, 0.85) daily                 0.94)
Ombitasvir/ paritaprevir/     25/150/100 +          400/100        6      1.14 (1.01, 1.17 (1.07,   1.24 (1.14, ritonavir+ dasabuvir1         dasabuvir 400       tablet twice              1.28)        1.28)        1.34) daily               2.04 (1.30, 2.17 (1.63,   2.36 (1.00,
3.20)        2.89)        5.55)
1.55 (1.16, 2.05 (1.49,   5.25 (3.33,
2.09)        2.81)        8.28)
0.99 (0.75, 0.93 (0.75,   0.68 (0.57,
1.31)        1.15)        0.80)
Pitavastatin1                  4 once daily         400/100        23        0.96        0.80          N/A tablet twice            (0.84-1.10) (0.73-0.87)
daily
Pravastatin                   20 once daily         400/100        12        1.26        1.33          N/A capsule twice             (0.87,   (0.91, 1.94)
daily                 1.83)
Rifabutin                    150 once daily         400/100        12        2.12        3.03          4.90 combo vs. 300 capsule twice                   (1.89,   (2.79, 3.30) (3.18, 5.76) once daily alone         daily                 2.38)
25-O-desacetyl rifabutin                                                     23.6        47.5          94.9
(13.7,   (29.3, 51.8) (74.0, 122)
25.3)
Rifabutin + 25-O-desacetyl                                                   3.46        5.73          9.53 rifabutin                                                                   (3.07,   (5.08, 6.46) (7.56, 12.01) 3.91)
Rilpivirine                  150 once daily         400/100        15        1.29        1.52          1.74 
capsules              (1.18-1.40) (1.36-1.70) (1.46-2.08)
twice daily
Rosuvastatin2                      20 once daily       400/100         15          4.66       2.08          1.04 tablet twice            (3.4, 6.4)   (1.66, 2.6)   (0.9, 1.2)
daily
Tenofovir alafenamide1             10 once daily       800/200         10    2.19 (1.72, 1.47 (1.17,        N/A tablet once                  2.79)      1.85)
daily
Tenofovir disoproxil               300 once daily      400/100         24    No Change        1.32          1.51 fumarate1                                            capsule twice                         (1.26, 1.38) (1.32, 1.66) daily
1 Data extracted from the U.S. prescribing information of co-administered drugs.
2 Kiser, et al. J Acquir Immune Defic Syndr. 2008 Apr 15;47(5):570-8.
3 Parallel group design
N/A = Not available.

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


Antiviral Activity
In the absence of human serum, the mean 50% effective concentration (EC50) values of lopinavir against five different HIV-1 subtype B laboratory strains in lymphoblastic cell lines 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 in peripheral blood lymphocytes (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. 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.


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 specific amino acid substitutions could be associated with resistance to KALETRA in the virus from 37 evaluable KALETRA-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. All four of these patients had previously received treatment with at least one protease inhibitor and 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.


Cross-resistance - Nonclinical Studies
Varying degrees of cross-resistance have been observed among HIV-1 protease inhibitors. The antiviral activity in cell culture of lopinavir against clinical isolates from patients previously treated with a single protease inhibitor was determined (Table 18).
Table 18. Susceptibility Reduction to Lopinavir Against Isolates from Patients Previously Treated With a Single Protease Inhibitor
Susceptibility reduced by >4 fold                    Susceptibility reduced to LPV Indinavir (n=16)                                         5.7 fold
Nelfinavir (n=13)                                        <4 fold
Ritonavir (n=3)                                        8.32 fold
Saquinavir (n=4)                                         <4 fold

Isolates from patients previously treated with two or more protease inhibitors showed greater reductions in susceptibility to lopinavir, as described in the following section.


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 19 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 (13.2) and (13.3)] 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 19. 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              Study 888 (Single   Study 765 (Single   Study 957 (Multiple protease inhibitor      protease inhibitor-       protease inhibitor-       protease inhibitor- substitutions at      experienced2, NNRTI- experienced3, NNRTI- experienced4, NNRTI- baseline1                  naïve) n=130                naïve) n=56              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 20.


Table 20. HIV-1 RNA Response at Week 48 by Baseline Lopinavir Susceptibility1 Lopinavir susceptibility2 at HIV-1 RNA <400 copies/mL HIV-1 RNA <50 copies/mL baseline                                         (%)                             (%) < 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.