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Reyataz

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Reyataz

CLINICAL PHARMACOLOGY

Mechanism Of Action

Atazanavir is an HIV-1 antiviral drug [see Microbiology].

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 (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]

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

Parameter 400 mg once daily 300 mg with ritonavir 100 mg once daily
Healthy Subjects
(n=14)
HIV-Infected Patients
(n=13)
Healthy Subjects
(n=28)
HIV-Infected Patients
(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)
an=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

Mean plasma concentrations of atazanavir at steady state after REYATAZ 400 mg once daily - Illustration

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 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 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. 39

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.

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)

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]

Pediatrics

The pharmacokinetic parameters for atazanavir at steady state in pediatric patients taking the powder formulation are summarized in Table 18 by weight ranges that correspond to the recommended doses. [See DOSAGE AND ADMINISTRATION]

Table 18: Steady-State Pharmacokinetics of Atazanavir (powder formulation) with Ritonavir in HIV-Infected Pediatric Patients

Body Weight (range in kg) [n] atazanavir/ ritonavir Dose (mg) Cmax ng/mL Geometric Mean (CV%) AUC ng•h/mL Geometric Mean (CV%) Cmin ng/mL Geometric Mean (CV%)
10 to < 15 [18] 200/80 5197 (53%) 50305 (67%) 572 (111%)
15 to < 25 [31] 250/80 5386 (47%) 55525 (46%) 678 (69%)

The pharmacokinetic parameters for atazanavir at steady state in pediatric patients taking the capsule formulation 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]

Table 19: Predicted Steady-State Pharmacokinetics of Atazanavir (capsule formulation) with Ritonavir in HIV-Infected Pediatric Patients

Body Weight (range in kg) atazanavir/ ritonavir Dose (mg) Cmax ng/mL Geometric Mean (CV%) AUC ng•h/mL Geometric Mean (CV%) Cmin ng/mL Geometric Mean (CV%)
15 to < 20 150/100 5213 (78.7%) 42902 (77.0%) 504 (99.5%)
20 to < 40 200/100 4954 (81.7%) 42999 (78.5%) 562 (98.9%)
≥ 40 300/100 5040 (84.6%) 46777 (80.6%) 691 (98.5%)

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
(n=5a)
3rd Trimester
(n=20)
Postpartumb
(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.
bAtazanavir 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.

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. For information regarding clinical recommendations, see DRUG INTERACTIONS.

Table 21: 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
atenolol 50 mg QD, d 7-11 (n=19) and d 19-23 400 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)
boceprevir 800 mg TID, d1-6, 25-31 300 mg QD/ritonavir 100 mg QD, d 10-31 atazanavir: 0.75 (0.64-0.88) atazanavir: 0.65 (0.55-0.78) atazanavir: 0.51 (0.44-0.61)
ritonavir: 0.73 (0.64-0.83) ritonavir: 0.64 (0.58-0.72) ritonavir: 0.55 (0.45-0.67)
clarithromycin 500 mg BID, d7-10 (n=29) and d 18-21 400 mg QD, d1-10 (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)b ddI: 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)c 400 mg d 8(fed) (n=34) 400 mg d 19 (fed) (n=31) 400 mg QD, d2-8 (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)
diltiazem 180 mg QD, d7-11 (n=30)and d19-23 400 mg QD, d1-11 (n=30) 1.04 (0.96,1.11) 1.00 (0.95,1.05) 0.98 (0.90,1.07)
efavirenz 600 mg QD, d7-20 (n=27) 400 mg QD, d1-20 (n=27) 0.41 (0.33,0.51) 0.26 (0.22,0.32) 0.07 (0.05,0.10)
600 mg QD, d7-20 (n=13) 400 mg QD, d1-6 (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), (simultaneously with efavirenz) (n=14) 1.17(1.08, 1.27) 1.00(0.91, 1.10) 0.58(0.49, 0.69)
famotidine 40 mg BID, d7-12 (n=15) 400 mg QD, d1-6 (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, d7-12 (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, d11-20 (n=14)d 300 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, d11-17 (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,f 0.91 (0.84,0.99) 0.90 (0.82,0.98) 0.81 (0.69,0.94)
40 mg QD(pm), d18-24 (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)f 0.89 (0.81,0.97) 0.88 (0.80,0.96) 0.77 (0.63,0.93)
40 mg BID, d18-24 (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)f 0.74 (0.66,0.84) 0.79 (0.70,0.88) 0.72 (0.63,0.83)
40 mg BID, d11-20 (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)
fluconazole 200 mg QD,d11-20 (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)
ketoconazole 200 mg QD, d7-13 (n=14) 400 mg QD, d1-13 (n=14) 0.99 (0.77,1.28) 1.10 (0.89,1.37) 1.03 (0.53,2.01)
nevirapineg,h 200 mg BID, d1-23 (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)i 0.72 (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)
omeprazole 40 mg QD, d7-12 (n=16)j 400 mg QD, d1-6 (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, d11-20 (n=15)j 300 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, d17-23 (am) (n=13) 300 mg QD/ritonavir 100 mg QD, d 7-16 (pm) (n=27), d 17-23 (pm) (n=13)k;l 0.61 (0.46,0.81) 0.58 (0.44,0.75) 0.54 (0.41,0.71)
20 mg QD, d17-23 (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,n 0.69 (0.58,0.83) 0.70 (0.57,0.86) 0.69 (0.54,0.88)
pitavastatin 4 mg QD for 5 days 300 mg QD for 5 days 1.13 (0.96,1.32) 1.06 (0.90,1.26) NA
rifabutin 150 mg QD, d15-28 (n=7) 400 mg QD, d1-28 (n=7) 1.34 (1.14,1.59) 1.15 (0.98,1.34) 1.13 (0.68,1.87)
rifampin 600 mg QD, d 17-26 (n=16) 300 mg QD/ritonavir 100 mg QD, d 7-16 (n=48), d17-26(n=16) 0.47 (0.41,0.53) 0.28 (0.25,0.32) 0.02 (0.02,0.03)
ritonaviro 100 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)
telaprevir 750 mg q8h for 10 days (n=7) 300 mg QD/ritonavir 100 mg QD for 20 days (n=7) 0.85 (0.73,0.98) 1.17 (0.97,1.43) 1.85 (1.40,2.44)
tenofovirp 300 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, d15-42 (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)
voriconazole (Subjects with at least one functional CYP2C19 allele) 200 mg BID,d 2-3, 22-30; 400 mg BID, d 1, 21(n=20) 300 mg/ritonavir 100 mg QD, d 11-30(n=20) 0.87(0.80, 0.96) 0.88(0.82, 0.95) 0.80(0.72, 0.90)
voriconazole (Subjects without a functional CYP2C19 allele) 50 mg BID,d 2-3, 22-30;100 mg BID, d 1, 21(n=8) 300 mg/ritonavir 100 mg QD, d 11-30(n=8) 0.81(0.66, 1.00) 0.80(0.65, 0.97) 0.69(0.54, 0.87)
a Data provided are under fed conditions unless otherwise noted.
bAll drugs were given under fasted conditions.
c 400 mg ddI EC and REYATAZ were administered together with food on Days 8 and 19.
dREYATAZ 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 after and 10 hours before atazanavir 300 mg and ritonavir 100 mg plus tenofovir 300 mg.
fAtazanavir/ritonavir/tenofovir was administered after a light meal.
g Study was conducted in HIV-infected individuals.
hCompared 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.
iParallel 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.
kOmeprazole 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.
lREYATAZ 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°). 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.
NA = not available.

Table 22: 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 Cmm
acetaminophen 1 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)
atenolol 50 mg QD, d7-11 (n=19) and d 19-23 400 mg QD, d1-11 (n=19) 1.34 (1.26,1.42) 1.25 (1.16,1.34) 1.02 (0.88,1.19)
boceprevir 800 mg TID, d1-6, 25-31 300 mg QD/ritonavir 100 mg QD, d10-31 0.93 (0.80,1.08) 0.95 (0.87,1.05) 0.82 (0.68,0.98)
clarithromycin 500 mg BID, d7-10 (n=21) and d18-21 400 mg QD, d1-10 (n=21) 1.50 (1.32,1.71) 1.94 (1.75,2.16) 2.60 (2.35,2.88)
OH-clarithromycin: 0.28 (0.24, 0.33) OH-clarithromycin: 0.30 (0.26, 0.34) OH-clarithromycin: 0.38 (0.34, 0.42)
didanosine (ddI) (buffered tablets) plus stavudine (d4T)b ddI: 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) ddI: 0.98(0.92, 1.05) NA
d4T: 1.08 (0.96, 1.22) d4T: 1.00 (0.97, 1.03) d4T: 1.04(0.94, 1.16)
ddI (enteric-coated [EC] capsules)c 400 mg d 1(fasted), d 8 (fed) (n=34) 400 mg QD, d2-8 (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)
diltiazem 180 mg QD, d7-11 (n=28) and d 19-23 400 mg QD, d1-11 (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 & norethindroned ® Ortho-Novum 7/7/7 QD, d 1-29 (n=19) 400 mg QD, d16-29 (n=19) ethinyl estradiol: 1.15 (0.99, 1.32) ethinyl estradiol: 1.48 (1.31, 1.68) ethinyl estradiol: 1.91 (1.57, 2.33)
norethindrone: 1.67 (1.42, 1.96) norethindrone: 2.10 (1.68, 2.62) norethindrone: 3.62 (2.57, 5.09)
ethinyl estradiol & norgestimatee Ortho Tri-Cyclen® QD, d 1-28 (n=18), then Ortho Tri-Cyclen® LO QD, d 29-42 f (n=14) 300 mg QD/ritonavir 100 mg QD, d 29-42 (n=14) ethinyl estradiol: 0.84 (0.74, 0.95) ethinyl estradiol: 0.81 (0.75, 0.87) ethinyl estradiol: 0.63 (0.55, 0.71)
17-deacetyl norgestimate:g 1.68 (1.51, 1.88) 17-deacetyl norgestimate:g 1.85 (1.67, 2.05) 17-deacetyl norgestimate:g 2.02 (1.77, 2.31)
fluconazole 200 mg QD, d1-10 (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)
methadone Stable maintenance dose, d 1-15 (n=16) 400 mg QD, d2-15 (n=16) (R)-methadoneh 0.91 (0.84, 1.0) (R)-methadoneh 1.03 (0.95, 1.10) (R)-methadoneh 1.11 (1.02, 1.20)
total: 0.85 (0.78, 0.93) total: 0.94 (0.87, 1.02) total: 1.02 (0.93, 1.12)
nevirapinei,j 200 mg BID, d1-23 (n=23) 300 mg QD/ ritonavir 100 mg QD, d 4-13, then 1.17 (1.09,1.25) 1.25 (1.17,1.34) 1.32 (1.22,1.43)
400 mg QD/ ritonavir 100 mg QD, d 14-23 (n=23) 1.21 (1.11,1.32) 1.26 (1.17,1.36) 1.35 (1.25,1.47)
omeprazolek 40 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
rifabutin 300 mg QD, d1-10 then 150 mg QD, d11-20 (n=3) 600 mg QD,l d11-20 (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)
150 mg twice weekly, d 1-15 (n=7) 300 mg QD/ ritonavir 100 mg QD, d 1-17 (n=7) 2.49m (2.03, 3.06) 25-O-desacetyl-rifabutin: 7.77 (6.13, 9.83) 1.48m (1.19, 1.84) 25-O-desacetyl-rifabutin: 10.90 (8.14, 14.61) 1.40m (1.05, 1.87) 25-O-desacetyl-rifabutin: 11.45 (8.15, 16.10)
pitavastatin 4 mg QD for 5 days 300 mg QD for 5 days 1.60 (1.39,1.85) 1.31 (1.23,1.39) NA
rosiglitazonen 4 mg single dose, d 1, 7, 17 (n=14) 400 mg QD, d2-7, then 300 mg QD/ ritonavir 100 mg QD, d 8-17 (n=14) 1.08 (1.03,1.13) 1.35 (1.26,1.44) NA
0.97 (0.91, 1.04) 0.83 (0.77, 0.89) NA
rosuvastatin 10 mg single dose 300 mg QD/ ritonavir 100 mg QD for 7 days ↑7-foldo ↑3-foldo NA
saquinavirp (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)
telaprevir 750 mg q8h for 10 days (n=14) 300 mg QD/ ritonavir 100 mg QD for 20 days (n=14) 0.79(0.74, 0.84) 0.80(0.76, 0.85) 0.85(0.75, 0.98)
tenofovirq 300 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)r 1.34 (1.20,1.51) 1.37 (1.30,1.45) 1.29 (1.21,1.36)
voriconazole (Subjects with at least one functional CYP2C19 allele) 200 mg BID, d2-3, 22-30; 400 mg BID, d 1, 21 (n=20) 300 mg/ritonavir 100 mg QD, d 11-30 (n=20) 0.90 (0.78,1.04) 0.67 (0.58,0.78) 0.61 (0.51,0.72)
voriconazole (Subjects without a functional CYP2C19 allele) 50 mg BID, d2-3, 22-30; 100 mg BID, d 1, 21 (n=8) 300 mg/ritonavir 100 mg QD, d 11-30 (n=8) 4.38 (3.55,5.39) 5.61 (4.51,6.99) 7.65 (5.71,10.2)
lamivudine + zidovudine 150 mg lamivudine + 300 mg zidovudine BID, d 1-12 (n=19) 400 mg QD, d7-12 (n=19) lamivudine: 1.04 (0.92, 1.16) lamivudine: 1.03 (0.98, 1.08) lamivudine: 1.12 (1.04, 1.21)
zidovudine: 1.05 (0.88, 1.24) zidovudine: 1.05 (0.96, 1.14) zidovudine: 0.69 (0.57, 0.84)
zidovudine glucuronide: 0.95(0.88, 1.02) zidovudine glucuronide: 1.00(0.97, 1.03) zidovudine glucuronide: 0.82(0.62, 1.08)
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 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 Cmax 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 and REYATAZ was separated by 12 hours.
r Administration of tenofovir and REYATAZ was temporally separated by 12 hours.
NA = not available.

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 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 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 + ritonavir 100 mg
(n=95)
REYATAZ 400 mg
(n=105)
Virologic Failure ( ≥ 50 copies/mL) at Week 96 15 (16%) 34 (32%)
Virologic Failure with Genotypes and Phenotypes Data 5 17
Virologic Failure Isolates with ATV-resistance at Week 96 0/5 (0%)b 4/17 (24%)b
Virologic Failure Isolates with I50L Emergence at Week 96c 0/5 (0%)b 2/17 (12%)b
Virologic Failure Isolates with Lamivudine Resistance at Week 96 2/5 (40%)b 11/17 (65%)b
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 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):No treatment-emergent ATV-associated substitutions were detected among treatment failures in AI424-397, but four known resistance-associated substitutions to other PIs arose in the viruses from one subject each (L19I/R, M36M/I, H69K/R, and I72I/V). None of these viruses acquired phenotypic resistance to ATV, ATV/RTV, or any NNRTI or NRTI. In AI424-451, ATV-associated resistance substitution (I84V) and other PI substitutions arose in the virus of one subject, including M46M/V, V82V/I, I84I/V, and L90L/M; however, these substitutions did not result in phenotypic resistance to ATV (ATV phenotypic fold change: 1.74, using a commercial investigational assay with an ATV cutoff of 2.2 fold change). Secondary PI substitutions also arose in the viruses of one subject each, including V11V/I, G16G/E, D30D/G, E35E/D, K45K/R, L63P/S, and I72I/T. Q61D and Q61/E/G emerged in the viruses of two subjects who failed treatment with ATV/RTV. Viruses from three subjects developed M184V in the reverse transcriptase, and all three exhibited phenotypic resistance to emtricitabine and lamivudine.

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 AI424045, As-Treated Analysis

Number and Type of Baseline PI Substitutionsa Virologic Response = HI ATV/RTV
(n=110)
V RNA < 400 copies/mLb LPV/RTV
(n=113)
3 or more primary PI substitutions including:c
  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)
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
(n=111)
LPV/RTV
(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.

Clinical Studies

Adult Patients Without Prior Antiretroviral Therapy

Study AI424-138: a 96-week study comparing the antiviral efficacy and safety of REYATAZ/ritonavir with lopinavir/ritonavir, each in combination with fixed-dose tenofoviremtricitabine in HIV-1 infected treatment-naive subjects. Study AI424-138 was 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 96 are presented in Table 26.

Table 26: Outcomes of Treatment Through Week 96 in Treatment-Naive Adults (Study AI424-138)

Outcome REYATAZ 300 mg + ritonavir 100 mg (once daily) with tenofovir/ emtricitabine (once daily)a
(n=441) 96 Weeks
lopinavir 400 mg + ritonavir 100 mg (twice daily) with tenofovir/ emtricitabine (once daily)a
(n=437) 96 Weeks
Responderb,c,d 75% 68%
Virologic failuree 17% 19%
  Rebound 8% 10%
  Never suppressed through Week 96 9% 9%
Death 1% 1%
Discontinued due to adverse event 3% 5%
Discontinued for other reasonsf 4% 7%
a As a fixed-dose combination: 300 mg tenofovir, 200 mg emtricitabine once daily.
b Patients achieved HIV RNA < 50 copies/mL at Week 96. Roche Amplicor®, v1.5 ultra-sensitive assay.
c Pre-specified ITT analysis at Week 48 using as-randomized cohort: ATV/RTV 78% and LPV/RTV 76% (difference estimate: 1.7% [95% confidence interval: -3.8%, 7.1%]).
d Pre-specified ITT analysis at Week 96 using as-randomized cohort: ATV/RTV 74% and LPV/RTV 68% (difference estimate: 6.1% [95% confidence interval: 0.3%, 12.0%]).
e Includes viral rebound and failure to achieve confirmed HIV RNA < 50 copies/mL through Week 96.
f Includes lost to follow-up, patient's withdrawal, noncompliance, protocol violation, and other reasons.

Through 96 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 (165 of 223 patients, 74%) and lopinavir/ritonavir (148 of 222 patients, 67%) arms. At 96 weeks, the median increase from baseline in CD4+ cell count was 261 cells/mm³ for the REYATAZ/ritonavir arm and 273 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 27.

Table 27: Outcomes of Randomized Treatment Through Week 48 in Treatment-Naive Adults (Study AI424-034)

Outcome REYATAZ 400 mg once daily + lamivudine + zidovudined
(n=405)
efavirenz 600 mg once daily + lamivudine + zidovudined
(n=405)
Respondera 67% (32%) 62% (37%)
Virologic failureb 20% 21%
  Rebound 17% 16%
  Never suppressed through Week 48 3% 5%
Death - < 1%
Discontinued due to adverse event 5% 7%
Discontinued for other reasonsc 8% 10%
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.

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 28.

Table 28: Outcomes of Randomized Treatment Through Week 48 in Treatment-Naive Adults (Study AI424-008)

Outcome REYATAZ 400 mg once daily + lamivudine + stavudine
(n=181)
nelfinavir 1250 mg twice daily + lamivudine + stavudine
(n=91)
Respondera 67% (33%) 59% (38%)
Virologic failureb 24% 27%
  Rebound 14% 14%
  Never suppressed through Week 48 10% 13%
Death < 1% -
Discontinued due to adverse event 1% 3%
Discontinued for other reasonsc 7% 10%
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.

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 was a 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, NNRTIs, and NRTIs. The mean time of prior exposure to antiretrovirals was 139 weeks for PIs, 85 weeks for NNRTIs, and 283 weeks for NRTIs. 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 29. 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 quantification. [See Microbiology, Tables 24 and 25]

Table 29: 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
(n=119)
lopinavir/ ritonavir (400/100 mg) twice daily + tenofovir + 1 NRTI
(n=118)
Differencea (REYATAZ- lopinavir/ritonavir) (CI)
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)d 116 123 -7 (-67, 52)
Percent of Patients Respondinge
  HIV RNA < 400 copies/mLb 55% 57% -2.2% (-14.8%,10.5%)
  HIV RNA < 50 copies/mLb 38% 45% -7.1% (-19.6%,5.4%)
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.

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].

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 was inferior to lopinavir/ritonavir in PI-experienced patients with prior virologic failure and is not recommended for such patients.

Pediatric Patients

Pediatric Trials With REYATAZ Capsules

Assessment of the pharmacokinetics, safety, tolerability, and virologic response of REYATAZ capsules was based on data from the open-label, multicenter clinical trial PACTG 1020A which included patients from 6 years to 21 years of age. In this study, 105 patients (43 antiretroviralnaive and 62 antiretroviral-experienced) received once daily REYATAZ capsule formulation, with or without ritonavir, in combination with two NRTIs.

One-hundred five (105) patients (6 to less than 18 years of age) treated with the REYATAZ capsule formulation, with or without ritonavir, were evaluated. Using an ITT analysis, the overall proportions of antiretroviral-naive and -experienced patients with HIV RNA < 400 copies/mL at Week 96 were 51% (22/43) and 34% (21/62), respectively. The overall proportions of antiretroviral-naive and -experienced patients with HIV RNA < 50 copies/mL at Week 96 were 47% (20/43) and 24% (15/62), respectively. The median increase from baseline in absolute CD4 count at 96 weeks of therapy was 335 cells/mm³ in antiretroviral-naive patients and 220 cells/mm³ in antiretroviral-experienced patients.

Pediatric Trials with REYATAZ Oral Powder

Assessment of the pharmacokinetics, safety, tolerability, and virologic response of REYATAZ oral powder was based on data from two open-label, multicenter clinical trials.

  • AI424-397 (PRINCE I): In pediatric patients from 3 months to less than 6 years of age
  • AI424-451 (PRINCE II): In pediatric patients from 3 months to less than 11 years of age

In these studies 134 patients (73 antiretroviral-naive and 61 antiretroviral-experienced) received once daily REYATAZ oral powder and ritonavir, in combination with two NRTIs.

For inclusion in both trials, treatment-naive patients had to have genotypic sensitivity to REYATAZ and two NRTIs, and treatment-experienced patients had to have documented genotypic and phenotypic sensitivity at screening to REYATAZ and at least 2 NRTIs. Patients exposed only to antiretrovirals in utero or intrapartum were considered treatment-naive. Patients who received REYATAZ or REYATAZ/ritonavir at any time prior to study enrollment or who had a history of treatment failure on two or more protease inhibitors were excluded from the trials.

Sixty-five (65) patients from both studies weighing 10 kg to less than 25 kg treated with REYATAZ oral powder with ritonavir were evaluated. Patients 10 kg to less than 15 kg received 200 mg REYATAZ and 80 mg ritonavir oral solution, and patients 15 kg to less than 25 kg received 250 mg REYATAZ and 80 mg ritonavir oral solution. Using a modified ITT analysis, the overall proportions of antiretroviral-naive and antiretroviral-experienced patients with HIV RNA < 400 copies/mL at Week 48 were 78% (32/41) and 71% (17/24), respectively in patients who received REYATAZ oral powder with ritonavir. The overall proportions of antiretroviralnaive and antiretroviral-experienced patients with HIV RNA < 50 copies/mL at Week 48 were 66% (27/41) and 58% (14/24), respectively in patients who received REYATAZ oral powder with ritonavir. The median increase from baseline in absolute CD4 count (percent) at 48 weeks of therapy was 412 cells/mm³ (10.5%) in antiretroviral-naive patients and 228 cells/mm³ (6%) in antiretroviral-experienced patients who received REYATAZ oral powder with ritonavir.

Last reviewed on RxList: 6/16/2014
This monograph has been modified to include the generic and brand name in many instances.

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