Atazanavir Sulfate (Page 7 of 11)

8.5 Geriatric Use

Clinical studies of atazanavir did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Based on a comparison of mean single-dose pharmacokinetic values for C max and AUC, a dose adjustment based upon age is not recommended. In general, appropriate caution should be exercised in the administration and monitoring of atazanavir in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6 Age/Gender

A study of the pharmacokinetics of atazanavir was performed in young (n=29; 18 to 40 years) and elderly (n=30; ≥65 years) healthy subjects. There were no clinically significant pharmacokinetic differences observed due to age or gender.

8.7 Impaired Renal Function

Atazanavir is not recommended for use in HIV-treatment-experienced patients with end-stage renal disease managed with hemodialysis [see Dosage and Administration (2.7) and Clinical Pharmacology (12.3)].

8.8 Impaired Hepatic Function

Atazanavir is not recommended for use in patients with severe hepatic impairment. Atazanavir/ritonavir is not recommended in patients with any degree of hepatic impairment [see Dosage and Administration (2.8) and Clinical Pharmacology (12.3)].

10 OVERDOSAGE

Human experience of acute overdose with atazanavir is limited. Single doses up to 1200 mg (three times the 400 mg maximum recommended dose) have been taken by healthy volunteers without symptomatic untoward effects. A single self-administered overdose of 29.2 g of atazanavir in an HIV-infected patient (73 times the 400 mg recommended dose) was associated with asymptomatic bifascicular block and PR interval prolongation. These events resolved spontaneously. At atazanavir doses resulting in high atazanavir exposures, jaundice due to indirect (unconjugated) hyperbilirubinemia (without associated liver function test changes) or PR interval prolongation may be observed [see Warnings and Precautions (5.1, 5.8) and Clinical Pharmacology (12.2)].
Treatment of overdosage with atazanavir should consist of general supportive measures, including monitoring of vital signs and ECG, and observations of the patient’s clinical status. If indicated, elimination of unabsorbed atazanavir should be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid removal of unabsorbed drug. There is no specific antidote for overdose with atazanavir. Since atazanavir is extensively metabolized by the liver and is highly protein bound, dialysis is unlikely to be beneficial in significant removal of this medicine.

11 DESCRIPTION

The active ingredient in atazanavir capsules is atazanavir sulfate, which is an HIV-1 protease inhibitor.
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 C 38 H 52 N 6 O 7• H 2 SO 4 , 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:

Chemical Structure
(click image for full-size original)

Atazanavir sulfate is a white to pale-yellow crystalline powder. It is slightly soluble in water (4 to 5 mg/mL, free base equivalent) with the pH of a saturated solution in water being about 1.9 at 24±3°C. Atazanavir capsules are available for oral administration in strengths of 100 mg, 150 mg, 200 mg, or 300 mg of atazanavir, which are equivalent to 113.903 mg, 170.854 mg, 227.805 mg, or 341.708 mg of atazanavir sulfate, respectively. The capsules also contain the following inactive ingredients: crospovidone, lactose monohydrate, and magnesium stearate. The capsule shells contain the following inactive ingredients: FD&C blue 2, gelatin, iron oxide black, iron oxide red, iron oxide yellow, and titanium dioxide. The capsules are printed with ink containing black iron oxide, potassium hydroxide, propylene glycol, shellac, and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Atazanavir is an HIV-1 antiretroviral drug [see Microbiology (12.4)] .

12.2 Pharmacodynamics

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

12.3 Pharmacokinetics

The pharmacokinetics of atazanavir were evaluated in healthy adult volunteers and in HIV- infected patients after administration of atazanavir 400 mg once daily and after administration of atazanavir 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
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)
C max (ng/mL)
Geometric mean (CV%) 5199 (26) 2298 (71) 6129 (31) 4422 (58)
Mean (SD) 5358 (1371) 3152 (2231) 6450 (2031) 5233 (3033)
T max (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)
C min (ng/mL)
Geometric mean (CV%) 159 (88) 120 (109) 1227 (53) 636 (97)
Mean (SD) 218 (191) 273 (298) b 1441 (757) 862 (838)
a n=26. b n=12.

Figure 1 displays the mean plasma concentrations of atazanavir at steady state after atazanavir 400 mg once daily (as two 200 mg capsules) with a light meal and after atazanavir 300 mg (as two 150 mg capsules) with ritonavir 100 mg once daily with a light meal in HIV-infected adult patients.

figure-1
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Absorption
Atazanavir is rapidly absorbed with a T max of approximately 2.5 hours. Atazanavir demonstrates nonlinear pharmacokinetics with greater than dose-proportional increases in AUC and C max 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 atazanavir with food enhances bioavailability and reduces pharmacokinetic variability. Administration of a single 400 mg dose of atazanavir with a light meal (357 kcal, 8.2 g fat, 10.6 g protein) resulted in a 70% increase in AUC and 57% increase in C max relative to the fasting state. Administration of a single 400 mg dose of atazanavir 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 C max relative to the fasting state. Administration of atazanavir with either a light meal or high-fat meal decreased the coefficient of variation of AUC and C max by approximately one-half compared to the fasting state.
Coadministration of a single 300 mg dose of atazanavir 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 C max 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 C max 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 T max increased from 2.0 to 5.0 hours. Coadministration of atazanavir with ritonavir with either a light or a high-fat meal decreased the coefficient of variation of AUC and C max 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 atazanavir 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 14 C-atazanavir, 79% and 13% of the total radioactivity was recovered in the feces and urine, respectively. Unchanged drug accounted for approximately 20% and 7% of the administered dose in the feces and urine, respectively. The mean elimination half-life of atazanavir in healthy volunteers (n=214) and HIV-infected adult patients (n=13) was approximately 7 hours at steady state following a dose of 400 mg daily with a light meal.
Specific Populations
Renal Impairment
In healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. Atazanavir 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 C max was 9% lower, AUC was 19% higher, and C min 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 C max , AUC, and C min were approximately 25% to 43% lower compared to subjects with normal renal function. The mechanism of this decrease is unknown. Atazanavir is not recommended for use in HIV-treatment-experienced patients with end-stage renal disease managed with hemodialysis [see Dosage and Administration (2.7)] .
Hepatic Impairment
Atazanavir 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. Atazanavir is not recommended for use in patients with severe hepatic impairment. The pharmacokinetics of atazanavir in combination with ritonavir has not been studied in subjects with hepatic impairment; thus, coadministration of atazanavir with ritonavir is not recommended for use in patients with any degree of hepatic impairment [see Dosage and Administration (2.8)] .
Pediatrics 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 (2.4)].

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) C max ng/mL Geometric Mean (CV%) AUC ng•h/mL Geometric Mean (CV%) C min ng/mL Geometric Mean (CV%)
15 to <35 200/100 3303 (86%) 37235 (84%) 538 (99%)
≥35 300/100 2980 (82%) 37643 (83%) 653 (89%)

Pregnancy The pharmacokinetic data from HIV-infected pregnant women receiving atazanavir 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=5 a) 3rd Trimester (n=20) Postpartum b (n=34)
C max 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)
C min ng/mL c 538.70 668.48 1462.59
Geometric mean (CV%) (46) (50) (45)
a Available data during the 2nd trimester are limited. b Atazanavir peak concentrations and AUCs were found to be approximately 28% to 43% higher during the postpartum period (4 to 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 C min is concentration 24 hours post-dose.

Drug Interaction Data
Atazanavir is a metabolism-dependent CYP3A inhibitor, with a K inact value of 0.05 to 0.06 min -1 and K i value of 0.84 to 1.0 µM. Atazanavir is also a direct inhibitor for UGT1A1 (K i =1.9 µM) and CYP2C8 (K i =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, atazanavir decreased the urinary ratio of endogenous 6β-OH cortisol to cortisol versus baseline, indicating that CYP3A production was not induced.
Clinically significant interactions are not expected between atazanavir and substrates of CYP2C19, CYP2C9, CYP2D6, CYP2B6, CYP2A6, CYP1A2, or CYP2E1. Clinically significant interactions are not expected between atazanavir when administered with ritonavir and substrates of CYP2C8. See the complete prescribing information for ritonavir for information on other potential drug interactions with ritonavir.
Based on known metabolic profiles, clinically significant drug interactions are not expected between atazanavir and dapsone, trimethoprim/sulfamethoxazole, azithromycin, or erythromycin. Atazanavir does not interact with substrates of CYP2D6 (e.g., nortriptyline, desipramine, metoprolol). Drug interaction studies were performed with atazanavir and other drugs likely to be coadministered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of coadministration of atazanavir on the AUC, C max , and C min are summarized in Tables 21 and 22. Neither didanosine EC nor diltiazem had a significant effect on atazanavir exposures (see Table 22 for effect of atazanavir on didanosine EC or diltiazem exposures). Atazanavir did not have a significant effect on the exposures of didanosine (when administered as the buffered tablet), stavudine, or fluconazole. For information regarding clinical recommendations, see Drug Interactions (7).

Table 21: Drug Interactions: Pharmacokinetic Parameters for Atazanavir in the Presence of Coadministered Drugs a
Coadministered Drug Coadministered Drug Dose/Schedule Atazanavir Dose/Schedule Ratio (90% Confidence Interval) of Atazanavir Pharmacokinetic Parameters with/without Coadministered Drug; No Effect = 1.00
C max AUC C min
atenolol 50 mg QD, d 7 to 11 (n=19) and d 19 to 23 400 mg QD, d 1 to 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, d 1 to 6, 25 to 31 300 mg QD/ritonavir 100 mg QD, d 10 to 31 atazanavir: 0.75 (0.64 to 0.88) ritonavir: 0.73 (0.64 to 0.83) atazanavir: 0.65 (0.55 to 0.78) ritonavir: 0.64 (0.58 to 0.72) atazanavir: 0.51 (0.44 to 0.61) ritonavir: 0.55 (0.45 to 0.67)
clarithromycin 500 mg BID, d 7 to 10 (n=29) and d 18 to 21 400 mg QD, d 1 to 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)
efavirenz 600 mg QD, d 7 to 20 (n=27) 400 mg QD, d 1 to 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 to 20 (n=13) 400 mg QD, d 1 to 6 (n=23) then 300 mg/ritonavir 100 mg QD, 2 h before efavirenz, d 7 to 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 to 24 (pm) (n=14) 300 mg QD/ritonavir 100 mg QD, d 1 to 10 (pm) (n=22), then 400 mg QD/ritonavir 100 mg QD, d 11 to 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, d 7 to 12 (n=15) 400 mg QD, d 1 to 6 (n=45), d 7 to 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 to 12 (n=14) 400 mg QD (pm), d 1 to 6 (n=14), d 7 to 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 to 20 (n=14) c 300 mg QD/ritonavir 100 mg QD, d 1 to 10 (n=46), d 11 to 20 d (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 to 17 (n=18) 300 mg QD/ritonavir 100 mg QD/tenofovir DF 300 mg QD, d 1 to 10 (am) (n=39), d 11 to 17 (am) (simultaneous administration with am famotidine) (n=18) d,e 0.91 (0.84, 0.99) 0.90 (0.82, 0.98) 0.81 (0.69, 0.94)
40 mg QD (pm), d 18 to 24 (n=20) 300 mg QD/ritonavir 100 mg QD/tenofovir DF 300 mg QD, d 1 to 10 (am) (n=39), d 18 to 24 (am) (12 h after pm famotidine) (n=20) e 0.89 (0.81, 0.97) 0.88 (0.80, 0.96) 0.77 (0.63, 0.93)
40 mg BID, d 18 to 24 (n=18) 300 mg QD/ritonavir 100 mg QD/tenofovir DF 300 mg QD, d 1 to 10 (am) (n=39), d 18 to 24 (am) (10 h after pm famotidine and 2 h before am famotidine) (n=18) e 0.74 (0.66, 0.84) 0.79 (0.70, 0.88) 0.72 (0.63, 0.83)
40 mg BID, d 11 to 20 (n=15) 300 mg QD/ritonavir 100 mg QD, d 1 to 10 (am) (n=46), then 400 mg QD/ritonavir 100 mg QD, d 11 to 20 (am) (n=15) 1.02 (0.87, 1.18) 1.03 (0.86, 1.22) 0.86 (0.68, 1.08)
grazoprevir/elbasvir grazoprevir 200 mg QD d 1 to 35 (n = 11) 300 mg QD/ritonavir 100 mg QD, d 1 to 35 (n = 11) 1.12 (1.01, 1.24) 1.43 (1.30, 1.57) 1.23 (1.13, 1.34)
elbasvir 50 mg QD d 1 to 35 (n = 8) 300 mg QD/ritonavir 100 mg QD, d 1 to 35 (n = 8) 1.02 (0.96, 1.08) 1.07 (0.98, 1.17) 1.15 (1.02, 1.29)
ketoconazole 200 mg QD, d 7 to 13 (n=14) 400 mg QD, d 1 to 13 (n=14) 0.99 (0.77, 1.28) 1.10 (0.89, 1.37) 1.03 (0.53, 2.01)
nevirapine f,g 200 mg BID, d 1 to 23 (n=23) 300 mg QD/ritonavir 100 mg QD, d 4 to 13, then 400 mg QD/ritonavir 100 mg QD, d 14 to 23 (n=23) h 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, d 7 to 12 (n=16) i 40 mg QD, d 11 to 20 (n=15) i 20 mg QD, d 17 to 23 (am) (n=13) 20 mg QD, d 17 to 23 (am) (n=14) 400 mg QD, d 1 to 6 (n=48), d 7 to 12 (n=16) 300 mg QD/ritonavir 100 mg QD, d 1 to 20 (n=15) 300 mg QD/ritonavir 100 mg QD, d 7 to 16 (pm) (n=27), d 17 to 23 (pm) (n=13) j,k 300 mg QD/ritonavir 100 mg QD, d 7 to 16 (am) (n=27), then 400 mg QD/ritonavir 100 mg QD, d 17 to 23 (am) (n=14) l,m 0.04 (0.04, 0.05) 0.28 (0.24, 0.32) 0.61 (0.46, 0.81) 0.69 (0.58, 0.83) 0.06 (0.05, 0.07) 0.24 (0.21, 0.27) 0.58 (0.44, 0.75) 0.70 (0.57, 0.86) 0.05 (0.03, 0.07) 0.22 (0.19, 0.26) 0.54 (0.41, 0.71) 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, d 15 to 28 (n=7) 400 mg QD, d 1 to 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 to 26 (n=16) 300 mg QD/ritonavir 100 mg QD, d 7 to 16 (n=48), d 17 to 26 (n=16) 0.47 (0.41, 0.53) 0.28 (0.25, 0.32) 0.02 (0.02, 0.03)
ritonavir n 100 mg QD, d 11 to 20 (n=28) 300 mg QD, d 1 to 20 (n=28) 1.86 (1.69, 2.05) 3.38 (3.13, 3.63) 11.89 (10.23, 13.82)
tenofovir DF o 300 mg QD, d 9 to 16 (n=34) 300 mg QD, d 15 to 42 (n=10) 400 mg QD, d 2 to 16 (n=34) 300 mg/ritonavir 100 mg QD, d 1 to 42 (n=10) 0.79 (0.73, 0.86) 0.72 p (0.50, 1.05) 0.75 (0.70, 0.81) 0.75 p (0.58, 0.97) 0.60 (0.52, 0.68) 0.77 p (0.54, 1.10)
voriconazole (Subjects with at least one functional CYP2C19 allele) 200 mg BID, d 2 to 3, 22 to 30; 400 mg BID, d 1, 21 (n=20) 300 mg/ritonavir 100 mg QD, d 11 to 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 to 3, 22 to 30; 100 mg BID, d 1, 21 (n=8) 300 mg/ritonavir 100 mg QD, d 11 to 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. b All drugs were given under fasted conditions. c Atazanavir 300 mg plus ritonavir 100 mg once daily coadministered with famotidine 40 mg twice daily resulted in atazanavir geometric mean C max that was similar and AUC and C min values that were 1.79- and 4.46-fold higher relative to atazanavir 400 mg once daily alone. d Similar results were noted when famotidine 20 mg BID was administered 2 hours after and 10 hours before atazanavir 300 mg and ritonavir 100 mg plus tenofovir DF 300 mg. e Atazanavir/ritonavir/tenofovir DF was administered after a light meal. f Study was conducted in HIV-infected individuals. g Compared with atazanavir 400 mg historical data without nevirapine (n=13), the ratio of geometric means (90% confidence intervals) for C max , AUC, and C min were 1.42 (0.98, 2.05), 1.64 (1.11, 2.42), and 1.25 (0.66, 2.36), respectively, for atazanavir/ritonavir 300/100 mg; and 2.02 (1.42, 2.87), 2.28 (1.54, 3.38), and 1.80 (0.94, 3.45), respectively, for atazanavir/ritonavir 400/100 mg. h Parallel group design; n=23 for atazanavir/ritonavir plus nevirapine, n=22 for atazanavir 300 mg/ritonavir 100 mg without nevirapine. Subjects were treated with nevirapine prior to study entry. i Omeprazole 40 mg was administered on an empty stomach 2 hours before atazanavir. j Omeprazole 20 mg was administered 30 minutes prior to a light meal in the morning and atazanavir 300 mg plus ritonavir 100 mg in the evening after a light meal, separated by 12 hours from omeprazole. k Atazanavir 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 C min (2.4-fold), with a decrease in C max (29%) relative to atazanavir 400 mg once daily in the absence of omeprazole (study days 1 to 6). l Omeprazole 20 mg was given 30 minutes prior to a light meal in the morning and atazanavir 400 mg plus ritonavir 100 mg once daily after a light meal, 1 hour after omeprazole. Effects on atazanavir concentrations were similar when atazanavir 400 mg plus ritonavir 100 mg was separated from omeprazole 20 mg by 12 hours. m atazanavir 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 C min (3.3-fold), with a decrease in C max (26%) relative to atazanavir 400 mg once daily in the absence of omeprazole (study days 1 to 6). n Compared with atazanavir 400 mg QD historical data, administration of atazanavir/ritonavir 300/100 mg QD increased the atazanavir geometric mean values of C max , AUC, and C min by 18%, 103%, and 671%, respectively. o Note that similar results were observed in studies where administration of tenofovir DF and atazanavir was separated by 12 hours. p Ratio of atazanavir plus ritonavir plus tenofovir DF to atazanavir plus ritonavir. Atazanavir 300 mg plus ritonavir 100 mg results in higher atazanavir exposure than atazanavir 400 mg (see footnote o). The geometric mean values of atazanavir pharmacokinetic parameters when coadministered with ritonavir and tenofovir DF were: C max = 3190 ng/mL, AUC = 34459 ng•h/mL, and C min = 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 Atazanavir a
Coadministered Drug Coadministered Drug Dose/Schedule Atazanavir Dose/Schedule Ratio (90% Confidence Interval) of Coadministered Drug Pharmacokinetic Parameters with/without Atazanavir ; No Effect = 1.00
C max AUC C min
acetaminophen 1 gm BID, d 1 to 20 (n=10) 300 mg QD/ritonavir 100 mg QD, d 11 to 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, d 7 to 11 (n=19) and d 19 to 23 400 mg QD, d 1 to 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, d 1 to 6, 25 to 31 300 mg QD/ritonavir 100 mg QD, d 10 to 31 0.93 (0.80, 1.08) 0.95 (0.87, 1.05) 0.82 (0.68, 0.98)
clarithromycin 500 mg BID, d 7 to 10 (n=21) and d 18 to 21 400 mg QD, d 1 to 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)
ddI (enteric-coated [EC] capsules) b 400 mg d 1 (fasted), d 8 (fed) (n = 34) 400 mg QD, d 2 to 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 to 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, d 7 to 11 (n=28) and d 19 to 23 400 mg QD, d 1 to 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 & norethindrone c Ortho-Novum ® 7/7/7 QD, d 1 to 29 (n=19) 400 mg QD, d 16 to 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 & norgestimate d Ortho Tri-Cyclen ® QD, d 1 to 28 (n=18), then Ortho Tri- Cyclen ® LO QD, d 29 to 42 e (n=14) 300 mg QD/ritonavir 100 mg QD, d 29 to 42 (n=14) ethinyl estradiol: 0.84 (0.74, 0.95) 17-deacetyl norgestimate: f 1.68 (1.51, 1.88) ethinyl estradiol: 0.81 (0.75, 0.87) 17-deacetyl norgestimate: f 1.85 (1.67, 2.05) ethinyl estradiol: 0.63 (0.55, 0.71) 17-deacetyl norgestimate: f 2.02 (1.77, 2.31)
glecaprevir/ pibrentasvir 300 mg glecaprevir (n=12) 300 mg QD/ritonavir 100 mg QD (n=12) ≥4.06g (3.15, 5.23) ≥6.53g (5.24, 8.14) ≥14.3g (9.85, 20.7)
120 mg pibrentasvir (n=12) 300 mg QD/ritonavir 100 mg QD (n=12) ≥1.29g (1.15, 1.45) ≥1.64g (1.48, 1.82) ≥2.29g (1.95, 2.68)
grazoprevir/ elbasvir grazoprevir 200 mg QD d 1 to 35 (n = 12) 300 mg QD/ritonavir 100 mg QD d 1 to 35 (n=12) 6.24 (4.42, 8.81) 10.58 (7.78, 14.39) 11.64 (7.96, 17.02)
elbasvir 50 mg QD d 1 to 35 (n = 10) 300 mg QD/ritonavir 100 mg QD,d 1 to 35 (n=10) 4.15 (3.46, 4.97) 4.76 (4.07, 5.56) 6.45 (5.51, 7.54)
methadone Stable maintenance dose, d 1 to 15 (n=16) 400 mg QD, d 2 to 15 (n=16) (R)-methadone h 0.91 (0.84, 1.0) total: 0.85 (0.78, 0.93) (R)-methadone h 1.03 (0.95, 1.10) total: 0.94 (0.87, 1.02) (R)-methadone h 1.11 (1.02, 1.20) total: 1.02 (0.93, 1.12)
nevirapine i,j 200 mg BID, d 1 to 23 (n=23) 300 mg QD/ ritonavir 100 mg QD, d 4 to 13, then 400 mg QD/ritonavir 100 mg QD, d 14 to 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)
omeprazole k 40 mg single dose, d 7 and d 20 (n=16) 400 mg QD, d 1 to 12 (n=16) 1.24 (1.04, 1.47) 1.45 (1.20, 1.76) NA
rifabutin 300 mg QD, d 1 to 10 then 150 mg QD, d 11 to 20 (n=3) 600 mg QD, l d 11 to 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 to 15 (n=7) 300 mg QD/ ritonavir 100 mg QD, d 1 to 17 (n=7) 2.49 m (2.03, 3.06) 25-O-desacetyl-rifabutin: 7.77 (6.13, 9.83) 1.48 m (1.19, 1.84) 25-O-desacetyl-rifabutin: 10.90 (8.14, 14.61) 1.40 m (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
rosiglitazone n 4 mg single dose, d 1, 7, 17 (n=14) 400 mg QD, d 2 to 7, then 300 mg QD/ ritonavir 100 mg QD, d 8 to 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
rosuvastatin 10 mg single dose 300 mg QD/ ritonavir 100 mg QD for 7 days ↑7-fold o ↑3-fold o NA
saquinavir p (soft gelatin capsules) 1200 mg QD, d 1 to 13 (n=7) 400 mg QD, d 7 to 13 (n=7) 4.39 (3.24, 5.95) 5.49 (4.04, 7.47) 6.86 (5.29, 8.91)
sofosbuvir/ velpatasvir/ voxilaprevir 400 mg sofosbuvir single dose (n=15) 300 mg/100 mg ritonavir single dose (n=15) 1.29 (1.09, 1.52) sofosbuvir metabolite GS-331007 1.05 (0.99, 1.12) 1.40 (1.25, 1.57) sofosbuvir metabolite GS-331007 1.25 (1.16, 1.36) NA
100 mg velpatasvir single dose (n=15) 300 mg/100 mg ritonavir single dose (n=15) 1.29 (1.07, 1.56) 1.93 (1.58, 2.36) NA
100 mg voxilaprevir single dose (n=15) 300 mg/100 mg ritonavir single dose (n=15) 4.42 (3.65, 5.35) 4.31 (3.76, 4.93) NA
tenofovir DF q 300 mg QD, d 9 to 16 (n=33) and d 24 to 30 (n=33) 400 mg QD, d 2 to 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 to 7 (pm) (n=14) d 25 to 34 (pm) (n=12) 300 mg QD/ritonavir 100 mg QD, d 25 to 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, d 2 to 3, 22 to 30; 400 mg BID, d 1, 21 (n=20) 300 mg/ritonavir 100 mg QD, d 11 to 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, d 2 to 3, 22 to 30; 100 mg BID, d 1, 21 (n=8) 300 mg/ritonavir 100 mg QD, d 11 to 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 to 12 (n=19) 400 mg QD, d 7 to 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)
a Data provided are under fed conditions unless otherwise noted. b 400 mg ddI EC and atazanavir were administered together with food on Days 8 and 19. c Upon further dose normalization of ethinyl estradiol 25 mcg with atazanavir relative to ethinyl estradiol 35 mcg without atazanavir, the ratio of geometric means (90% confidence intervals) for C max , AUC, and C min were 0.82 (0.73, 0.92), 1.06 (0.95, 1.17), and 1.35 (1.11, 1.63), respectively. d Upon further dose normalization of ethinyl estradiol 35 mcg with atazanavir/ritonavir relative to ethinyl estradiol 25 mcg without atazanavir/ritonavir, the ratio of geometric means (90% confidence intervals) for C max , AUC, and C min were 1.17 (1.03, 1.34), 1.13 (1.05, 1.22), and 0.88 (0.77, 1.00), respectively. e All subjects were on a 28-day lead-in period; one full cycle of Ortho Tri-Cyclen ®. Ortho Tri-Cyclen ® contains 35 mcg of ethinyl estradiol. Ortho Tri-Cyclen ® LO contains 25 mcg of ethinyl estradiol. Results were dose normalized to an ethinyl estradiol dose of 35 mcg. f 17-deacetyl norgestimate is the active component of norgestimate g Effect of atazanavir and ritonavir on the first dose of glecaprevir and pibrentasvir is reported. h (R)-methadone is the active isomer of methadone. i Study was conducted in HIV-infected individuals. j Subjects were treated with nevirapine prior to study entry. k Omeprazole was used as a metabolic probe for CYP2C19. Omeprazole was given 2 hours after atazanavir 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 d 1 to 10 (n=14). Total of rifabutin + 25-O-desacetyl-rifabutin: AUC 2.19 (1.78, 2.69). n Rosiglitazone used as a probe substrate for CYP2C8. o Mean ratio (with/without coadministered drug). ↑ indicates an increase in rosuvastatin exposure. p The combination of atazanavir and saquinavir 1200 mg QD produced daily saquinavir exposures similar to the values produced by the standard therapeutic dosing of saquinavir at 1200 mg TID. However, the C max is about 79% higher than that for the standard dosing of saquinavir (soft gelatin capsules) alone at 1200 mg TID. q Note that similar results were observed in a study where administration of tenofovir DF and atazanavir was separated by 12 hours. r Administration of tenofovir DF and atazanavir was temporally separated by 12 hours. NA = not available.

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