Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.2        Pharmacodynamics
Cardiac Electrophysiology

Concentration- and dose-dependent prolongation of the PR interval in the electrocardiogram has been observed in healthy volunteers receiving atazanavir. In a placebo-controlled study (AI424-076), the mean (±SD) maximum change in PR interval from the predose value was 24 (±15) msec following oral dosing with 400 mg of atazanavir (n=65) compared to
13 (±11) msec following dosing with placebo (n=67). The PR interval prolongations in this study were asymptomatic. There is limited information on the potential for a pharmacodynamic interaction in humans between atazanavir and other drugs that prolong the PR interval of the electrocardiogram [see Warnings and Precautions (5.1)].
Electrocardiographic effects of atazanavir were determined in a clinical pharmacology study of 72 healthy subjects. Oral doses of 400 mg (maximum recommended dosage) and 800 mg (twice the maximum recommended dosage) were compared with placebo; there was no concentration- dependent effect of atazanavir on the QTc interval (using Fridericia’s correction). In 1793 HIV- infected patients receiving antiretroviral regimens, QTc prolongation was comparable in the atazanavir and comparator regimens. No atazanavir-treated healthy subject or HIV-infected patient in clinical trials had a QTc interval >500 msec [see Warnings and Precautions (5.1)].

Pharmacokinetic Properties

12.3        Pharmacokinetics

The pharmacokinetics of atazanavir were evaluated in healthy adult volunteers and in HIV- infected patients after administration of REYATAZ 400 mg once daily and after administration of REYATAZ 300 mg with ritonavir 100 mg once daily (see Table 17).
Table 17:                  Steady-State Pharmacokinetics of Atazanavir in Healthy Subjects or HIV-Infected Patients in the Fed State
300 mg with ritonavir
400 mg once daily               100 mg once daily
Healthy        HIV-Infected      Healthy       HIV-Infected
Subjects         Patients        Subjects        Patients
Parameter                             (n=14)           (n=13)          (n=28)          (n=10) Cmax (ng/mL)
Geometric mean (CV%)             5199 (26)        2298 (71)       6129 (31)       4422 (58) Mean (SD)                       5358 (1371)      3152 (2231)     6450 (2031)     5233 (3033) Tmax (h)
Median                              2.5              2.0             2.7             3.0 AUC (ng•h/mL)
Geometric mean (CV%)             28132 (28)      14874 (91)      57039 (37)       46073 (66) Mean (SD)                       29303 (8263)    22262 (20159)   61435 (22911)   53761 (35294) T-half (h)
Mean (SD)                         7.9 (2.9)       6.5 (2.6)      18.1 (6.2)a       8.6 (2.3) Cmin (ng/mL)
Geometric mean (CV%)              159 (88)        120 (109)       1227 (53)        636 (97) Mean (SD)                        218 (191)       273 (298)b      1441 (757)       862 (838) a n=26.
b n=12.

Figure 1 displays the mean plasma concentrations of atazanavir at steady state after REYATAZ 400 mg once daily (as two 200-mg capsules) with a light meal and after REYATAZ 300 mg (as two 150-mg capsules) with ritonavir 100 mg once daily with a light meal in HIV-infected adult patients.
Figure 1:              Mean (SD) Steady-State Plasma Concentrations of Atazanavir 400 mg (n=13) and 300 mg with Ritonavir (n=10) for HIV-Infected Adult
Patients



Absorption

Atazanavir is rapidly absorbed with a Tmax of approximately 2.5 hours. Atazanavir demonstrates nonlinear pharmacokinetics with greater than dose-proportional increases in AUC and Cmax values over the dose range of 200 to 800 mg once daily. Steady state is achieved between Days 4 and 8, with an accumulation of approximately 2.3 fold.
Food Effect

Administration of REYATAZ with food enhances bioavailability and reduces pharmacokinetic variability. Administration of a single 400-mg dose of REYATAZ with a light meal (357 kcal, 8.2 g fat, 10.6 g protein) resulted in a 70% increase in AUC and 57% increase in C max relative to the fasting state. Administration of a single 400-mg dose of REYATAZ with a high-fat meal (721 kcal, 37.3 g fat, 29.4 g protein) resulted in a mean increase in AUC of 35% with no change in Cmax relative to the fasting state. Administration of REYATAZ with either a light meal or high-fat meal decreased the coefficient of variation of AUC and Cmax by approximately one-half compared to the fasting state.
Coadministration of a single 300-mg dose of REYATAZ and a 100-mg dose of ritonavir with a light meal (336 kcal, 5.1 g fat, 9.3 g protein) resulted in a 33% increase in the AUC and a 40% increase in both the Cmax and the 24-hour concentration of atazanavir relative to the fasting state. Coadministration with a high-fat meal (951 kcal, 54.7 g fat, 35.9 g protein) did not affect the AUC of atazanavir relative to fasting conditions and the Cmax was within 11% of fasting values. The 24-hour concentration following a high-fat meal was increased by approximately 33% due to delayed absorption; the median Tmax increased from 2.0 to 5.0 hours.
Coadministration of REYATAZ with ritonavir with either a light or a high-fat meal decreased the coefficient of variation of AUC and Cmax by approximately 25% compared to the fasting state.
Distribution

Atazanavir is 86% bound to human serum proteins and protein binding is independent of concentration. Atazanavir binds to both alpha-1-acid glycoprotein (AAG) and albumin to a similar extent (89% and 86%, respectively). In a multiple-dose study in HIV-infected patients dosed with REYATAZ 400 mg once daily with a light meal for 12 weeks, atazanavir was detected in the cerebrospinal fluid and semen. The cerebrospinal fluid/plasma ratio for atazanavir (n=4) ranged between 0.0021 and 0.0226 and seminal fluid/plasma ratio (n=5) ranged between 0.11 and 4.42.
Metabolism

Atazanavir is extensively metabolized in humans. The major biotransformation pathways of atazanavir in humans consisted of monooxygenation and dioxygenation. Other minor biotransformation pathways for atazanavir or its metabolites consisted of glucuronidation, N-dealkylation, hydrolysis, and oxygenation with dehydrogenation. Two minor metabolites of atazanavir in plasma have been characterized. Neither metabolite demonstrated in vitro antiviral activity. In vitro studies using human liver microsomes suggested that atazanavir is metabolized by CYP3A.
Elimination
14
Following a single 400-mg dose of        C-atazanavir, 79% and 13% of the total radioactivity was recovered in the feces and urine, respectively. Unchanged drug accounted for approximately 20% and 7% of the administered dose in the feces and urine, respectively. The mean elimination half-life of atazanavir in healthy volunteers (n=214) and HIV-infected adult patients (n=13) was approximately 7 hours at steady state following a dose of 400 mg daily with a light meal.
Specific Populations

Renal Impairment

In healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. REYATAZ has been studied in adult subjects with severe renal impairment (n=20), including those on hemodialysis, at multiple doses of 400 mg once daily. The mean atazanavir Cmax was 9% lower, AUC was 19% higher, and Cmin was 96% higher in subjects with severe renal impairment not undergoing hemodialysis (n=10), than in age-, weight-, and gender-matched subjects with normal renal function. In a 4-hour dialysis session, 2.1% of the administered dose was removed. When atazanavir was administered either prior to, or following hemodialysis (n=10), the geometric means for Cmax, AUC, and Cmin were approximately 25% to 43% lower compared to subjects with normal renal function. The mechanism of this decrease is unknown. REYATAZ is not recommended for use in HIV-treatment-experienced patients with end stage renal disease managed with hemodialysis [see Dosage and Administration (2.4)].

Hepatic Impairment

REYATAZ has been studied in adult subjects with moderate-to-severe hepatic impairment (14 Child-Pugh B and 2 Child-Pugh C subjects) after a single 400-mg dose. The mean AUC(0-) was 42% greater in subjects with impaired hepatic function than in healthy volunteers. The mean half-life of atazanavir in hepatically impaired subjects was 12.1 hours compared to 6.4 hours in healthy volunteers. A dose reduction to 300 mg is recommended for patients with moderate hepatic impairment (Child-Pugh Class B) who have not experienced prior virologic failure as increased concentrations of atazanavir are expected. REYATAZ is not recommended for use in patients with severe hepatic impairment. The pharmacokinetics of REYATAZ in combination with ritonavir has not been studied in subjects with hepatic impairment; thus, coadministration of REYATAZ with ritonavir is not recommended for use in patients with any degree of hepatic impairment [see Dosage and Administration (2.5)].

Pediatrics

The pharmacokinetic parameters for atazanavir at steady state in pediatric patients were predicted by a population pharmacokinetic model and are summarized in Table 19 by weight ranges that correspond to the recommended doses [see Dosage and Administration (2.3).] Table 19:                  Predicted Steady-State Pharmacokinetics of Atazanavir (capsule formulation) with Ritonavir in HIV-Infected Pediatric Patients
Cmax ng/mL             AUC ng•h/mL              Cmin ng/mL
Body Weight       atazanavir/ritonavir    Geometric Mean          Geometric Mean          Geometric Mean (range in kg)          Dose (mg)             (CV%)                   (CV%)                   (CV%) 15 to <35              200/100                3303 (86%)          37235 (84%)             538 (99%) 35                  300/100                2980 (82%)          37643 (83%)             653 (89%) 
Pregnancy

The pharmacokinetic data from HIV-infected pregnant women receiving REYATAZ Capsules with ritonavir are presented in Table 20.

Table 20:                  Steady-State Pharmacokinetics of Atazanavir with Ritonavir in HIV-Infected Pregnant Women in the Fed State
Pharmacokinetic Parameter                           Atazanavir 300 mg with ritonavir 100 mg 2nd Trimester             3rd Trimester           Postpartumb
(n=5a)                    (n=20)                  (n=34)
Cmax ng/mL                                3078.85                  3291.46                    5721.21 Geometric mean (CV%)                       (50)                     (48)                       (31) AUC ng•h/mL                               27657.1                  34251.5                    61990.4 Geometric mean (CV%)                       (43)                     (43)                       (32) Cmin ng/mLc                               538.70                    668.48                    1462.59 Geometric mean (CV%)                   (46)                      (50)                       (45) a
Available data during the 2nd trimester are limited.
b
Atazanavir peak concentrations and AUCs were found to be approximately 28% to 43% higher during the postpartum period (4-12 weeks) than those observed historically in HIV-infected, non-pregnant patients.
Atazanavir plasma trough concentrations were approximately 2.2-fold higher during the postpartum period when compared to those observed historically in HIV-infected, non-pregnant patients.
c
Cmin is concentration 24 hours post-dose.

Drug Interaction Data

Atazanavir is a metabolism-dependent CYP3A inhibitor, with a Kinact value of 0.05 to 0.06 min−1 and Ki value of 0.84 to 1.0 µM. Atazanavir is also a direct inhibitor for UGT1A1 (Ki=1.9 µM) and CYP2C8 (Ki=2.1 µM).

Atazanavir has been shown in vivo not to induce its own metabolism nor to increase the biotransformation of some drugs metabolized by CYP3A. In a multiple-dose study, REYATAZ decreased the urinary ratio of endogenous 6β-OH cortisol to cortisol versus baseline, indicating that CYP3A production was not induced.
Clinically significant interactions are not expected between atazanavir and substrates of CYP2C19, CYP2C9, CYP2D6, CYP2B6, CYP2A6, CYP1A2, or CYP2E1. Clinically significant interactions are not expected between atazanavir when administered with ritonavir and substrates of CYP2C8. See the complete prescribing information for ritonavir for information on other potential drug interactions with ritonavir.
Based on known metabolic profiles, clinically significant drug interactions are not expected between REYATAZ and dapsone, trimethoprim/sulfamethoxazole, azithromycin, or erythromycin. REYATAZ does not interact with substrates of CYP2D6 (eg, nortriptyline, desipramine, metoprolol).
Drug interaction studies were performed with REYATAZ and other drugs likely to be coadministered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of coadministration of REYATAZ on the AUC, Cmax, and Cmin are summarized in Tables 21 and 22. Neither didanosine EC nor diltiazem had a significant effect on atazanavir exposures
(see Table 22 for effect of atazanavir on didanosine EC or diltiazem exposures). REYATAZ did not have a significant effect on the exposures of didanosine (when administered as the buffered tablet), stavudine, or fluconazole. For information regarding clinical recommendations, see Drug Interactions (7).

Table 21:                     Drug Interactions: Pharmacokinetic Parameters for Atazanavir in the Presence of Coadministered Drugsa
Coadministered       Coadministered Drug        REYATAZ                 Ratio (90% Confidence Interval) of Atazanavir Drug                Dose/Schedule          Dose/Schedule              Pharmacokinetic Parameters with/without Coadministered Drug;
No Effect = 1.00
Cmax              AUC                   Cmin atenolol               50 mg QD, d 7–11      400 mg QD, d 1–11           1.00               0.93                0.74 (n=19) and d 19–23          (n=19)             (0.89, 1.12)       (0.85, 1.01)        (0.65, 0.86)  boceprevir               800 mg TID,         300 mg QD/ritonavir   atazanavir: 0.75   atazanavir: 0.65    atazanavir: 0.51 d 1–6, 25–31        100 mg QD, d 10–31      (0.64-0.88)        (0.55-0.78)         (0.44-0.61)  ritonavir: 0.73     ritonavir: 0.64     ritonavir: 0.55
(0.64-0.83)         (0.58-0.72)         (0.45-0.67)
 clarithromycin        500 mg BID, d 7–10     400 mg QD, d 1–10           1.06               1.28                1.91 (n=29) and d 18–21          (n=29)             (0.93, 1.20)       (1.16, 1.43)        (1.66, 2.21)  didanosine (ddI)     ddI: 200 mg  1 dose,     400 mg  1 dose           0.11               0.13                0.16 (buffered tablets)   d4T: 40 mg  1 dose     simultaneously with     (0.06, 0.18)       (0.08, 0.21)        (0.10, 0.27) plus stavudine              (n=31)               ddI and d4T
(d4T)b                                             (n=31)
Table 21:                 Drug Interactions: Pharmacokinetic Parameters for Atazanavir in the Presence of Coadministered Drugsa
Coadministered   Coadministered Drug           REYATAZ                    Ratio (90% Confidence Interval) of Atazanavir Drug            Dose/Schedule             Dose/Schedule                  Pharmacokinetic Parameters with/without Coadministered Drug;
No Effect = 1.00
Cmax              AUC                   Cmin ddI: 200 mg  1 dose,        400 mg  1 dose              1.12              1.03                  1.03 d4T: 40 mg  1 dose         1 h after ddI + d4T       (0.67, 1.18)      (0.64, 1.67)          (0.61, 1.73) (n=32)                      (n=32)
 efavirenz         600 mg QD, d 7–20         400 mg QD, d 1–20              0.41                0.26                0.07 (n=27)                    (n=27)                (0.33, 0.51)        (0.22, 0.32)        (0.05, 0.10) 
600 mg QD, d 7–20      400 mg QD, d 1–6 (n=23)           1.14                1.39                1.48 (n=13)               then 300 mg/ritonavir      (0.83, 1.58)        (1.02, 1.88)        (1.24, 1.76) 100 mg QD, 2 h before efavirenz, d 7–20 (n=13)

600 mg QD,            300 mg QD/ritonavir             1.17                1.00                0.58 d 11–24 (pm)        100 mg QD, d 1–10 (pm)        (1.08, 1.27)        (0.91, 1.10)        (0.49, 0.69) (n=14)             (n=22), then 400 mg
QD/ritonavir 100 mg QD,
d 11–24 (pm),
(simultaneously with efavirenz)
(n=14)
 famotidine        40 mg BID, d 7–12      400 mg QD, d 1–6 (n=45),          0.53               0.59                 0.58 (n=15)              d 7–12 (simultaneous        (0.34, 0.82)       (0.40, 0.87)         (0.37, 0.89) administration)
(n=15)

40 mg BID, d 7–12       400 mg QD (pm), d 1–6            1.08                0.95                0.79
(n=14)            (n=14), d 7–12 (10 h after,   (0.82, 1.41)        (0.74, 1.21)        (0.60, 1.04) 2 h before famotidine)
(n=14)

40 mg BID, d 11–20        300 mg QD/ritonavir            0.86                0.82                0.72
(n=14)c           100 mg QD, d 1–10 (n=46),     (0.79, 0.94)        (0.75, 0.89)        (0.64, 0.81) d 11–20d (simultaneous administration)
(n=14)

20 mg BID, d 11–17        300 mg QD/ritonavir            0.91                0.90                0.81
(n=18)            100 mg QD/tenofovir DF       (0.84, 0.99)        (0.82, 0.98)        (0.69, 0.94) 300 mg QD, d 1–10 (am)
(n=39), d 11–17 (am)
(simultaneous administration with am famotidine) (n=18)d,e

40 mg QD (pm),           300 mg QD/ritonavir            0.89                0.88                0.77 d 18–24            100 mg QD/tenofovir DF       (0.81, 0.97)        (0.80, 0.96)        (0.63, 0.93) (n=20)            300 mg QD, d 1–10 (am)
(n=39), d 18–24 (am) (12 h after pm famotidine)
(n=20)e
Table 21:                  Drug Interactions: Pharmacokinetic Parameters for Atazanavir in the Presence of Coadministered Drugsa
Coadministered   Coadministered Drug            REYATAZ                   Ratio (90% Confidence Interval) of Atazanavir Drug            Dose/Schedule              Dose/Schedule                 Pharmacokinetic Parameters with/without Coadministered Drug;
No Effect = 1.00
Cmax              AUC                   Cmin
40 mg BID, d 18–24         300 mg QD/ritonavir           0.74              0.79                  0.72
(n=18)            100 mg QD/tenofovir DF       (0.66, 0.84)      (0.70, 0.88)          (0.63, 0.83) 300 mg QD, d 1–10 (am)
(n=39), d 18–24 (am) (10 h after pm famotidine and 2 h before am famotidine)
(n=18)e

40 mg BID, d 11–20       300 mg QD/ritonavir             1.02                1.03                0.86
(n=15)           100 mg QD, d 1–10 (am)        (0.87, 1.18)        (0.86, 1.22)        (0.68, 1.08) (n=46), then 400 mg
QD/ritonavir 100 mg QD,
d 11–20 (am) (n=15)
 grazoprevir/     grazoprevir 200 mg QD    300 mg QD/ritonavir 100          1.12                1.43                1.23 elbasvir                d 1 - 35              mg QD, d 1- 35           (1.01, 1.24)        (1.30, 1.57)        (1.13, 1.34) (n = 11)                 (n = 11)

 elbasvir 50 mg QD      300 mg QD/ritonavir 100          1.02               1.07                 1.15 d 1 - 35              mg QD, d 1 - 35          (0.96, 1.08)        (0.98,1.17)         (1.02, 1.29) (n = 8)                  (n = 8)

 ketoconazole      200 mg QD, d 7–13         400 mg QD, d 1–13              0.99                1.10                1.03 (n=14)                    (n=14)                (0.77, 1.28)        (0.89, 1.37)        (0.53, 2.01)  nevirapinef,g        200 mg BID,            300 mg QD/ritonavir            0.72                0.58                0.28 d 1–23             100 mg QD, d 4–13, then      (0.60, 0.86)        (0.48, 0.71)        (0.20, 0.40) (n=23)              400 mg QD/ritonavir            1.02                0.81                0.41 100 mg QD, d 14–23         (0.85, 1.24)        (0.65, 1.02)        (0.27, 0.60) (n=23)h
 omeprazole         40 mg QD, d 7–12      400 mg QD, d 1–6 (n=48),          0.04                0.06                0.05 (n=16)i                d 7–12 (n=16)            (0.04, 0.05)        (0.05, 0.07)        (0.03, 0.07) 
40 mg QD, d 11–20        300 mg QD/ritonavir             0.28                0.24                0.22
(n=15)i           100 mg QD, d 1–20 (n=15)      (0.24, 0.32)        (0.21, 0.27)        (0.19, 0.26) 
20 mg QD, d 17–23         300 mg QD/ritonavir            0.61                0.58                0.54
(am)              100 mg QD, d 7–16 (pm)       (0.46, 0.81)        (0.44, 0.75)        (0.41, 0.71) (n=13)              (n=27), d 17–23 (pm)
(n=13)j,k

20 mg QD, d 17–23        300 mg QD/ritonavir             0.69                0.70                0.69
(am) (n=14)         100 mg QD, d 7–16 (am)        (0.58, 0.83)        (0.57, 0.86)        (0.54, 0.88) (n=27), then 400 mg
QD/ritonavir 100 mg QD,
d 17–23 (am) (n=14)l,m
 pitavastatin           4 mg QD                  300 mg QD                  1.13                1.06                NA for 5 days                for 5 days            (0.96, 1.32)        (0.90, 1.26)  rifabutin         150 mg QD, d 15–28        400 mg QD, d 1–28              1.34                1.15                1.13 (n=7)                     (n=7)                (1.14, 1.59)        (0.98, 1.34)        (0.68, 1.87) Table 21:                    Drug Interactions: Pharmacokinetic Parameters for Atazanavir in the Presence of Coadministered Drugsa
Coadministered      Coadministered Drug            REYATAZ                Ratio (90% Confidence Interval) of Atazanavir Drug               Dose/Schedule              Dose/Schedule              Pharmacokinetic Parameters with/without Coadministered Drug;
No Effect = 1.00
Cmax              AUC                   Cmin rifampin            600 mg QD, d 17–26        300 mg QD/ritonavir          0.47              0.28                  0.02 (n=16)           100 mg QD, d 7–16 (n=48),   (0.41, 0.53)      (0.25, 0.32)          (0.02, 0.03) d 17–26 (n=16)
 ritonavirn          100 mg QD, d 11–20           300 mg QD, d 1–20         1.86                3.38               11.89 (n=28)                      (n=28)           (1.69, 2.05)        (3.13, 3.63)       (10.23, 13.82)  tenofovir DFo        300 mg QD, d 9–16           400 mg QD, d 2–16         0.79                0.75                0.60 (n=34)                      (n=34)           (0.73, 0.86)        (0.70, 0.81)        (0.52, 0.68) 
300 mg QD, d 15–42       300 mg/ritonavir 100 mg      0.72p               0.75p               0.77p (n=10)                  QD, d 1–42           (0.50, 1.05)        (0.58, 0.97)        (0.54, 1.10) (n=10) voriconazole            200 mg BID,          300 mg/ritonavir 100 mg       0.87                0.88                0.80 (Subjects with at       d 2–3, 22–30;             QD, d 11–30          (0.80, 0.96)        (0.82, 0.95)        (0.72, 0.90) least one            400 mg BID, d 1, 21             (n=20) functional                 (n=20)
CYP2C19 allele)
 voriconazole             50 mg BID,          300 mg/ritonavir 100 mg       0.81                0.80                0.69 (Subjects without       d 2–3, 22–30;             QD, d 11–30          (0.66, 1.00)        (0.65, 0.97)        (0.54, 0.87) a functional         100 mg BID, d 1, 21              (n=8)
CYP2C19 allele)             (n=8) a
Data provided are under fed conditions unless otherwise noted.
b
All drugs were given under fasted conditions.
c
REYATAZ 300 mg plus ritonavir 100 mg once daily coadministered with famotidine 40 mg twice daily resulted in atazanavir geometric mean Cmax that was similar and AUC and Cmin values that were 1.79- and 4.46-fold higher relative to REYATAZ   400 mg once daily alone.
d
Similar results were noted when famotidine 20 mg BID was administered 2 hours after and 10 hours before atazanavir 300 mg and ritonavir 100 mg plus tenofovir DF 300 mg.
e
Atazanavir/ritonavir/tenofovir DF was administered after a light meal.
f
Study was conducted in HIV-infected individuals.
g
Compared with atazanavir 400 mg historical data without nevirapine (n=13), the ratio of geometric means (90% confidence intervals) for Cmax, AUC, and Cmin were 1.42 (0.98, 2.05), 1.64 (1.11, 2.42), and 1.25 (0.66, 2.36), respectively, for atazanavir/ritonavir 300/100 mg; and 2.02 (1.42, 2.87), 2.28 (1.54, 3.38), and 1.80 (0.94, 3.45), respectively, for atazanavir/ritonavir 400/100 mg.
h
Parallel group design; n=23 for atazanavir/ritonavir plus nevirapine, n=22 for atazanavir 300 mg/ritonavir 100 mg without nevirapine. Subjects were treated with nevirapine prior to study entry.
i
Omeprazole 40 mg was administered on an empty stomach 2 hours before REYATAZ.
j
Omeprazole 20 mg was administered 30 minutes prior to a light meal in the morning and REYATAZ 300 mg plus ritonavir 100 mg in the evening after a light meal, separated by 12 hours from omeprazole.
k
REYATAZ 300 mg plus ritonavir 100 mg once daily separated by 12 hours from omeprazole 20 mg daily resulted in increases in atazanavir geometric mean AUC (10%) and Cmin (2.4-fold), with a decrease in Cmax (29%) relative to REYATAZ 400 mg once daily in the absence of omeprazole (study days 1 –6).
l
Omeprazole 20 mg was given 30 minutes prior to a light meal in the morning and REYATAZ 400 mg plus ritonavir 100 mg once daily after a light meal, 1 hour after omeprazole. Effects on atazanavir concentrations were similar when REYATAZ   400 mg plus ritonavir 100 mg was separated from omeprazole 20 mg by 12 hours.
m
REYATAZ 400 mg plus ritonavir 100 mg once daily administered with omeprazole 20 mg once daily resulted in increases in atazanavir geometric mean AUC (32%) and Cmin (3.3-fold), with a decrease in Cmax (26%) relative to REYATAZ 400 mg once daily in the absence of omeprazole (study days 1–6).
n
Compared with atazanavir 400 mg QD historical data, administration of atazanavir/ritonavir 300/100 mg QD increased the atazanavir geometric mean values of Cmax, AUC, and Cmin by 18%, 103%, and 671%, respectively.
o
Note that similar results were observed in studies where administration of tenofovir DF and REYATAZ was separated by 12 hours.
p
Ratio of atazanavir plus ritonavir plus tenofovir DF to atazanavir plus ritonavir. Atazanavir 300 mg plus ritonavir 100 mg results in higher atazanavir exposure than atazanavir 400 mg (see footnote o). The geometric mean values of atazanavir pharmacokinetic parameters when coadministered with ritonavir and tenofovir DF were: Cmax = 3190 ng/mL, AUC = 34459 ng•h/mL, and Cmin = 491 ng/mL. Study was conducted in HIV-infected individuals.
NA = not available.

Table 22:    Drug Interactions: Pharmacokinetic Parameters for Coadministered Drugs in the Presence of REYATAZa


Coadministered     Coadministered           REYATAZ                 Ratio (90% Confidence Interval) of Coadministered Drug Drug               Drug                Dose/Schedule             Pharmacokinetic Parameters with/without REYATAZ; Dose/Schedule                                                       No Effect = 1.00 Cmax                    AUC                     Cmin
 acetaminophen        1 gm BID, d 1–20      300 mg QD/ritonavir            0.87                      0.97                   1.26 (n=10)           100 mg QD, d 11–20         (0.77, 0.99)              (0.91, 1.03)           (1.08, 1.46) (n=10)
 atenolol             50 mg QD, d 7–11      400 mg QD, d 1–11              1.34                      1.25                   1.02 (n=19) and d 19–23          (n=19)                (1.26, 1.42)              (1.16, 1.34)           (0.88, 1.19)  boceprevir             800 mg TID,         300 mg QD/ritonavir            0.93                      0.95                   0.82 d 1–6, 25–31            100 mg QD,             (0.80, 1.08)              (0.87, 1.05)           (0.68, 0.98) d 10–31
 clarithromycin         500 mg BID,         400 mg QD, d 1–10             1.50                      1.94                    2.60 d 7–10 (n=21) and           (n=21)               (1.32, 1.71)              (1.75, 2.16)            (2.35, 2.88) d 18–21                                  OH-clarithromycin:        OH-clarithromycin:             OH- 0.28                      0.30              clarithromycin:
(0.24, 0.33)              (0.26, 0.34)                0.38
(0.34, 0.42) ddI (enteric-       400 mg d 1 (fasted),    400 mg QD, d 2–8              0.64                      0.66                   1.13 coated [EC]              d 8 (fed)               (n=34)               (0.55, 0.74)              (0.60, 0.74)           (0.91, 1.41) capsules)b                (n=34)
400 mg d 1 (fasted),   300 mg QD/ritonavir            0.62                      0.66                   1.25 d 19 (fed)         100 mg QD, d 9–19          (0.52, 0.74)              (0.59, 0.73)           (0.92, 1.69) (n=31)                  (n=31) diltiazem           180 mg QD, d 7–11      400 mg QD, d 1–11              1.98                      2.25                   2.42 (n=28) and d 19–23          (n=28)                (1.78, 2.19)              (2.09, 2.16)           (2.14, 2.73) desacetyl-diltiazem:      desacetyl-diltiazem:          desacetyl-
2.72                      2.65                  diltiazem:
(2.44, 3.03)              (2.45, 2.87)                 2.21
(2.02, 2.42) ethinyl estradiol    0.035 mg ethinyl         400 mg QD,         ethinyl estradiol: 1.15   ethinyl estradiol: 1.48   ethinyl estradiol: & norethindronec       estradiol and            d 16–29               (0.99, 1.32)              (1.31, 1.68)                1.91 0.5/0.75/1 mg              (n=19)           norethindrone: 1.67       norethindrone: 2.10          (1.57, 2.33) norethindrone                                   (1.42, 1.96)              (1.68, 2.62)          norethindrone: tablets*                                                                                         3.62 QD,                                                                                        (2.57, 5.09) d 1–29
(n=19)
ethinyl estradiol     0.035mg ethinyl       300 mg QD/ritonavir   ethinyl estradiol:   ethinyl estradiol:     ethinyl & norgestimated         estradiol and           100 mg QD,               0.84                 0.81           estradiol: 0.180/0.215/0.250            d 29–42            (0.74, 0.95)         (0.75, 0.87)          0.63 mg norgestimate *             (n=14)                                                   (0.55, 0.71) QD, d 1–28 (n=18),                              17-deacetyl          17-deacetyl then 0.025mg                                norgestimate:f       norgestimate:f      17-deacetyl ethinyl estradiol and                               1.68                 1.85           norgestima 0.180/0.215/0.250                              (1.51, 1.88)         (1.67, 2.05)           te:f mg norgestimate                                                                           2.02 *QD,                                                                            (1.77, 2.31) d 29–42e
(n=14)
glecaprevir/    300 mg glecaprevir     300 mg QD/ritonavir          ≥4.06g             ≥6.53g             ≥14.3g pibrentasvir         (n=12)                100 mg QD             (3.15, 5.23)       (5.24, 8.14)       (9.85, 20.7) (n=12)
120 mg pibrentasvir    300 mg QD/ritonavir          ≥1.29g             ≥1.64g             ≥2.29g (n=12)               100 mg QD             (1.15, 1.45)       (1.48, 1.82)       (1.95, 2.68) (n=12) grazoprevir/     grazoprevir 200 mg     300 mg QD/ritonavir           6.24              10.58              11.64 elbasvir                QD                  100 mg QD             (4.42, 8.81)      (7.78, 14.39)      (7.96, 17.02) d 1 - 35                d 1 - 35
(n = 12)                (n=12)

 elbasvir 50 mg QD     300 mg QD/ritonavir           4.15               4.76              6.45 d 1 - 35             100 mg QD             (3.46, 4.97)       (4.07, 5.56)       (5.51 7.54) (n = 10)               d 1 - 35
(n=10)

 methadone        Stable maintenance     400 mg QD, d 2–15       (R)-methadoneh     (R)-methadoneh     (R)-methadoneh dose, d 1–15             (n=16)                   0.91               1.03               1.11 (n=16)                                      (0.84, 1.0)       (0.95, 1.10)       (1.02, 1.20) total: 0.85        total: 0.94        total: 1.02
(0.78, 0.93)       (0.87, 1.02)       (0.93, 1.12)
 nevirapine,i,j      200 mg BID,              300 mg QD/               1.17               1.25               1.32 d 1–23           ritonavir 100 mg QD, d     (1.09, 1.25)       (1.17, 1.34)       (1.22, 1.43) (n=23)                 4–13, then
400 mg QD/               1.21               1.26               1.35 ritonavir 100 mg QD, d     (1.11, 1.32)       (1.17, 1.36)       (1.25, 1.47) 14–23
(n=23) omeprazolek       40 mg single dose,     400 mg QD, d 1–12            1.24               1.45               NA d 7 and d 20               (n=16)            (1.04, 1.47)       (1.20, 1.76) (n=16)
 rifabutin        300 mg QD, d 1–10         600 mg QD,l                 1.18               2.10               3.43 then 150 mg QD,            d 11–20               (0.94, 1.48)       (1.57, 2.79)       (1.98, 5.96) d 11–20                 (n=3)             25-O-desacetyl-    25-O-desacetyl-    25-O-desacetyl- (n=3)                                    rifabutin: 8.20   rifabutin: 22.01    rifabutin: 75.6 (5.90, 11.40)     (15.97, 30.34)      (30.1, 190.0)
150 mg twice             300 mg QD/                2.49m              1.48m              1.40m weekly, d 1–15        ritonavir 100 mg          (2.03, 3.06)       (1.19, 1.84)       (1.05, 1.87) (n=7)             QD, d 1–17 (n=7)       25-O-desacetyl-    25-O-desacetyl-    25-O-desacetyl- rifabutin: 7.77   rifabutin: 10.90   rifabutin: 11.45
(6.13, 9.83)      (8.14, 14.61)      (8.15, 16.10)

 pitavastatin          4 mg QD               300 mg QD                 1.60               1.31               NA for 5 days             for 5 days           (1.39, 1.85)       (1.23, 1.39) 
 rosiglitazonen    4 mg single dose,          400 mg QD,               1.08               1.35               NA d 1, 7, 17               d 2–7, then         (1.03, 1.13)       (1.26, 1.44) (n=14)                 300 mg QD/               0.97               0.83               NA ritonavir 100 mg QD, d     (0.91, 1.04)       (0.77, 0.89)
8–17
(n=14)
 rosuvastatin            10 mg                300 mg QD/             7-foldo           3-foldo             NA single dose          ritonavir 100 mg
QD for 7 days
saquinavirp (soft            1200 mg QD,          400 mg QD, d 7–13               4.39                     5.49                   6.86 gelatin capsules)               d 1–13                  (n=7)                 (3.24, 5.95)             (4.04, 7.47)           (5.29, 8.91) (n=7)
 sofosbuvir/               400 mg sofosbuvir     300 mg/100 mg ritonavir            1.29                     1.40                  NA velpatasvir/                 single dose             single dose               (1.09, 1.52)             (1.25, 1.57) voxilaprevir                   (n=15)                   (n=15)            sofosbuvir metabolite    sofosbuvir metabolite GS-331007                GS-331007
1.05                     1.25
(0.99, 1.12)             (1.16, 1.36)
100 mg velpatasvir    300 mg/100 mg ritonavir            1.29                     1.93                  NA single dose             single dose               (1.07, 1.56)             (1.58, 2.36) (n=15)                   (n=15)

100 mg voxilaprevir   300 mg/100 mg ritonavir           4.42                     4.31                   NA single dose            single dose              (3.65, 5.35)             (3.76, 4.93) (n=15)                  (n=15)

Tenofovir DFq             300 mg QD, d 9–16       400 mg QD, d 2–16               1.14                     1.24                   1.22 (n=33) and d 24–30           (n=33)                 (1.08, 1.20)             (1.21, 1.28)           (1.15, 1.30) (n=33)
300 mg QD, d 1–7       300 mg QD/ritonavir              1.34                     1.37                   1.29 (pm) (n=14)         100 mg QD, d 25–34           (1.20, 1.51)             (1.30, 1.45)           (1.21, 1.36) d 25–34 (pm)             (am) (n=12)r
(n=12)
 voriconazole                 200 mg BID,        300 mg/ritonavir 100 mg           0.90                     0.67                   0.61 (Subjects with at least      d 2–3, 22–30;           QD, d 11–30              (0.78, 1.04)             (0.58, 0.78)           (0.51, 0.72) one functional               400 mg BID,                (n=20)
CYP2C19 allele)                 d 1, 21
(n=20)

 voriconazole                  50 mg BID,        300 mg/ritonavir 100 mg           4.38                     5.61                   7.65 (Subjects without a          d 2–3, 22–30;           QD, d 11–30              (3.55, 5.39)             (4.51, 6.99)           (5.71, 10.2) functional CYP2C19           100 mg BID,                 (n=8) allele)                         d 1, 21
(n=8)
 lamivudine +              150 mg lamivudine       400 mg QD, d 7–12        lamivudine: 1.04           lamivudine: 1.03      lamivudine: 1.12 zidovudine                    + 300 mg                 (n=19)                 (0.92, 1.16)               (0.98, 1.08)          (1.04, 1.21) zidovudine BID,                                 zidovudine: 1.05           zidovudine: 1.05      zidovudine: 0.69 d 1–12                                         (0.88, 1.24)               (0.96, 1.14)          (0.57, 0.84) (n=19)                                         zidovudine          zidovudine glucuronide:      zidovudine glucuronide: 0.95                 1.00           glucuronide: 0.82
(0.88, 1.02)               (0.97, 1.03)          (0.62, 1.08)
 a
Data provided are under fed conditions unless otherwise noted.
b
400 mg ddI EC and REYATAZ were administered together with food on Days 8 and 19.
c
Upon further dose normalization of ethinyl estradiol 25 mcg with atazanavir relative to ethinyl estradiol 35 mcg without atazanavir, the ratio of geometric means (90% confidence intervals) for Cmax, AUC, and Cmin were 0.82 (0.73, 0.92), 1.06 (0.95, 1.17), and 1.35 (1.11, 1.63), respectively.
d
Upon further dose normalization of ethinyl estradiol 35 mcg with atazanavir/ritonavir relative to ethinyl estradiol 25 mcg without atazanavir/ritonavir, the ratio of geometric means (90% confidence intervals) for C max, AUC, and Cmin were 1.17 (1.03, 1.34), 1.13 (1.05, 1.22), and 0.88 (0.77, 1.00), respectively.
e
All subjects were on a 28 day lead-in period; one full cycle of Ortho Tri-Cyclen®. Ortho Tri-Cyclen® contains 35 mcg of ethinyl estradiol. Ortho Tri-Cyclen® LO contains 25 mcg of ethinyl estradiol. Results were dose normalized to an ethinyl estradiol dose of 35 mcg.
f
17-deacetyl norgestimate is the active component of norgestimate.
g
Effect of atazanavir and ritonavir on the first dose of glecaprevir and pibrentasvir is reported.
h
(R)-methadone is the active isomer of methadone.
i
Study was conducted in HIV-infected individuals.
j
Subjects were treated with nevirapine prior to study entry.
k
Omeprazole was used as a metabolic probe for CYP2C19. Omeprazole was given 2 hours after REYATAZ on Day 7; and was given alone 2 hours after a light meal on Day 20.
l
Not the recommended therapeutic dose of atazanavir.
m
When compared to rifabutin 150 mg QD alone d1–10 (n=14). Total of rifabutin + 25-O-desacetyl-rifabutin: AUC 2.19 (1.78,   2.69).
n
Rosiglitazone used as a probe substrate for CYP2C8.
o
Mean ratio (with/without coadministered drug).  indicates an increase in rosuvastatin exposure.
p
The combination of atazanavir and saquinavir 1200 mg QD produced daily saquinavir exposures similar to the values produced by the standard therapeutic dosing of saquinavir at 1200 mg TID. However, the C max is about 79% higher than that for the standard dosing of saquinavir (soft gelatin capsules) alone at 1200 mg TID.
q
Note that similar results were observed in a study where administration of tenofovir DF and REYATAZ was separated by 12 hours.
r
Administration of tenofovir DF and REYATAZ was temporally separated by 12 hours.
NA = not available.

12.4             Microbiology

Mechanism of Action
Atazanavir (ATV) is an azapeptide HIV-1 protease inhibitor (PI). The compound selectively inhibits the virus-specific processing of viral Gag and Gag-Pol polyproteins in HIV-1 infected cells, thus preventing formation of mature virions.
Antiviral Activity in Cell Culture

Atazanavir exhibits anti-HIV-1 activity with a mean 50% effective concentration (EC50) in the absence of human serum of 2 to 5 nM against a variety of laboratory and clinical HIV-1 isolates grown in peripheral blood mononuclear cells, macrophages, CEM-SS cells, and MT-2 cells.
ATV has activity against HIV-1 Group M subtype viruses A, B, C, D, AE, AG, F, G, and J isolates in cell culture. ATV has variable activity against HIV-2 isolates (1.9-32 nM), with EC50 values above the EC50 values of failure isolates. Two-drug combination antiviral activity studies with ATV showed no antagonism in cell culture with PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir), NNRTIs (delavirdine, efavirenz, and nevirapine), NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir DF, and zidovudine), the HIV-1 fusion inhibitor enfuvirtide, and two compounds used in the treatment of viral hepatitis, adefovir and ribavirin, without enhanced cytotoxicity.
Resistance

In Cell Culture: HIV-1 isolates with a decreased susceptibility to ATV have been selected in cell culture and obtained from patients treated with ATV or atazanavir/ritonavir (ATV/RTV). HIV-1 isolates with 93- to 183-fold reduced susceptibility to ATV from three different viral strains were selected in cell culture by 5 months. The substitutions in these HIV-1 viruses that contributed to ATV resistance include I50L, N88S, I84V, A71V, and M46I. Changes were also observed at the protease cleavage sites following drug selection. Recombinant viruses containing the I50L substitution without other major PI substitutions were growth impaired and displayed increased susceptibility in cell culture to other PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir). The I50L and I50V substitutions yielded selective resistance to ATV and amprenavir, respectively, and did not appear to be cross-resistant.
Clinical Studies of Treatment-Naive Patients: Comparison of Ritonavir-Boosted REYATAZ vs.
Unboosted REYATAZ: Study AI424-089 compared REYATAZ 300 mg once daily with ritonavir 100 mg vs. REYATAZ 400 mg once daily when administered with lamivudine and extended- release stavudine in HIV-infected treatment-naive patients. A summary of the number of virologic failures and virologic failure isolates with ATV resistance in each arm is shown in Table 23.

Table 23:                 Summary of Virologic Failuresa at Week 96 in Study AI424-089: Comparison of Ritonavir Boosted REYATAZ vs. Unboosted
REYATAZ: Randomized Patients
REYATAZ 300 mg                 REYATAZ 400 mg
+ ritonavir 100 mg
(n=95)                         (n=105)
Virologic Failure (50 copies/mL) at Week 96           15 (16%)                       34 (32%) Virologic Failure with Genotypes and
5                              17
Phenotypes Data
Virologic Failure Isolates with ATV-resistance
0/5 (0%)b                     4/17 (24%)b at Week 96
Virologic Failure Isolates with I50L Emergence
0/5 (0%)b                     2/17 (12%)b at Week 96c
Virologic Failure Isolates with Lamivudine
2/5 (40%)b                    11/17 (65%)b
Resistance at Week 96 a
Virologic failure includes patients who were never suppressed through Week 96 and on study at Week 96, had virologic rebound or discontinued due to insufficient viral load response.
b
Percentage of Virologic Failure Isolates with genotypic and phenotypic data.
c
Mixture of I50I/L emerged in 2 other ATV 400 mg-treated patients. Neither isolate was phenotypically resistant to ATV.
Clinical Studies of Treatment-Naive Patients Receiving REYATAZ 300 mg with Ritonavir 100 mg: In Phase III Study AI424-138, an as-treated genotypic and phenotypic analysis was conducted on samples from patients who experienced virologic failure (HIV-1 RNA 400 copies/mL) or discontinued before achieving suppression on ATV/RTV (n=39; 9%) and LPV/RTV (n=39; 9%) through 96 weeks of treatment. In the ATV/RTV arm, one of the virologic failure isolates had a 56-fold decrease in ATV susceptibility emerge on therapy with the development of PI resistance-associated substitutions L10F, V32I, K43T, M46I, A71I, G73S, I85I/V, and L90M. The NRTI resistance-associated substitution M184V also emerged on treatment in this isolate conferring emtricitabine resistance. Two ATV/RTV-virologic failure isolates had baseline phenotypic ATV resistance and IAS-defined major PI resistance-associated substitutions at baseline. The I50L substitution emerged on study in one of these failure isolates and was associated with a 17-fold decrease in ATV susceptibility from baseline and the other failure isolate with baseline ATV resistance and PI substitutions (M46M/I and I84I/V) had additional IAS-defined major PI substitutions (V32I, M46I, and I84V) emerge on ATV treatment associated with a 3-fold decrease in ATV susceptibility from baseline. Five of the treatment failure isolates in the ATV/RTV arm developed phenotypic emtricitabine resistance with the emergence of either the M184I (n=1) or the M184V (n=4) substitution on therapy and none developed phenotypic tenofovir disoproxil resistance. In the LPV/RTV arm, one of the virologic failure patient isolates had a 69-fold decrease in LPV susceptibility emerge on therapy with the development of PI substitutions L10V, V11I, I54V, G73S, and V82A in addition to baseline PI substitutions L10L/I, V32I, I54I/V, A71I, G73G/S, V82V/A, L89V, and L90M. Six LPV/RTV virologic failure isolates developed the M184V substitution and phenotypic emtricitabine resistance and two developed phenotypic tenofovir disoproxil resistance.
Clinical Studies of Treatment-Naive Patients Receiving REYATAZ 400 mg without Ritonavir: ATV-resistant clinical isolates from treatment-naive patients who experienced virologic failure on REYATAZ 400 mg treatment without ritonavir often developed an I50L substitution (after an average of 50 weeks of ATV therapy), often in combination with an A71V substitution, but also developed one or more other PI substitutions (eg, V32I, L33F, G73S, V82A, I85V, or N88S) with or without the I50L substitution. In treatment-naive patients, viral isolates that developed the I50L substitution, without other major PI substitutions, showed phenotypic resistance to ATV but retained in cell culture susceptibility to other PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir); however, there are no clinical data available to demonstrate the effect of the I50L substitution on the efficacy of subsequently administered PIs.
Clinical Studies of Treatment-Experienced Patients: In studies of treatment-experienced patients treated with ATV or ATV/RTV, most ATV-resistant isolates from patients who experienced virologic failure developed substitutions that were associated with resistance to multiple PIs and displayed decreased susceptibility to multiple PIs. The most common protease substitutions to develop in the viral isolates of patients who failed treatment with ATV 300 mg once daily and RTV 100 mg once daily (together with tenofovir DF and an NRTI) included V32I, L33F/V/I, E35D/G, M46I/L, I50L, F53L/V, I54V, A71V/T/I, G73S/T/C, V82A/T/L, I85V, and L89V/Q/M/T. Other substitutions that developed on ATV/RTV treatment including E34K/A/Q, G48V, I84V, N88S/D/T, and L90M occurred in less than 10% of patient isolates. Generally, if multiple PI resistance substitutions were present in the HIV-1 virus of the patient at baseline, ATV resistance developed through substitutions associated with resistance to other PIs and could include the development of the I50L substitution. The I50L substitution has been detected in treatment-experienced patients experiencing virologic failure after long-term treatment. Protease cleavage site changes also emerged on ATV treatment but their presence did not correlate with the level of ATV resistance.
Clinical Studies of Pediatric Subjects in AI424-397 (PRINCE I) and AI424-451 (PRINCE II): Treatment-emergent ATV/RTV resistance-associated amino acid substitution M36I in the protease was detected in the virus of one subject among treatment failures in AI424-397. In addition, three known resistance-associated substitutions for other PIs arose in the viruses from one subject each (L19I/R, H69K/R, and I72I/V). Reduced susceptibility to ATV, RTV, or ATV/RTV was not seen with these viruses. In AI424-451, ATV/RTV resistance-associated substitutions G16E, V82A/I/T, I84V, and/or L90M arose in the viruses of two subjects. The virus population harboring the M46M/V, V82V/I, I84I/V, and L90L/M substitutions acquired phenotypic resistance to RTV (RTV phenotypic fold-change of 3.5, with a RTV cutoff of 2.5- fold change). However, these substitutions did not result in phenotypic resistance to ATV (ATV phenotypic fold-change of <1.8, with an ATV cutoff of 2.2-fold change). Secondary PI resistance-associated amino acid substitutions also arose in the viruses of one subject each, including V11V/I, D30D/G, E35E/D, K45K/R, L63P/S, and I72I/T. Q61D and Q61E/G emerged in the viruses of two subjects who failed treatment with ATV/RTV. Viruses from nine subjects in the two studies developed NRTI resistance-associated substitutions: K65K/R (n=1), M184V (n=7), and T215I (n=1).
Cross-Resistance

Cross-resistance among PIs has been observed. Baseline phenotypic and genotypic analyses of clinical isolates from ATV clinical trials of PI-experienced patients showed that isolates cross- resistant to multiple PIs were cross-resistant to ATV. Greater than 90% of the isolates with substitutions that included I84V or G48V were resistant to ATV. Greater than 60% of isolates containing L90M, G73S/T/C, A71V/T, I54V, M46I/L, or a change at V82 were resistant to ATV, and 38% of isolates containing a D30N substitution in addition to other changes were resistant to ATV. Isolates resistant to ATV were also cross-resistant to other PIs with >90% of the isolates resistant to indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir, and 80% resistant to amprenavir. In treatment-experienced patients, PI-resistant viral isolates that developed the I50L substitution in addition to other PI resistance-associated substitution were also cross-resistant to other PIs.
Baseline Genotype/Phenotype and Virologic Outcome Analyses

Genotypic and/or phenotypic analysis of baseline virus may aid in determining ATV susceptibility before initiation of ATV/RTV therapy. An association between virologic response at 48 weeks and the number and type of primary PI resistance-associated substitutions detected in baseline HIV-1 isolates from antiretroviral-experienced patients receiving ATV/RTV once daily or lopinavir (LPV)/RTV twice daily in Study AI424-045 is shown in Table 24.
Overall, both the number and type of baseline PI substitutions affected response rates in treatment-experienced patients. In the ATV/RTV group, patients had lower response rates when 3 or more baseline PI substitutions, including a substitution at position 36, 71, 77, 82, or 90, were present compared to patients with 1–2 PI substitutions, including one of these substitutions.

Table 24:                HIV RNA Response by Number and Type of Baseline PI Substitution, Antiretroviral-Experienced Patients in Study AI424-
045, As-Treated Analysis

Virologic Response = HIV RNA <400 copies/mLb
Number and Type of Baseline PI                          ATV/RTV                  LPV/RTV Substitutionsa                                           (n=110)                  (n=113) 3 or more primary PI substitutions includingc:
D30N                                                   75% (6/8)                 50% (3/6) M36I/V                                                19% (3/16)                33% (6/18) M46I/L/T                                              24% (4/17)                23% (5/22) I54V/L/T/M/A                                          31% (5/16)                31% (5/16) A71V/T/I/G                                            34% (10/29)               39% (12/31) G73S/A/C/T                                             14% (1/7)                 38% (3/8) V77I                                                  47% (7/15)                44% (7/16) V82A/F/T/S/I                                          29% (6/21)                27% (7/26) I84V/A                                                 11% (1/9)                 33% (2/6) N88D                                                   63% (5/8)                 67% (4/6) L90M                                                  10% (2/21)                44% (11/25) Table 24:                    HIV RNA Response by Number and Type of Baseline PI Substitution, Antiretroviral-Experienced Patients in Study AI424-
045, As-Treated Analysis

Virologic Response = HIV RNA <400 copies/mLb
Number and Type of Baseline PI                                  ATV/RTV                  LPV/RTV Substitutionsa                                                   (n=110)                  (n=113) Number of baseline primary PI substitutionsa
All patients, as-treated                                        58% (64/110)           59% (67/113) 0–2 PI substitutions                                            75% (50/67)             75% (50/67) 3–4 PI substitutions                                            41% (14/34)             43% (12/28) 5 or more PI substitutions                                        0% (0/9)               28% (5/18) a
Primary substitutions include any change at D30, V32, M36, M46, I47, G48, I50, I54, A71, G73, V77, V82, I84, N88, and L90.
b
Results should be interpreted with caution because the subgroups were small.
c
There were insufficient data (n<3) for PI substitutions V32I, I47V, G48V, I50V, and F53L.

The response rates of antiretroviral-experienced patients in Study AI424-045 were analyzed by baseline phenotype (shift in susceptibility in cell culture relative to reference, Table 25). The analyses are based on a select patient population with 62% of patients receiving an NNRTI-based regimen before study entry compared to 35% receiving a PI-based regimen. Additional data are needed to determine clinically relevant break points for REYATAZ.

Table 25:                    Baseline Phenotype by Outcome, Antiretroviral-Experienced Patients in Study AI424-045, As-Treated Analysis

Baseline Phenotypea                              Virologic Response = HIV RNA <400 copies/mLb ATV/RTV                            LPV/RTV
(n=111)                            (n=111)
0–2                                         71% (55/78)                        70% (56/80) >2–5                                         53% (8/15)                         44% (4/9) >5–10                                        13% (1/8)                          33% (3/9) >10                                          10% (1/10)                        23% (3/13) a
Fold change susceptibility in cell culture relative to the wild-type reference.
b
Results should be interpreted with caution because the subgroups were small.