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Reyataz (Atazanavir Sulfate) - Description and Clinical Pharmacology

 
 



DESCRIPTION

REYATAZ® (atazanavir sulfate) is an azapeptide inhibitor of HIV-1 protease.

The chemical name for atazanavir sulfate is (3 S,8 S,9 S,12 S)-3,12-Bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester, sulfate (1:1). Its molecular formula is C38H52N6O7•H2SO4, which corresponds to a molecular weight of 802.9 (sulfuric acid salt). The free base molecular weight is 704.9. Atazanavir sulfate has the following structural formula:

Atazanavir sulfate is a white to pale yellow crystalline powder. It is slightly soluble in water (4–5 mg/mL, free base equivalent) with the pH of a saturated solution in water being about 1.9 at 24 ± 3° C.

REYATAZ Capsules are available for oral administration in strengths containing the equivalent of 100 mg, 150 mg, 200 mg, or 300 mg of atazanavir as atazanavir sulfate and the following inactive ingredients: crospovidone, lactose monohydrate, and magnesium stearate. The capsule shells contain the following inactive ingredients: gelatin, FD&C Blue #2, titanium dioxide, black iron oxide, red iron oxide, and yellow iron oxide. The capsules are printed with ink containing shellac, titanium dioxide, FD&C Blue #2, isopropyl alcohol, ammonium hydroxide, propylene glycol, n-butyl alcohol, simethicone, and dehydrated alcohol.

CLINICAL PHARMACOLOGY

Mechanism of Action

Atazanavir is an antiviral drug [see Clinical Pharmacology ].

Pharmacodynamics

Effects on Electrocardiogram

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 .]

Electrocardiographic effects of atazanavir were determined in a clinical pharmacology study of 72 healthy subjects. Oral doses of 400 mg and 800 mg 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 .]

In a pharmacokinetic study between atazanavir 400 mg once daily and diltiazem 180 mg once daily, a CYP3A substrate, there was a 2-fold increase in the diltiazem plasma concentration and an additive effect on the PR interval. In a pharmacokinetic study between atazanavir 400 mg once daily and atenolol 50 mg once daily, there was no substantial additive effect of atazanavir and atenolol on the PR interval. [See Warnings and Precautions .]

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 14).

Table 14: Steady-State Pharmacokinetics of Atazanavir in Healthy Subjects or HIV-Infected Patients in the Fed State
400 mg once daily 300 mg with ritonavir
100 mg once daily
Parameter Healthy Subjects
(n=14)
HIV-Infected Patients
(n=13)
Healthy Subjects
(n=28)
HIV-Infected Patients
(n=10)
a n=26.
b n=12.
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)
   Median2.52.02.73.0
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)a8.6 (2.3)
Cmin (ng/mL)
   Geometric mean (CV%)159 (88)120 (109)1227 (53)636 (97)
   Mean (SD)218 (191)273 (298)b1441 (757)862 (838)

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 200–800 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 Cmax 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 (atazanavir sulfate) 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

Following a single 400-mg dose of 14C-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.

Special Populations

Pediatrics

The pharmacokinetic data from pediatric patients receiving REYATAZ Capsules with ritonavir based on body surface area are presented in Table 15.

Table 15: Steady-State Pharmacokinetics of Atazanavir with ritonavir in HIV-Infected Pediatric Patients (6 to less than 18 years of age) in the Fed State
205 mg/m2 atazanavir with 100 mg/m2 ritonavir once daily
Age Range (years)
at least 6 to 13
(n=17)
at least 13 to 18
(n=10)
Dose mg   
   Median 200400
   [min-max][150–400][250–500]
Cmax ng/mL  
   Geometric Mean (CV%)4451 (33)3711 (46)
AUC (ng•h/mL)  
   Geometric Mean (CV%)42503 (36)44970 (34)
Cmin ng/mL  
   Geometric Mean (CV%)535 (62)1090 (60)

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=1.9µM) 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.

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 16 and 17. For information regarding clinical recommendations, see Drug Interactions (7) .

Table 16: Drug Interactions: Pharmacokinetic Parameters for Atazanavir in the Presence of Coadministered Drugsa
Coadministered Drug Coadministered Drug
Dose/Schedule
REYATAZ
Dose/Schedule
Ratio (90% Confidence Interval) of Atazanavir Pharmacokinetic Parameters with/without Coadministered Drug;
No Effect = 1.00
Cmax AUC Cmin
a Data provided are under fed conditions unless otherwise noted.
b All drugs were given under fasted conditions.
c 400 mg ddI EC and REYATAZ were administered together with food on Days 8 and 19.
d 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.
e Similar results were noted when famotidine 20 mg BID was administered 2 hours afterand 10 hours before atazanavir 300 mg and ritonavir 100 mg plus tenofovir 300 mg.
f Atazanavir/ritonavir/tenofovir was administered after a light meal.
g Study was conducted in HIV-infected individuals.
h 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.
i 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.
j Omeprazole 40 mg was administered on an empty stomach 2 hours before REYATAZ.
k 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.
l 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).
m 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.
n 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).
o 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.
p Note that similar results were observed in studies where administration of tenofovir and REYATAZ was separated by 12 hours.
q Ratio of atazanavir plus ritonavir plus tenofovir 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 were: Cmax = 3190 ng/mL, AUC = 34459 ng•h/mL, and Cmin = 491 ng/mL. Study was conducted in HIV-infected individuals.
atenolol50 mg QD, d 7−11 (n=19) and d 19−23400 mg QD, d 1−11 (n=19)1.00
(0.89, 1.12)
0.93
(0.85, 1.01)
0.74
(0.65, 0.86)
clarithromycin500 mg BID, d 7−10 (n=29) and d 18−21400 mg QD, d 1−10 (n=29)1.06
(0.93, 1.20)
1.28
(1.16, 1.43)
1.91
(1.66, 2.21)
didanosine (ddI) (buffered tablets) plus stavudine (d4T)bddI: 200 mg x 1 dose,
d4T: 40 mg x 1 dose (n=31)
400 mg x 1 dose simultaneously with ddI and d4T (n=31)0.11
(0.06, 0.18)
0.13
(0.08, 0.21)
0.16
(0.10, 0.27)
 ddI: 200 mg x 1 dose,
d4T: 40 mg x 1 dose (n=32)
400 mg x 1 dose 1 h after ddI + d4T (n=32)1.12
(0.67, 1.18)
1.03
(0.64, 1.67)
1.03
(0.61, 1.73)
ddI (enteric-coated [EC] capsules)c400 mg d 8 (fed) (n=34) 400 mg d 19 (fed) (n=31)400 mg QD, d 2−8 (n=34) 300 mg/ritonavir 100 mg QD, d 9−19 (n=31)1.03
(0.93, 1.14)
1.04
(1.01, 1.07)
0.99
(0.91, 1.08)
1.00
(0.96, 1.03)
0.98
(0.89, 1.08)
0.87
(0.82, 0.92)
diltiazem180 mg QD, d 7−11 (n=30) and d 19−23400 mg QD, d 1−11 (n=30)1.04
(0.96, 1.11)
1.00
(0.95, 1.05)
0.98
(0.90, 1.07)
efavirenz600 mg QD, d 7−20 (n=27)400 mg QD, d 1−20 (n=27)0.41
(0.33, 0.51)
0.26
(0.22, 0.32)
0.07
(0.05, 0.10)
 600 mg QD, d 7−20 (n=13)400 mg QD, d 1−6 (n=23) then 300 mg/ritonavir 100 mg QD, 2 h before efavirenz, d 7−20 (n=13)1.14
(0.83, 1.58)
1.39
(1.02, 1.88)
1.48
(1.24, 1.76)
 600 mg QD, d 11–24 (pm) (n=14)300 mg QD/ritonavir 100 mg QD, d 1–10 (pm) (n=22), then 400 mg QD/ritonavir 100 mg QD, d 11–24 (pm), (simultaneous with efavirenz) (n=14)1.17
(1.08, 1.27)
1.00
(0.91, 1.10)
0.58
(0.49, 0.69)
famotidine40 mg BID, d 7−12 (n=15)400 mg QD, d 1−6 (n=45), d 7−12 (simultaneous administration) (n=15)0.53
(0.34, 0.82)
0.59
(0.40, 0.87)
0.58
(0.37, 0.89)
 40 mg BID, d 7−12 (n=14)400 mg QD (pm), d 1−6 (n=14), d 7−12 (10 h after, 2 h before famotidine) (n=14)1.08
(0.82, 1.41)
0.95
(0.74, 1.21)
0.79
(0.60, 1.04)
 40 mg BID, d 11−20 (n=14)d300 mg QD/ritonavir 100 mg QD, d 1−10 (n=46), d 11−20d (simultaneous administration) (n=14)0.86
(0.79, 0.94)
0.82
(0.75, 0.89)
0.72
(0.64, 0.81)
 20 mg BID, d 11−17 (n=18)300 mg QD/ ritonavir 100 mg QD/tenofovir 300 mg QD, d 1−10 (am) (n=39), d 11−17 (am) (simultaneous administration with am famotidine) (n=18)e,f0.91
(0.84, 0.99)
0.90
(0.82, 0.98)
0.81
(0.69, 0.94)
 40 mg QD (pm),
d 18−24 (n=20)
300 mg QD/ ritonavir 100 mg QD/tenofovir 300 mg QD, d 1−10 (am) (n=39), d 18−24 (am) (12 h after pm famotidine) (n=20)f0.89
(0.81, 0.97)
0.88
(0.80, 0.96)
0.77
(0.63, 0.93)
 40 mg BID, d 18−24 (n=18)300 mg QD/ritonavir 100 mg QD/tenofovir 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)f0.74
(0.66, 0.84)
0.79
(0.70, 0.88)
0.72
(0.63, 0.83)
 40 mg BID, d 11−20 (n=15)300 mg QD/ritonavir 100 mg QD, d 1−10 (am) (n=46), then 400 mg QD/ritonavir 100 mg QD, d 11−20 (am) (n=15)1.02
(0.87, 1.18)
1.03
(0.86, 1.22)
0.86
(0.68, 1.08)
fluconazole200 mg QD, d 11−20 (n=29)300 mg QD/ ritonavir 100 mg QD, d 1−10 (n=19), d 11−20 (n=29)1.03
(0.95, 1.11)
1.04
(0.95, 1.13)
0.98
(0.85, 1.13)
ketoconazole200 mg QD, d 7−13 (n=14)400 mg QD, d 1−13 (n=14)0.99
(0.77, 1.28)
1.10
(0.89, 1.37)
1.03
(0.53, 2.01)
nevirapineg,h200 mg BID, d 1–23 (n=23)300 mg QD/ritonavir 100 mg QD, d 4–13, then 400 mg QD/ritonavir 100 mg QD, d 14–23 (n=23)i0.72
(0.60, 0.86)
1.02
(0.85, 1.24)
0.58
(0.48, 0.71)
0.81
(0.65, 1.02)
0.28
(0.20, 0.40)
0.41
(0.27, 0.60)
omeprazole40 mg QD, d 7−12 (n=16)j400 mg QD, d 1−6 (n=48), d 7−12 (n=16)0.04
(0.04, 0.05)
0.06
(0.05, 0.07)
0.05
(0.03, 0.07)
 40 mg QD, d 11−20 (n=15)j300 mg QD/ritonavir 100 mg QD, d 1−20 (n=15)0.28
(0.24, 0.32)
0.24
(0.21, 0.27)
0.22
(0.19, 0.26)
 20 mg QD, d 17−23 (am) (n=13)300 mg QD/ritonavir 100 mg QD, d 7−16 (pm) (n=27), d 17−23 (pm) (n=13)k,l0.61
(0.46, 0.81)
0.58
(0.44, 0.75)
0.54
(0.41, 0.71)
 20 mg QD, d 17−23 (am) (n=14)300 mg QD/ritonavir 100 mg QD, d 7−16 (am) (n=27), then 400 mg QD/ritonavir 100 mg QD, d 17−23 (am) (n=14)m,n0.69
(0.58, 0.83)
0.70
(0.57, 0.86)
0.69
(0.54, 0.88)
rifabutin150 mg QD, d 15−28 (n=7)400 mg QD, d 1−28 (n=7)1.34
(1.14, 1.59)
1.15
(0.98, 1.34)
1.13
(0.68, 1.87)
rifampin600 mg QD, d 17−26 (n=16)300 mg QD/ritonavir 100 mg QD, d 7−16 (n=48), d 17−26 (n=16)0.47
(0.41, 0.53)
0.28
(0.25, 0.32)
0.02
(0.02, 0.03)
ritonaviro100 mg QD, d 11−20 (n=28)300 mg QD, d 1−20 (n=28)1.86
(1.69, 2.05)
3.38
(3.13, 3.63)
11.89
(10.23, 13.82)
tenofovirp300 mg QD, d 9−16 (n=34)400 mg QD, d 2−16 (n=34)0.79
(0.73, 0.86)
0.75
(0.70, 0.81)
0.60
(0.52, 0.68)
 300 mg QD, d 15−42 (n=10)300 mg/ritonavir 100 mg QD, d 1−42 (n=10)0.72q
(0.50, 1.05)
0.75q
(0.58, 0.97)
0.77q
(0.54, 1.10)
Table 17: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drugs in the Presence of REYATAZa
Coadministered Drug Coadministered Drug
Dose/Schedule
REYATAZ
Dose/Schedule
Ratio (90% Confidence Interval) of Coadministered Drug Pharmacokinetic Parameters with/without REYATAZ;
No Effect = 1.00
Cmax AUC Cmin
a Data provided are under fed conditions unless otherwise noted.
b All drugs were given under fasted conditions.
c 400 mg ddI EC and REYATAZ were administered together with food on Days 8 and 19.
d 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.
e 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 Cmax, AUC, and Cmin were 1.17 (1.03, 1.34), 1.13 (1.05, 1.22), and 0.88 (0.77, 1.00), respectively.
f 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.
g 17-deacetyl norgestimate is the active component of norgestimate.
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 Rosiglitazone used as a probe substrate for CYP2C8.
n 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 Cmax is about 79% higher than that for the standard dosing of saquinavir (soft gelatin capsules) alone at 1200 mg TID.
o Note that similar results were observed in a study where administration of tenofovir and REYATAZ was separated by 12 hours.
p Administration of tenofovir and REYATAZ was temporally separated by 12 hours.
NA = not available.
acetaminophen1 gm BID, d 1−20 (n=10)300 mg QD/ritonavir 100 mg QD, d 11−20 (n=10)0.87
(0.77, 0.99)
0.97
(0.91, 1.03)
1.26
(1.08, 1.46)
atenolol50 mg QD, d 7−11 (n=19) and d 19−23400 mg QD, d 1−11 (n=19)1.34
(1.26, 1.42)
1.25
(1.16, 1.34)
1.02
(0.88, 1.19)
clarithromycin500 mg BID, d 7−10 (n=21) and d 18−21400 mg QD, d 1−10 (n=21)1.50
(1.32, 1.71)
OH-
clarithromycin:
0.28
(0.24, 0.33)
1.94
(1.75, 2.16)
OH-
clarithromycin:
0.30
(0.26, 0.34)
2.60
(2.35, 2.88)
OH-
clarithromycin:
0.38
(0.34, 0.42)
didanosine (ddI) (buffered tablets) plus stavudine (d4T)bddI: 200 mg x 1 dose,
d4T: 40 mg x 1 dose (n=31)
400 mg x 1 dose simultaneous with ddI and d4T (n=31)ddI: 0.92
(0.84, 1.02)
d4T: 1.08
(0.96, 1.22)
ddI: 0.98
(0.92, 1.05)
d4T: 1.00
(0.97, 1.03)
NA

d4T: 1.04
(0.94, 1.16)
ddI (enteric-coated [EC] capsules)c400 mg d 1 (fasted), d 8 (fed) (n=34)400 mg QD, d 2−8 (n=34)0.64
(0.55, 0.74)
0.66
(0.60, 0.74)
1.13
(0.91, 1.41)
 400 mg d 1 (fasted), d 19 (fed) (n=31)300 mg QD/ritonavir 100 mg QD, d 9−19 (n=31)0.62
(0.52, 0.74)
0.66
(0.59, 0.73)
1.25
(0.92, 1.69)
diltiazem180 mg QD, d 7−11 (n=28) and d 19−23400 mg QD, d 1−11 (n=28)1.98
(1.78, 2.19)
desacetyl-
diltiazem:
2.72
(2.44, 3.03)
2.25
(2.09, 2.16)
desacetyl-
diltiazem:
2.65
(2.45, 2.87)
2.42
(2.14, 2.73)
desacetyl-
diltiazem:
2.21
(2.02, 2.42)
ethinyl estradiol & norethindronedOrtho-Novum® 7/7/7 QD, d 1−29 (n=19)400 mg QD, d 16−29 (n=19)ethinyl estradiol:
1.15
(0.99, 1.32)
norethindrone:
1.67
(1.42, 1.96)
ethinyl estradiol:
1.48
(1.31, 1.68)
norethindrone:
2.10
(1.68, 2.62)
ethinyl estradiol:
1.91
(1.57, 2.33)
norethindrone:
3.62
(2.57, 5.09)
ethinyl estradiol & norgestimateeOrtho Tri-Cyclen® QD, d 1–28 (n=18), then Ortho Tri-Cyclen® LO QD, d 29–42f (n=14)300 mg QD/ritonavir 100 mg QD, d 29–42 (n=14) ethinyl estradiol:
0.84
(0.74, 0.95)
17-deacetyl norgestimate:g
1.68
(1.51, 1.88)
ethinyl estradiol:
0.81
(0.75, 0.87)
17-deacetyl norgestimate:g
1.85
(1.67, 2.05)
ethinyl estradiol:
0.63
(0.55, 0.71)
17-deacetyl norgestimate:g
2.02
(1.77, 2.31)
fluconazole200 mg QD, d 1−10 (n=11) and 200 mg QD, d 11−20 (n=29)300 mg QD/ritonavir 100 mg QD, d 11−20 (n=29)1.05
(0.99, 1.10)
1.08
(1.02, 1.15)
1.07
(1.00, 1.15)
methadoneStable maintenance dose, d 1−15 (n=16)400 mg QD, d 2−15 (n=16)(R)-methadoneh
0.91
(0.84, 1.0)
total:0.85
(0.78, 0.93)
(R)-methadoneh
1.03
(0.95, 1.10)
total:0.94
(0.87, 1.02)
(R)-methadoneh
1.11
(1.02, 1.20)
total:1.02
(0.93, 1.12)
nevirapinei,j200 mg BID, d 1–23 (n=23)300 mg QD/ritonavir 100 mg QD, d 4–13, then 400 mg QD/ritonavir 100 mg QD, d 14–23 (n=23)1.17
(1.09, 1.25)
1.21
(1.11, 1.32)
1.25
(1.17, 1.34)
1.26
(1.17, 1.36)
1.32
(1.22, 1.43)
1.35
(1.25, 1.47)
omeprazolek40 mg single dose, d 7 and d 20 (n=16)400 mg QD, d 1−12 (n=16)1.24
(1.04, 1.47)
1.45
(1.20, 1.76)
NA
rifabutin300 mg QD, d 1−10 then 150 mg QD, d 11−20 (n=3)600 mg QD,l d 11−20 (n=3)1.18
(0.94, 1.48)
25-O-desacetyl-
rifabutin: 8.20
(5.90, 11.40)
2.10
(1.57, 2.79)
25-O-desacetyl-
rifabutin: 22.01
(15.97, 30.34)
3.43
(1.98, 5.96)
25-O-desacetyl-
rifabutin: 75.6
(30.1, 190.0)
rosiglitazonem4 mg single dose, d 1, 7, 17 (n=14)400 mg QD, d 2–7, then 300 mg QD/ritonavir 100 mg QD, d 8–17 (n=14)1.08
(1.03, 1.13)
0.97
(0.91, 1.04)
1.35
(1.26, 1.44)
0.83
(0.77, 0.89)
NA


NA
saquinavirn (soft gelatin capsules)1200 mg QD, d 1−13 (n=7)400 mg QD, d 7−13 (n=7)4.39
(3.24, 5.95)
5.49
(4.04, 7.47)
6.86
(5.29, 8.91)
tenofoviro300 mg QD, d 9−16 (n=33) and d 24−30 (n=33)400 mg QD, d 2−16 (n=33)1.14
(1.08, 1.20)
1.24
(1.21, 1.28)
1.22
(1.15, 1.30)
 300 mg QD, d 1−7 (pm) (n=14) d 25−34 (pm) (n=12)300 mg QD/ritonavir 100 mg QD, d 25−34 (am) (n=12)p1.34
(1.20, 1.51)
1.37
(1.30, 1.45)
1.29
(1.21, 1.36)
lamivudine + zidovudine150 mg lamivudine + 300 mg zidovudine BID, d 1−12 (n=19)400 mg QD, d 7−12 (n=19)lamivudine: 1.04
(0.92, 1.16)
zidovudine: 1.05
(0.88, 1.24)
zidovudine
glucuronide: 0.95
(0.88, 1.02)
lamivudine: 1.03
(0.98, 1.08)
zidovudine: 1.05
(0.96, 1.14)
zidovudine
glucuronide: 1.00
(0.97, 1.03)
lamivudine: 1.12
(1.04, 1.21)
zidovudine: 0.69
(0.57, 0.84)
zidovudine
glucuronide: 0.82
(0.62, 1.08)

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 to 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 NNRTIs (delavirdine, efavirenz, and nevirapine), PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir), NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, 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 18.

Table 18: Summary of Virologic Failuresa at Week 96 in Study AI424-089: Comparison of Ritonavir Boosted REYATAZ vs. Unboosted REYATAZ: Randomized Patients
  REYATAZ 300 mg + ritonavir 100 mg REYATAZ 400 mg
(n=95) (n=105)
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.
Virologic Failure (≥50 copies/mL) at Week 96 15 (16%)34 (32%)
Virologic Failure with Genotypes and Phenotypes Data517
Virologic Failure Isolates with ATV-resistance at Week 96 0/5 (0%)b4/17 (24%)b
Virologic Failure Isolates with I50L Emergence at Week 96c0/5 (0%)b2/17 (12%)b
Virologic Failure Isolates with Lamivudine Resistance at Week 962/5 (40%)b11/17 (65%)b

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 ≥400 copies/mL or discontinued before achieving suppression on ATV/RTV (n=32; 7%) and LPV/RTV (n=33; 8%). In the ATV/RTV arm, 2 of the virologic failure isolates had 4- and 56-fold decreases in ATV susceptibility emerge on therapy with the development of PI substitutions M46I, V77V/I, and N88S (4-fold isolate); and L10F, V32I, K43T, M46I, A71I, G73S, I85I/V, and L90M (56-fold isolate). Four of the treatment failure isolates in the ATV/RTV arm developed emtricitabine resistance with the emergence of the M184V substitution on therapy. In the LPV/RTV arm, none of the virologic failure patient isolates developed LPV resistance (fold change:>10-fold) or had major PI substitutions emerge on therapy. Three of the failure isolates in the LPV/RTV arm developed emtricitabine resistance with the emergence of the M184V substitution.

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 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.

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 19.

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 19: HIV RNA Response by Number and Type of Baseline PI Substitution, Antiretroviral-Experienced Patients in Study AI424-045, As-Treated Analysis
Number and Type of Baseline PI Substitutionsa Virologic Response = HIV RNA <400 copies/mLb
ATV/RTV
(n=110)
LPV/RTV
(n=113)
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.
3 or more primary PI substitutions including:c
   D30N75% (6/8)50% (3/6)
   M36I/V19% (3/16)33% (6/18)
   M46I/L/T24% (4/17)23% (5/22)
   I54V/L/T/M/A31% (5/16)31% (5/16)
   A71V/T/I/G34% (10/29)39% (12/31)
   G73S/A/C/T14% (1/7)38% (3/8)
   V77I47% (7/15)44% (7/16)
   V82A/F/T/S/I29% (6/21)27% (7/26)
   I84V/A11% (1/9)33% (2/6)
   N88D63% (5/8)67% (4/6)
   L90M10% (2/21)44% (11/25)
Number of baseline primary PI substitutionsa
All patients, as-treated58% (64/110)59% (67/113)
0–2 PI substitutions75% (50/67)75% (50/67)
3–4 PI substitutions41% (14/34)43% (12/28)
5 or more PI substitutions0% (0/9)28% (5/18)

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 20). 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 20: 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
(n=111)
LPV/RTV
(n=111)
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.
0–271% (55/78)70% (56/80)
>2–553% (8/15)44% (4/9)
>5–1013% (1/8)33% (3/9)
>1010% (1/10)23% (3/13)

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Two-year carcinogenicity studies in mice and rats were conducted with atazanavir. At the high dose in female mice, the incidence of benign hepatocellular adenomas was increased at systemic exposures 7.2-fold higher than those in humans at the recommended 400-mg clinical dose. There were no increases in the incidence of tumors in male mice at any dose in the study. In rats, no significant positive trends in the incidence of neoplasms occurred at systemic exposures up to 5.7-fold higher than those in humans at the recommended 400-mg clinical dose. The clinical relevance of the carcinogenic findings in female mice is unknown.

Atazanavir tested positive in an in vitro clastogenicity test using primary human lymphocytes, in the absence and presence of metabolic activation. Atazanavir tested negative in the in vitro Ames reverse-mutation assay, in vivo micronucleus and DNA repair tests in rats, and in vivo DNA damage test in rat duodenum (comet assay).

Reproductive Toxicology Studies

At the systemic drug exposure levels (AUC) equal to (in male rats) or two times (in female rats) those at the human clinical dose (400 mg once daily), atazanavir did not produce significant effects on mating, fertility, or early embryonic development.

CLINICAL STUDIES

Adult Patients Without Prior Antiretroviral Therapy

Study AI424-138: a 96-week study comparing the antiviral efficacy and safety of atazanavir/ritonavir with lopinavir/ritonavir, each in combination with fixed-dose tenofovir-emtricitabine in HIV-1 infected treatment naive subjects. Study AI424-138 is a 96-week open-label, randomized, multicenter study, comparing REYATAZ (300 mg once daily) with ritonavir (100 mg once daily) to lopinavir with ritonavir (400/100 mg twice daily), each in combination with fixed-dose tenofovir with emtricitabine (300/200 mg once daily), in 878 antiretroviral treatment-naive treated patients. Patients had a mean age of 36 years (range: 19–72), 49% were Caucasian, 18% Black, 9% Asian, 23% Hispanic/Mestizo/mixed race, and 68% were male. The median baseline plasma CD4+ cell count was 204 cells/mm3 (range: 2 to 810 cells/mm3) and the mean baseline plasma HIV-1 RNA level was 4.94 log10 copies/mL (range: 2.60 to 5.88 log10 copies/mL). Treatment response and outcomes through Week 48 are presented in Table 21.

Table 21: Outcomes of Treatment Through Week 48 (Study AI424-138)
Outcome REYATAZ 300 mg + ritonavir 100 mg (once daily) with tenofovir/emtricitabine (once daily)a lopinavir 400 mg + ritonavir 100 mg (twice daily) with tenofovir/emtricitabine (once daily)a
(n=441) (n=437)
a As a fixed-dose combination: 300 mg tenofovir, 200 mg emtricitabine once daily.
b Patients achieved confirmed HIV RNA <50 copies/mL at Week 48. Roche Amplicor®, v1.5 ultra-sensitive assay.
c Pre-specified ITT analysis using as-randomized cohort: ATV/RTV 78% and LPV/RTV 76% [difference estimate: 1.7 (95% confidence interval: −3.8, 7.1)].
d Includes viral rebound and failure to achieve confirmed HIV RNA <50 copies/mL through Week 48.
e Includes lost to follow-up, patient’s withdrawal, noncompliance, protocol violation, and other reasons.
Responderb,c78%77%
Virologic failured12%10%
    Rebound4%4%
    Never suppressed through Week 489%6%
Death1%<1%
Discontinued due to adverse event2%3%
Discontinued for other reasonse6%9%

Through 48 weeks of therapy, the proportion of responders among patients with high viral loads (ie, baseline HIV RNA ≥100,000 copies/mL) was comparable for the REYATAZ/ritonavir (164 of 223 patients, 74%) and lopinavir/ritonavir (161 of 222 patients, 73%) arms. The median increase from baseline in CD4+ cell count was 191 cells/mm3 for the REYATAZ/ritonavir arm and 200 cells/mm3 for the lopinavir/ritonavir arm.

Study AI424-034: REYATAZ once daily compared to efavirenz once daily, each in combination with fixed-dose lamivudine + zidovudine twice daily. Study AI424-034 was a randomized, double-blind, multicenter trial comparing REYATAZ (400 mg once daily) to efavirenz (600 mg once daily), each in combination with a fixed-dose combination of lamivudine (3TC) (150 mg) and zidovudine (ZDV) (300 mg) given twice daily, in 810 antiretroviral treatment-naive patients. Patients had a mean age of 34 years (range: 18 to 73), 36% were Hispanic, 33% were Caucasian, and 65% were male. The mean baseline CD4+ cell count was 321 cells/mm3 (range: 64 to 1424 cells/mm3) and the mean baseline plasma HIV-1 RNA level was 4.8 log10 copies/mL (range: 2.2 to 5.9 log10 copies/mL). Treatment response and outcomes through Week 48 are presented in Table 22.

Table 22: Outcomes of Randomized Treatment Through Week 48 (Study AI424-034)
Outcome REYATAZ
400 mg once daily
+ lamivudine + zidovudined
efavirenz
600 mg once daily
+ lamivudine + zidovudined
(n=405) (n=405)
a Patients achieved and maintained confirmed HIV RNA <400 copies/mL (<50 copies/mL) through Week 48. Roche Amplicor® HIV-1 Monitor Assay, test version 1.0 or 1.5 as geographically appropriate.
b Includes viral rebound and failure to achieve confirmed HIV RNA <400 copies/mL through Week 48.
c Includes lost to follow-up, patient’s withdrawal, noncompliance, protocol violation, and other reasons.
d As a fixed-dose combination: 150 mg lamivudine, 300 mg zidovudine twice daily.
Respondera67% (32%)62% (37%)
Virologic failureb20%21%
   Rebound17%16%
   Never suppressed through Week 483%5%
Death<1%
Discontinued due to adverse event5%7%
Discontinued for other reasonsc8%10%

Through 48 weeks of therapy, the proportion of responders among patients with high viral loads (ie, baseline HIV RNA ≥100,000 copies/mL) was comparable for the REYATAZ and efavirenz arms. The mean increase from baseline in CD4+ cell count was 176 cells/mm3 for the REYATAZ arm and 160 cells/mm3 for the efavirenz arm.

Study AI424-008: REYATAZ 400 mg once daily compared to REYATAZ 600 mg once daily, and compared to nelfinavir 1250 mg twice daily, each in combination with stavudine and lamivudine twice daily. Study AI424-008 was a 48-week, randomized, multicenter trial, blinded to dose of REYATAZ, comparing REYATAZ at two dose levels (400 mg and 600 mg once daily) to nelfinavir (1250 mg twice daily), each in combination with stavudine (40 mg) and lamivudine (150 mg) given twice daily, in 467 antiretroviral treatment-naive patients. Patients had a mean age of 35 years (range: 18 to 69), 55% were Caucasian, and 63% were male. The mean baseline CD4+ cell count was 295 cells/mm3 (range: 4 to 1003 cells/mm3) and the mean baseline plasma HIV-1 RNA level was 4.7 log10 copies/mL (range: 1.8 to 5.9 log10 copies/mL). Treatment response and outcomes through Week 48 are presented in Table 23.

Table 23: Outcomes of Randomized Treatment Through Week 48 (Study AI424-008)
Outcome REYATAZ
400 mg once daily
+ lamivudine + stavudine
(n=181)
nelfinavir
1250 mg twice daily
+ lamivudine + stavudine
(n=91)
a Patients achieved and maintained confirmed HIV RNA <400 copies/mL (<50 copies/mL) through Week 48. Roche Amplicor® HIV-1 Monitor Assay, test version 1.0 or 1.5 as geographically appropriate.
b Includes viral rebound and failure to achieve confirmed HIV RNA <400 copies/mL through Week 48.
c Includes lost to follow-up, patient’s withdrawal, noncompliance, protocol violation, and other reasons.
Respondera67% (33%)59% (38%)
Virologic failureb24%27%
   Rebound14%14%
   Never suppressed through Week 4810%13%
Death<1%
Discontinued due to adverse event1%3%
Discontinued for other reasonsc7%10%

Through 48 weeks of therapy, the mean increase from baseline in CD4+ cell count was 234 cells/mm3 for the REYATAZ 400-mg arm and 211 cells/mm3 for the nelfinavir arm.

Adult Patients With Prior Antiretroviral Therapy

Study AI424-045: REYATAZ once daily + ritonavir once daily compared to REYATAZ once daily + saquinavir (soft gelatin capsules) once daily, and compared to lopinavir + ritonavir twice daily, each in combination with tenofovir + one NRTI. Study AI424-045 is an ongoing, randomized, multicenter trial comparing REYATAZ (300 mg once daily) with ritonavir (100 mg once daily) to REYATAZ (400 mg once daily) with saquinavir soft gelatin capsules (1200 mg once daily), and to lopinavir + ritonavir (400/100 mg twice daily), each in combination with tenofovir and one NRTI, in 347 (of 358 randomized) patients who experienced virologic failure on HAART regimens containing PIs, NRTIs, and NNRTIs. The mean time of prior exposure to antiretrovirals was 139 weeks for PIs, 283 weeks for NRTIs, and 85 weeks for NNRTIs. The mean age was 41 years (range: 24 to 74); 60% were Caucasian, and 78% were male. The mean baseline CD4+ cell count was 338 cells/mm3 (range: 14 to 1543 cells/mm3) and the mean baseline plasma HIV-1 RNA level was 4.4 log10 copies/mL (range: 2.6 to 5.88 log10 copies/mL).

Treatment outcomes through Week 48 for the REYATAZ/ritonavir and lopinavir/ritonavir treatment arms are presented in Table 24. REYATAZ/ritonavir and lopinavir/ritonavir were similar for the primary efficacy outcome measure of time-averaged difference in change from baseline in HIV RNA level. Study AI424-045 was not large enough to reach a definitive conclusion that REYATAZ/ritonavir and lopinavir/ritonavir are equivalent on the secondary efficacy outcome measure of proportions below the HIV RNA lower limit of detection. [See Clinical Pharmacology, Tables 19 and 20 .]

Table 24: Outcomes of Treatment Through Week 48 in Study AI424-045 (Patients with Prior Antiretroviral Experience)
Outcome REYATAZ 300 mg
+ ritonavir 100 mg once daily + tenofovir + 1 NRTI
lopinavir/ritonavir
(400/100 mg) twice daily + tenofovir + 1 NRTI
Differencea
(REYATAZ-lopinavir/ritonavir)
(n=119) (n=118) (CI)
a Time-averaged difference through Week 48 for HIV RNA; Week 48 difference in HIV RNA percentages and CD4+ mean changes, REYATAZ/ritonavir vs lopinavir/ritonavir; CI = 97.5% confidence interval for change in HIV RNA; 95% confidence interval otherwise.
b Roche Amplicor® HIV-1 Monitor Assay, test version 1.5.
c Protocol-defined primary efficacy outcome measure.
d Based on patients with baseline and Week 48 CD4+ cell count measurements (REYATAZ/ritonavir, n=85; lopinavir/ritonavir, n=93).
e Patients achieved and maintained confirmed HIV-1 RNA <400 copies/mL (<50 copies/mL) through Week 48.
HIV RNA Change from Baseline (log10 copies/mL)b−1.58−1.70+0.12c
(−0.17, 0.41)
CD4+ Change from Baseline (cells/mm3)d116123−7
(−67, 52)
Percent of Patients Respondinge
   HIV RNA <400 copies/mLb55%57%-2.2%
(−14.8%, 10.5%)
   HIV RNA <50 copies/mLb38%45%−7.1%
(−19.6%, 5.4%)

No patients in the REYATAZ/ritonavir treatment arm and three patients in the lopinavir/ritonavir treatment arm experienced a new-onset CDC Category C event during the study.

In Study AI424-045, the mean change from baseline in plasma HIV-1 RNA for REYATAZ 400 mg with saquinavir (n=115) was −1.55 log10 copies/mL, and the time-averaged difference in change in HIV-1 RNA levels versus lopinavir/ritonavir was 0.33. The corresponding mean increase in CD4+ cell count was 72 cells/mm3. Through 48 weeks of treatment, the proportion of patients in this treatment arm with plasma HIV-1 RNA <400 (<50) copies/mL was 38% (26%). In this study, coadministration of REYATAZ and saquinavir did not provide adequate efficacy [see Drug Interactions (7) ].

Study AI424-045 also compared changes from baseline in lipid values. [See Adverse Reactions . ]

Study AI424-043: Study AI424-043 was a randomized, open-label, multicenter trial comparing REYATAZ (400 mg once daily) to lopinavir/ritonavir (400/100 mg twice daily), each in combination with two NRTIs, in 300 patients who experienced virologic failure to only one prior PI-containing regimen. Through 48 weeks, the proportion of patients with plasma HIV-1 RNA <400 (<50) copies/mL was 49% (35%) for patients randomized to REYATAZ (n=144) and 69% (53%) for patients randomized to lopinavir/ritonavir (n=146). The mean change from baseline was −1.59 log10 copies/mL in the REYATAZ treatment arm and −2.02 log10 copies/mL in the lopinavir/ritonavir arm. Based on the results of this study, REYATAZ without ritonavir is inferior to lopinavir/ritonavir in PI-experienced patients with prior virologic failure and is not recommended for such patients.

Pediatric Patients

Assessment of the pharmacokinetics, safety, tolerability, and efficacy of REYATAZ is based on data from the open-label, multicenter clinical trial PACTG 1020A conducted in patients from 3 months to 21 years of age. In this study, 182 patients (83 antiretroviral-naive and 99 antiretroviral-experienced) received once daily REYATAZ, with or without ritonavir, in combination with two NRTIs.

Ninety-nine patients (6 to less than 18 years of age) treated with the REYATAZ capsule formulation, with or without ritonavir, were evaluated. In this cohort, the overall proportions of antiretroviral-naive and -experienced patients with HIV RNA <400 copies/mL at week 24 were 68% (28/41) and 33% (19/58), respectively. The overall proportions of antiretroviral-naive and experienced patients with HIV RNA <50 copies/mL at week 24 were 59% (24/41) and 24% (14/58), respectively. The median increase from baseline in absolute CD4 count at 20 weeks of therapy was 171 cells/mm3 in antiretroviral-naive patients and 116 cells/mm3 in antiretroviral-experienced patients.

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