Norvir
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Norvir - Scientific Information

Manufacture: AbbVie
Country: Canada
Condition: HIV Infection
Class: Antiviral boosters, Protease inhibitors
Form: Tablets, Syrup
Ingredients: ritonavir, copovidone, colloidal silicon dioxide/colloidal anhydrous silica, dibasic calcium phosphate anhydrous/calcium hydrogen phosphate anhydrous, hydroxypropyl cellulose, hypromellose, polyethylene glycol 400/macrogol type 400, polyethylene glycol 3350/macrogol type 3350, polysorbate 80, sorbitan monolaurate/sorbitan laurate, sodium stearyl fumarate, talc and titanium dioxide E171

Pharmaceutical information

Drug Substance

Proper name:ritonavir
Chemical name:10-Hydroxy-2-methyl-5-(1-methylethyl)-1- [2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester, [5S-(5R*,8R*,10R*,11R*)]
Molecular formula and molecular mass:C37H48N6O5S2 720.95
Structural formula:



Physicochemical properties:Ritonavir is a white to light tan powder.
Solubility:Ritonavir has a bitter metallic taste. It is freely soluble in methanol and ethanol, soluble in isopropanol and practically insoluble in water.

Clinical Trials

The activity of NORVIR (ritonavir) as monotherapy or in combination with nucleoside reverse transcriptase inhibitors has been evaluated in 1446 patients enrolled in two double-blind, randomized trials. NORVIR therapy in combination with zidovudine and zalcitabine was also evaluated in an open-label, non-comparative study of 32 patients.

Study Demographics and Trial Design

Table 1. Summary of Patient Demographics for Clinical Trials in Specific Indication
Study #Trial DesignDosage, Route of Administration and DurationStudy SubjectsMean Age (Range)Gender
Race
(% M/F)
(%C/O)1
Mean Baseline CD4 Cell Count (Range)
Advanced Patients with Prior Antiretroviral Therapy
M94-247Double blind, randomized, two-arm, parallel, multicenter internationalNORVIR liquid or semi-solid capsules
(600 mg b.i.d.)
vs.
Placebo

Oral

6 months double-blind followed by 14 months open-label follow-up
109038.9 years (15-72)92/8
86/14
32 cells/microliter
(0-154)2
Patients Without Prior Antiretroviral Therapy
M94-245Double blind, randomized, three-arm, parallel, multicenterNORVIR liquid or semi-solid capsules
(600 mg b.i.d.)
vs.
zidovudine capsules
(200 mg t.i.d.)
vs.
NORVIR liquid or semi-solid capsules
(600 mg b.i.d.) + zidovudine capsules
(200 mg t.i.d.)

Oral

8-12 months
35636.0 years
(18-69)
91/9
83/17
364 cells/ microliter
Range: 139-1054 (200-500)3
Combination Therapy in Anti-retroviral Naïve Patients
M94-208Phase II, open-label, multicenterTriple Therapy Combination:
NORVIR
(600 mg b.i.d.) +
zidovudine (200 mg t.i.d.) +
zalcitabine (0.75 mg t.i.d.)

Oral
6 months
3238.1 years (29-52)88/12
97/3
Median: 83
> 100 cells/ microliter
(81%)4

1: % Male/Female; % Caucasian/Other.

2: Approximately 50% of patients had baseline CD4 cell counts ≤ 20 cells/microliter, and only 22% had counts > 50 cells/microliter.

3: Approximately 75% of the patients were evenly distributed between this range.

4: The majority (81%) of patients had baseline CD4 values > 100 cells/microliter.

Definitions: b.i.d. = twice daily; t.i.d. = three times daily.

Study Results

Advanced Patients with Prior Antiretroviral Therapy

Study M94-247 was a randomized, double-blind trial conducted in HIV-infected patients with at least nine months of prior antiretroviral therapy and baseline CD4 cells counts ≤ 100 cells/microliter. NORVIR 600 mg twice daily or placebo was added to each patient's baseline antiretroviral therapy regimen, which could have consisted of up to two approved antiretroviral agents. The study accrued 1090 patients, with mean baseline CD4 cell count at study entry of 32 cells/ microliter. Median duration of follow-up was 6 months.

The six month cumulative incidence of clinical disease progression or death was 17% for patients randomized to NORVIR compared to 34% for patients randomized to placebo. This difference in rates was statistically significant.

The six-month cumulative mortality was 5.8% for patients randomized to NORVIR and 10.1% for patients randomized to placebo. This difference in rates was statistically significant.

In addition, analyses of mean CD4 cell count changes from baseline over the first 16 weeks of study for the first 211 patients enrolled (mean baseline CD4 cell count = 29 cells/microliter) showed that NORVIR was associated with larger increases in CD4 cell counts than was placebo. Compared to placebo, NORVIR also produced a greater mean decrease in HIV RNA levels from baseline.

Patients Without Prior Antiretroviral Therapy

In Study M94-245, 356 antiretroviral-naive HIV-infected patients (mean baseline CD4 = 364 cells/microliter) were randomized to receive either NORVIR 600 mg twice daily, zidovudine 200 mg three times daily, or a combination of these drugs. In analyses of average CD4 cell count changes from baseline over the first 16 weeks of study, both NORVIR monotherapy and combination therapy produced greater mean increases in CD4 cell count than did zidovudine monotherapy. The CD4 cell count increases for NORVIR monotherapy were larger than the increases for combination therapy. Similarly, the mean decreases in HIV RNA level from baseline were larger with NORVIR monotherapy than with combination therapy or zidovudine monotherapy.

Combination Therapy with NORVIR, Zidovudine, and Zalcitabine in Antiretroviral- Naive Patients

In Study M94-208, an open-label uncontrolled trial, 32 antiretroviral- naive HIV-infected patients initially received NORVIR 600 mg twice daily monotherapy. Zidovudine 200 mg three times daily and zalcitabine 0.75 mg three times daily were added after 14 days of NORVIR monotherapy. Results of combination therapy for the first 20 weeks of this study show median increases in CD4 cell counts from baseline levels of 83 to 106 cells/microliter over the treatment period. Mean decreases from baseline in HIV RNA particle levels ranged from 1.69 to 1.92 logs.

Summary of Clinical Trials

Pivotal Comparative Bioavailability Studies

NORVIR Film-coated Tablets

A Phase 1, single-dose, open-label, randomized, two-period, crossover comparative bioavailability study, with a two-stage group sequential design was conducted under fed (moderate-fat) conditions. In order to protect the overall α level at 0.05, the confidence intervals were set at 92.8% at each of the first and second stages of the study. The study was stopped based on the results of the first-stage analysis in which the rate and extent of absorption of ritonavir was compared following a single dose of 1 x 100 mg film-coated NORVIR tablet or 1 x 100 mg NORVIR soft elastic capsule*, which were administered to 84 healthy adult male and female volunteers. The results from the first-stage analysis are provided below in Table 2.

Table 2. Comparative Bioavailability Data for the 100 mg NORVIR Film-Coated Tablet Versus the NORVIR Soft Elastic Capsule*
Ritonavir
(1 x 100 mg)
From measured data
Geometric Mean
Arithmetic Mean (CV%)
Parameter Test
Non-Fasting -
Regimen A
(n = 84)
Reference
Non-Fasting -
Regimen B
Reference
(n = 84)
% RATIO OF
GEOMETRIC
MEANS
% Ratio of
Geometric Means+
92.8%
Confidence
Interval
AUCt
(mcg•h/mL)
3.154
3.6 (54)
2.780
3.3 (78)
113.4 107-121
AUCinf
(mcg•h/mL)
3.253
3.7 (55)
2.949
3.5 (82)
110.3 104-117
Cmax
(mcg/mL)
0.367
0.44 (66)
0.290
0.35 (75)
126.4 115-139
Tmaxa
(h)
4.4 (26) 6.0 (66)
T1/2b
(h)
6.10 (22) 6.45 (28)

* : Product no longer marketed in Canada.

Regimen A: 100 mg dosed as ritonavir film-coated tablet, test, non-fasting.

Regimen B: 100 mg dosed as ritonavir soft elastic capsule* (Market formulation), non-fasting.

a Tmax: Expressed as arithmetic mean (%CV) only.

b T1/2 : Expressed as harmonic mean (%CV) only.

In addition, in a Phase 1, randomized, single-dose, fasting and non-fasting, open-label, three-period, crossover study was conducted in a total of 27 healthy adult male and female volunteers. Subjects were randomly assigned to three treatments to assess the bioequivalence of 100 mg NORVIR dosed as 100 mg film-coated tablet dosed under fasting, moderate-fat and high-fat conditions. Table 3 summarizes the comparative bioavailability data.

Table 3. Comparative Bioavailability Data for the 100 mg NORVIR Film-Coated Tablet Dosed Under Fasting, Moderate-Fat and High-Fat Conditions.
Ritonavir
(1 x 100 mg)
From measured data
Geometric Mean
Arithmetic Mean (CV%)
Parameter REFERENCE
Fasting -
Regimen C
(n = 26)
TEST
High-Fat -
Regimen A
(n = 26)
TEST
Moderate-Fat -
Regimen B
(n = 27)
% RATIO OF
GEOMETRIC
MEANS
(CONFIDENCE
INTERVALS)
AUCt
(mcg•h/mL)
3.981
4.6 (43)
3.044
3.6 (44)
3.135
3.8 (51)
A/C = 77 (70-84)
B/C = 79 (72-87)1
AUCinf
(mcg•h/mL)
4.049
4.7 (43)
3.137
3.7 (45)
3.218
3.9 (52)
A/C = 78 (70-85)
B/C = 80 (72-87)
Cmax
(mcg/mL)
0.501
0.60 (51)
0.384
0.44 (46)
0.392
0.47 (56)
A/C = 77 (66-90)
B/C = 78 (68-91)
Tmaxa
(h)
3.2 (37) 4.8 (23) 4.3 (27)
T1/2b
(h)
5.49 (20) 5.98 (20) 5.81 (20)

Regimen A: 100 mg ritonavir film-coated tablet, test, high-fat condition.

Regimen B: 100 mg ritonavir film-coated tablet, test, moderate-fat condition.

Regimen C: 100 mg ritonavir film-coated tablet, reference, fasting.

a Tmax: Expressed as arithmetic mean (%CV) only.

b t1/2: Expressed as harmonic mean (%CV) only.

NORVIR SEC (Soft Elastic Capsules)*

In a Phase1, randomized, single-dose, fasting and non-fasting, open-label, three-period, crossover study, a total of 57 healthy adult male and female volunteers were randomly assigned to three dosing regimens to assess the bioequivalence of 600 mg NORVIR dosed as 100 mg soft elastic capsules* to 7.5 mL of 80 mg/mL NORVIR oral solution. Table 3 summarizes the comparative bioavailability data.

Table 3. Comparative Bioavailability Data for the 100 mg NORVIR Soft Elastic Capsule* versus the 80 mg/mL NORVIR Oral Solution
Parameter REFERENCE
Non-fasting -
Regimen A
(n = 57)
TEST
Non-Fasting -
Regimen B
(n = 57)
TEST
Fasting -
Regimen C
(n = 57)
% RATIO/RATIO
OF
GEOMETRIC
MEANS
AUCt
(mcg•h/mL)
77.0
109.3 (54.4)
104.2
121.4 (44.2)
93.3
108.5 (47.7)
B/A = 135.4
C/B = 89.5
AUC40
(mcg•h/mL)
77.1
109.3 (54.4)
104.2
121.4 (44.2)
93.3
108.5 (47.7)
B/A = 135.3
C/B = 89.5
AUCinf
(mcg•h/mL)
77.2
109.6 (54.5)
104.6
121.7 (44.2)
93.5
108.5 (47.7)
B/A = 135.4
C/B = 89.4
Cmax
(mcg/mL)
8.8
11.9 (44.6))
11.91
13.6 (39.5)
12.73
14.5 (40.2)
B/A = 135.3
C/B = 107.0
Tmaxa
(h)
3.8
4.1 (38.4)
5.2
5.5 (35.9)
3.9
4.4 (70.2)
B/A = 138.3
C/B = 74.0
T1/2b
(h)
4.31
4.23 (20.0)
4.04
3.96 (23.3)
4.30
4.21 (21.7)
B/A = 93.6
C/B = 106.6
Beta
h-1
0.161
0.164 (20.0)
0.172
0.175 (18.5)
0.161
0.165 (21.9)
B/A = 106.8
C/B = 93.8
CL/F
(L/h)
6.8
28.0 (405.5)
5.7
9.8 (260.3)
6.4
12.7 (357.6)
B/A = 83.8
C/B = 111.8

*: Product no longer marketed in Canada

Regimen A: 600 mg NORVIR as 7.5 mL (80 mg/mL) liquid, reference, non-fasting (Market formulation K-5).

Regimen B: 600 mg NORVIR as six 100 mg SEC*, test, non-fasting, formulation 2.

Regimen C: 600 mg NORVIR as six 100 mg SEC*, test, fasting, formulation 2.

a Tmax: Expressed as arithmetic mean (%CV) only.

b t1/2: Expressed as harmonic mean only.

Detailed Pharmacology

Pharmacodynamics

Ritonavir was administered orally to mice or rats at doses of 5 to 50 mg/kg to determine potential effects on various neuropharmacological endpoints. In mice, ritonavir had no meaningful effect on rotarod performance, ethanol-induced sleep time or pentobarbital-induced sleep time. In rats, no effect was observed on spontaneous motor activity or rotarod performance.

Ritonavir produced no pharmacologically significant effects on heart rate or blood pressure when administered orally to unanesthetized rats at doses of 20 or 50 mg/kg. The compound was also infused intravenously in a vehicle consisting of 20% ethanol and 15% propylene glycol in 5% dextrose water to pentobarbital-anesthetized dogs instrumented to measure various cardiovascular parameters.

Mean peak plasma levels of ritonavir were as high as 15.11 mcg/mL. Although the vehicle itself produced hemodynamic changes consistent with cardiac depression, ritonavir produced no consistent additional effects on systemic or pulmonary pressures or resistance, central venous pressure, cardiac output, left ventricular dP/dt or end-diastolic pressure.

Ritonavir had no effect on isolated guinea pig ileum basal tone or on carbachol-induced contractions.

Human

Pharmacodynamics

A Phase 1, multiple-dose, open-label, placebo and active controlled (moxifloxacin 400 mg once daily), randomized study was conducted according to a crossover design in healthy volunteers. NORVIR was dosed at 400 mg twice daily. On Day 3, ritonavir concentrations were approximately 1.5 fold higher than that observed with the 600 mg twice daily dose at steady state. Digital EKGs were performed in triplicate on study Day 3 and compared to time-matched baseline EKGs. At these increased concentrations, the maximum increase in QTcF was 5.5 msec with an upper bound 95% CI of 7.6 msec. This increase is not clinically significant.

The absolute PR interval on Day 3 and change from baseline were also evaluated. The maximum PR interval was 252 msec and no second or third degree heart block was observed. Exposure-response analysis predicted that the PR effect of ritonavir plateaus around 20 msec, thus ritonavir 600 mg twice daily is unlikely to result in clinically significant PR prolongation.

Pharmacokinetics

For details regarding the ritonavir pharmacokinetics refer to section (ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).

The effects of co-administration of ritonavir on the AUC, Cmax, and Cmin are summarized in Table 4 (effect of other drugs on ritonavir) and Table 5 (effect of ritonavir on other drugs).

Table 4. Drug Interactions: Pharmacokinetic Parameters for Ritonavir in the Presence of the Co-administered Drug
Co-
Administered
Drug
Dose of Co-
Administered Drug
NORVIR
Dosage
n AUC %
(95% CI)
Cmax%
(95% CI)
Cmin%
(95% CI)
Clarithromycin500 mg every 12 h
4 days
200 mg every
8 h 4 days
22↑ 12%
(2, 23%)
↑ 15%
(2, 28%)
↑ 14%
(-3, 36%)
Didanosine200 mg every 12 h
4 days, about 2.5 h
before NORVIR
600 mg every
12 h 4 days
12
Fluconazole400 mg Day 1,
200 mg daily
4 days
200 mg every
6 h 4 days
8↑ 12%
(5, 20%)
↑ 15%
(7, 22%)
↑ 14%
(0, 26%)
Fluoxetine30 mg every 12 h
8 days
600 mg single
dose
16↑ 19%
(7, 34%)
ND
Ketoconazole200 mg daily
7 days
500 mg every
12 h 10 days
12↑ 18%
(-3, 52%)
↑ 10%
(-11, 36%)
ND
Rifampin600 mg or 300 mg daily
10 days
500 mg every
12 h 20 days
7,9*↓ 35%
(7, 55%)
↓ 25%
(-5, 46%)
↓ 49%
(-14, 91%)
Voriconazole400 mg every 12 h,
1 day; then 200 mg
every 12 h
8 days
400 mg every
12 h 9 days
17ND
Zidovudine200 mg every 8 h 4 days300 mg every 6 h 4 days10

↑ Indicates increase; ↓ indicates decrease; ↔ indicates no change.

* Parallel group design; entries are subjects receiving combination and control regimens, respectively.

Definitions: h = hour; ND = not detected.

Table 5. Drug Interactions: Pharmacokinetic Parameters for Co-administered Drug in the Presence of ritonavir
Co-Administered
Drug
Dose of Co-
Administered Drug
NORVIR
Dosage
n AUC %
(95% Cl)
Cmax%
(95% Cl)
Cmin%
(95% Cl)
HIV-Antiviral Agents
Atazanavir300 mg every 24h
Days 1 to 20
100 mg every
24h Days 11 to
20
28↑ 3.4-fold↑ 1.9-fold↑ 11.9-fold
Darunavir800 mg
single dose
Titrated:
300 to 600 mg
every 12h over
6 days
8↑ 9.2-fold↑ 2-foldnot reported
Indinavir1400 mg every 12h
15 days
400 mg every 12h
15 days
10
Day 14↑ 6%
(-14, 29%)
↓ 51%
(40, 61%)
↑ 4-fold
(2.8, 6.8X)
Day 15↓ 7%
(-22, 28%)
↓ 62%
(52, 70%)
↑ 4-fold
(2.5, 6.5X)
Saquinavir2400 mg every 12h
steady state
400 mg every
12h steady-
state
7↑ 17-fold
(9, 31X)
↑ 14-fold
(7, 28X)
ND
Maraviroc100 mg every 12h100 mg every
12h
8↑ 28%↑ 161%not reported
Other agents
Alprazolam1 mg
single dose
500 mg every 12h
10 days
12↓ 12%
(-5, 30%)
↓ 16%
(5, 27%)
ND
Clarithromycin500 mg every 12h
4 days
200 mg every 8h
4 days
22↑ 77%
(56, 103%)
↑ 31%
(15, 51%)
↑ 2.8-fold
(2.4, 3.3X)
14-OH
clarithromycin
metabolite
↓100%↓ 99%↓ 100%
Desipramine100 mg
single dose
500 mg every 12h
12 days
14↑ 145%
(103, 211%)
↑ 22%
(12, 35%)
ND
2-OH desipramine
metabolite
↓ 15%
(3, 26%)
↓ 67%
(62, 72%)
ND
Didanosine200 mg every 12h
4 days, about 2.5 h
before NORVIR
600 mg every
12h
4 days
12↓ 13%
(0, 23%)
↓ 16%
(5, 26%)
Ethinyl estradiol50 mcg
single dose
500 mg every
12h
16 days
23↓ 40%
(31, 49%)
↓ 32%
(24, 39%)
ND
Fluticasone
propionate aqueous
nasal spray
200 mcg daily
7 days
100 mg every
12h
7 days
18↑ approx.
350-fold6
↑ approx.
25-fold6
Ketoconazole200 mg daily
7 days
500 mg every
12h
10 days
12↑ 3.4-fold
(2.8, 4.3X)
↑ 55%
(40, 72%)
ND
Meperidine50 mg
oral single dose
500 mg every
12h
10 days
8↓ 62%
(59, 65%)
↓ 59%
(42, 72%)
ND
Normeperidine
metabolite
6↑ 47%
(-24, 345%)
↑ 87%
(42, 147%)
ND
Methadone35 mg
single dose
500 mg every
12h
15 days
11↓ 36%
(16, 52%)
↓ 38%
(28, 46%)
ND
Raltegravir400 mg
single dose
100 mg every
12 h
16 days
10↓ 16%
(-30, 1%)
↓ 24%
(-45, 4%)
↓ 1%
(-30, 40%)
Rifabutin150 mg daily
16 days
500 mg every
12h
10 days
5,11*↑ 4-fold
(2.8, 6.1X)
↑ 2.5-fold
(1.9, 3.4X)
↑ 6-fold
(3.5, 18.3X)
25-O-desacetyl
rifabutin metabolite
↑ 38-fold
(28, 56X)
↑ 16-fold
(13, 20X)
↑ 181-
fold(ND)
Sildenafil100 mg
single dose
500 mg b.i.d.‡
8 days
28↑ 11-fold↑ 4-foldND
Sulfamethoxazole4800 mg
single dose
500 mg every
12h
12 days
15↓ 20%
(16, 23%)
ND
Tadalafil20 mg
single dose
200 mg every
12h
↑ 124%ND
Theophylline3 mg/kg every 8h
15 days
500 mg every
12h
10 days
13, 11*↓ 43%
(42, 45%)
↓ 32%
(29, 34%)
↓ 57%
(55, 59%)
Trazodone50 mg
single dose
200 mg every
12h
10 days
10↑ 2.4-fold↑ 34%
Trimethoprim4160 mg
single dose
500 mg every
12h
12 days
15↑ 20%
(3, 43%)
ND
Vardenafil5 mg600 mg every
12h
↑ 49-fold↑ 13-foldND
Voriconazole400 mg every 12h,
1day; then
200 mg every 12h
8 days
400 mg every
12h
9 days
17↓ 82%↓ 66%not reported
Warfarin
S-Warfarin
5 mg
single dose
400 mg every
12h
12 days
12↑ 9%
(-17, 44%)5
↓ 9%
(-16, -2%)5
ND
R-Warfarin↓ 33%
(-38, -27%)5
ND
Zidovudine200 mg every 8h
4 days
300 mg every
6h
4 days
9↓ 25%
(15, 34%)
↓ 27%
(4, 45%)
ND

1: NORVIR and indinavir were co-administered for 15 days; Day 14 doses were administered after a 15% fat breakfast (757 Kcal) and 9% fat evening snack (236 Kcal), and Day 15 doses were administered after a 15% fat breakfast (757 Kcal) and 32% fat dinner (815 Kcal). Indinavir Cmin was also increased 4-fold. Effects were assessed relative to an indinavir 800 mg every 8h regimen under fasting conditions.

2: Comparison to a standard saquinavir 600 mg every 8h regimen (n = 114).

3: Effects were assessed on a dose normalized comparison to a methadone 20 mg single dose.

4: Sulfamethoxazole and trimethoprim taken as single combination tablet.

5: 90% CI presented for R- and S-warfarin AUC and Cmax ratios.

6: This significant increase in plasma fluticasone propionate exposure resulted in a significant decrease (86%) in plasma cortisol AUC.

‡ Subjects in the entire study, a subset of subjects were administered the specified regimen.

* Parallel group design; entries are subjects receiving combination and control regimens, respectively.

↑ Indicates increase; ↓ indicates decrease; ↔ indicates no change.

Definitions: b.i.d. = twice daily; ND = not detected.

Microbiology

Resistance

HIV-1 isolates with reduced susceptibility to ritonavir have been selected in vitro. Genotypic analysis of these isolates showed mutations in the HIV protease gene at amino acid positions 84 (Ile to Val), 82 (Val to Phe), 71 (Ala to Val), and 46 (Met to Ile). Phenotypic (n = 18) and genotypic (n = 44) changes in HIV isolates from selected patients treated with ritonavir were monitored in Phase 1/2 trials over a period of 3 to 32 weeks. Mutations associated with the HIV viral protease in isolates obtained from 41 patients appeared to occur in a stepwise and ordered fashion; in sequence, these mutations were position 82 (Val to Ala/Phe), 54 (Ile to Val), 71 (Ala to Val/Thr), and 36 (Ile to Leu), followed by combinations of mutations at an additional 5 specific amino acid positions.

Of 18 patients for which both phenotypic and genotypic analysis were performed on free virus isolated from plasma, 12 showed reduced susceptibility to ritonavir in vitro. All 18 patients possessed one or more mutations in the viral protease gene. The 82 mutation appeared to be necessary but not sufficient to confer phenotypic resistance. Phenotypic resistance was defined as a ≥ 5-fold decrease in viral sensitivity in vitro from baseline. The clinical relevance of phenotypic and genotypic changes associated with NORVIR therapy has not been established.

Cross-resistance to other antiretrovirals

Among protease inhibitors variable cross-resistance has been recognized. Serial HIV isolates obtained from six patients during NORVIR therapy showed a decrease in ritonavir susceptibility in vitro but did not demonstrate a concordant decrease in susceptibility to saquinavir in vitro when compared to matched baseline isolates. However, isolates from two of these patients demonstrated decreased susceptibility to indinavir in vitro (8-fold). Isolates from five patients were also tested for cross-resistance to amprenavir and nelfinavir; isolates from two patients had a decrease in susceptibility to nelfinavir (12- to 14-fold), and none to amprenavir. Cross-resistance between ritonavir and reverse transcriptase inhibitors is unlikely because of the different enzyme targets involved. One ZDV-resistant HIV isolate tested in vitro retained full susceptibility to ritonavir.

Toxicology

The toxicology of ritonavir has been assessed in mice, rats, dogs and rabbits in studies ranging in duration from a single dose to six months of oral administration. All phases of the reproductive process have been evaluated for potential adverse effects, and a generally accepted battery of in vitro and in vivo mutagenicity studies has been conducted. The following section summarizes the findings from these studies. The most significant target organs in the toxicity studies have been the liver and retina. Retinal changes secondary to phospholipidosis were limited to rodents only and were considered not to pose any undue risk to humans. Dogs appeared to be less sensitive than the rodent to the hepatotoxic effects of ritonavir. Human clinical studies have not disclosed a high incidence of hepatic complications. See (ADVERSE REACTIONS).

Acute Toxicity

Ritonavir has a low order of acute toxicity in rodents by oral route but is more toxic when given intravenously. The difference is probably due to the fact that the acute toxicity produced by ritonavir is more related to plasma Cmax than AUC values, and Cmax is most likely considerably higher following intravenous injection. When given orally in a vehicle of propylene glycol and ethyl alcohol (95:5, v/v) containing two molar equivalents of p-toluene sulfonic acid monohydrate, the median lethal dose (LD50) generally exceeds the limited dose of 2500 mg/kg for both mice and rats. Toxic signs for both species consisted of decreased activity, ataxia, dyspnea, squinting, prostration, and tremors.

When administered intravenously, the approximately lethal dose (ALD) ranged from 35 to 80 mg/kg for both species. Signs of toxicity included decreased activity, ataxia, dyspnea, exophthalmos, and clonic convulsions.

Sub-chronic Toxicity

Rat

A one-month rat study was conducted by gavage at 0, 15, 50, and 150/100 (male/female) mg/kg/day. Drug exposure (AUC) values toward the end of the treatment period were 3.64, 27.61 and 63.32 mcg•h/mL for males and 5.34, 24.50 and 91.34 mcg•h/mL for females treated at 15, 50 and 150/100 mg/kg/day, respectively.

Treatment-related clinical signs of decreased activity, emaciation, hunched posture, weakness, and urine-staining of abdominal hair occurred in rats at the high dosages. Rats in the high dosage group also had lower mean body weights and body weight gains than the controls. Treatment-related differences from the controls in clinical pathology were limited to minimally increased serum globulin and monocystosis in rats treated at 50 mg/kg/day and higher. No changes in liver enzyme activities were noted. Mean liver weights were increased at 50 mg/kg/day and above and thyroid gland weights were increased in female rats at 100 mg/kg/day. Target organs were identified as the liver, thyroid, and eye. Changes in the liver consisted of hepatomegaly, multinucleated hepatocytes and/or mild focal periportal inflammation in rats at 50 mg/kg/day and higher. Mild to moderate hypertrophy of follicular epithelium also occurred in rats at 50 mg/kg/day and above.

Minimal hypertrophy and cytoplasmic granularity of the retinal pigment epithelium (RPE) were found in rats at the high dosage. Effects in the thyroid gland and the eye were reversible after a one-month recovery period, but the liver changes were not reversible following one-month of recovery. The no-toxic-effect level in this study was 15 mg/kg/day corresponding to a systemic exposure of 3.6 to 4.7 mcg•h/mL in male rats and 5.3 to 8.9 mcg•h/mL in female rats (approximately 1/25th of the expected human exposure of 150 mcg•h/mL from a dose of 600 mg twice daily).

A three-month oral gavage study was conducted in rats at dosages of 0, 25, 75, and 175/125 (male/female) mg/kg/day. The mean AUC values toward the end of the treatment period were 18, 43, 97 mcg•h/mL for males and 21, 73 and 98 mcg•h/mL for females at corresponding dosages of 25, 75 and 175 (males) and 125 (females) mg/kg/day, respectively. Three male rats that received 175 mg/kg/day and two females given 125 mg/kg/day died during the treatment period. Ataxia, decreased activity, dehydration, emaciation, rough coat, hunched posture, weakness, tremors, cold to touch, pale and squinting eyes, urine-staining of abdominal hair, and discoloration of urine were noted in rats at the high dosage. Group mean body weights and food consumption for rats in the high-dosage group were significantly lower than the controls. At the preterminal eye examination, pale choroidal vasculature and dilated retinal vessels were seen in rats at the high dosage. Electroretinograms (ERGs) recorded near the end of the treatment period revealed decreases in mean values of A- and B-wave amplitudes and mean amplitude values for rod response along with a prolongation of the implicit times of the A-wave in the high dosage rats. The eye changes along with the effects on A- and B-wave amplitude values were still evident in rats that were held for a three-month recovery period. The mean values of erythrocytic parameters for the high dosage rats were significantly lower than the controls. The ALT and AST activities for the drug-treated rats were significantly increased over the controls. Increased mean GGT activities and cholesterol values were found for the mid and high dosage rats. The mean serum thyroid stimulating hormone (TSH) values for the drug-treated rats were higher than the controls, while the T4 (thyroxine) values for the mid and high dosage males were lower than the controls. The liver weights of rats at all dosage levels were increased over the controls. Histopathologic evaluation revealed that the liver, eye, and stomach were major target organs. The hepatic changes (multinucleated hepatocytes, single cell necrosis, histiocytic microgranulomas, and chronic pericholangitis) were found in rats at all dosage levels, and the retinal alternations (hypertrophy of the RPE and retinal degeneration) were observed mainly in mid and high dosage rats. Minimal to mild pyloric gastritis and necrosis were noted in rats at mid and high dosages.

Ultrastructural evaluation of the eye revealed a considerable accumulation of phagosomes in the RPE of rats at mid and high dosages. Reduced or absent photoreceptor outer segments also occurred in rats at the high dosage. The liver from the drug-treated rats contained abundant irregular, dense-staining inclusions in both hepatocytes and phagocytic cells upon ultrastructural evaluation. The changes in the liver and eye were not reversible after three months of recovery. The no-toxic-effect level in this study was considered to be less than 25 mg/kg/day corresponding to a systemic exposure of 18 to 21 mcg•h/mL (approximately one-eighth of the expected human exposure of 150 mcg·h/mL from a dose of 600 mg twice daily).

A six month study was conducted in rats by oral gavage at dosages of 0, 25, 75, and 175/125 (male/female) mg/kg/day during Study Days 0 to 79. Thereafter, the high dosage levels for males and females were lowered to 150 and 100 mg/kg/day, respectively, due to excessive toxicity. The group mean AUC values on Study Day 174 were 14.3, 60.7 and 83.4 mcg•h/mL for males and 21.5, 76.2 and 174.5 mcg•h/mL for females at the corresponding dosages of 25, 75 and 150 (males)/100 (females) mg/kg/day. One mid dosage female, two high dosage males, and five high dosage females died during the study. Dehydration, emaciation, hunched posture, decreased activity, weakness, sedation, tremors, cold to touch, matted hair, rough coat, squinting eyes, urine-staining of hair, salivation, and abnormal stool were noted in the high dosage rats. Group mean body weights and food consumption for rats in the high dosage group were lower than the controls. Pale choroidal vessels and/or dilated retinal vessels were seen in some of the high dosage rats at the preterminal eye examination. Significantly decreased hemoglobin and hematocrit values occurred in the mid and high dosage groups. Red blood cell (RBC) morphology changes suggested that a mild low grade hemolytic anemia occurred in individual rats. A mild to marked increase in serum ALT and AST values in some individual rats were seen at all dosage levels. Elevations of GGT, total bilirubin, ALP, and serum cholesterol values also occurred in the mid and high dosage rats. Mean serum triglyceride levels for male rats at all dosage levels were significantly decreased compared to the controls, while triglyceride values of the high dosage female rats were increased. The mean TSH values for the drug-treated rats were higher than the controls, and the T4 (thyroxine) values for the mid and high dosage rats were lower than the controls. The mean liver weights in rats at all dosage levels were increased over the controls. Histopathology evaluations revealed that liver, eye, kidney, and thyroid were the major target organs. The changes in liver and eye were similar to those observed in the three-month rat studies. Treatment-related histologic changes in the kidney included mild to moderate, multifocal tubular degeneration occurring in rats in all dosage groups. Mild epithelial hypertrophy in the thyroid gland was noted in mid and high dosage rats. The reversibility of these changes was not assessed in this six-month study. The no-toxic-effect level in this study was less than 25 mg/kg/day corresponding to a systemic exposure of 14 to 22 mcg•h/mL which was approximately one-eighth of the expected human exposure of 150 mcg•h/mL from a dosage of 600 mg twice daily.

Dog

A one-month study in dogs was conducted by oral gavage at dosages of 0, 10, 50, and 200 mg/kg/day. No clear sex difference in mean plasma drug levels was apparent. The group mean AUC values for both males and females on Day 0 were 25.9, 75.2 and 160.7 mcg•h/mL and on Day 27 were 21.1, 17.1 and 240.3 mcg•h/mL at corresponding dosages of 10, 50 and 200 mg/kg/day, respectively. No deaths occurred during the course of treatment. Clinical signs were observed in dogs at 50 and 200 mg/kg/day and included emesis, increased salivation, diarrhea and/or abnormal stool. Dogs in the high dosage group also had incidences of dehydration, ataxia, decreased activity, and involuntary movements. Body weight loss was seen in some dogs at 200 mg/kg/day. Two female and one male high dosage dogs required supplemental feed to maintain their health. Treatment-related changes in clinical pathology were limited to mild increases in ALT, ALP, GGT, and bile acids in some high dosage dogs. Mean liver weights were significantly increased in dogs at the high dosage.

Target organs were identified as liver and thymus (liver hydropic degeneration and thymic atrophy) in dogs that received 200 mg/kg/day corresponding to a systemic exposure of 200 mcg•h/mL. Drug-related effects on the target organs were reversed during one-month of recovery. The no-toxic-effect level in this study was 50 mg/kg/day corresponding to a systemic exposure of 17.1 to 75.2 mcg•h/mL which was approximately one-third of the expected human exposure of 150 mcg•h/mL from a dose of 600 mg twice daily.

A three-month study was conducted in dogs at dosages of 0, 10, 50, and 100 to 200 mg/kg/day. Dogs in the high dosage group received 200 mg/kg/day for 21 days, but due to excessive weight loss and morbidity, the dosage was reduced to 100 mg/kg/day in male dogs (Days 21 to 92) and suspended in female dogs. Treatment at 100 mg/kg/day was resumed after 13 days of recovery (Days 21 to 33) in the high dosage female dogs. The group mean AUC values on Study Day 82 were 25.1, 80.2 and 147.4 mcg•h/mL for males and 22.7, 50.5 and 22.3 mcg•h/mL for females at corresponding dosages of 10, 50 and 100 mg/kg/day, respectively. One high dosage female dog was euthanized on Day 86 in moribund condition. Decreased activity, emesis, excessive salivation, and diarrhea/abnormal stool were observed in mid and high dosage dogs. In female dogs that received 200 mg/kg/day, dehydration, emaciation, ataxia, weakness, tremors, hunched posture, and involuntary body movements were noted for Study Days 0 to 20. Body weight loss was evident in the high dosage dogs. Elevations of serum ALT, ALP, and GGT activities occurred in one male and four female dogs that received 200 mg/kg/day and achieving AUC values > 200 mcg•h/mL prior to the suspension of drug-treatment on Day 21. However, at the end of the treatment period no significant elevations in serum enzyme activity were found with the exception of a single high dosage female dog that was euthanized on Day 86. This dog had elevated ALP, ALT, GGT, and bile acids. The liver was a target organ, as evidenced by increased weight and histopathologic findings (pericholangitis, biliary hyperplasia, fibrosis, hydropic degeneration), in dogs that received 200/100 mg/kg/day and achieving AUC values > 200 mcg•h/mL on Study Day 14. However, none of the above changes were seen in dogs that were held for a two-month recovery period. The liver changes seen in the study appeared to be reversible. The no-toxic effect exposure (AUC) in this study was considered to be < 200 mcg·h/mL and the expected human exposure from a dose of 600 mg twice daily was 150 mcg•h/mL.

Ritonavir was administered by oral gavage to beagle dogs at dosages of 0, 10, 50 or 125 mg/kg/day for six months. The group mean AUC values on Study Day 152 were 18.3, 64.2 and 115.0 mcg•h/mL in males and 25.7, 133.6 and 204.6 mcg•h/mL in females at corresponding dosages of 10, 50 and 125 mg/kg/day, respectively. No deaths occurred during the study. Emesis, abnormal stool and/or diarrhea were observed in mid and high dosage dogs. Additional clinical signs seen in the high dosage dogs were decreased activity and a thin and/or emaciated appearance. Mean body weights and weight gains for the high dosage dogs were lower than the controls. Dietary supplementation was used for some high dosage dogs as a precaution against excessive weight loss and associated debilitation. Increases in serum ALP values were present in the mid and high dosage groups. Target organs were the liver and thymus. Liver changes included increased organ weights and hepatomegaly in the high dosage group. Diffuse hepatocellular hydropic degeneration was found in a single female in the high dosage group. This dog was found to have the highest individual plasma drug exposure (AUC = 482 mcg•h/mL). Decreased thymic weights and thymic atrophy were apparent in the high dosage male dogs. The reversibility of changes seen in the liver and thymus was not assessed in this six-month study. The no-toxic-effect level in this study was considered to be 10 mg/kg/day corresponding to a systemic exposure of 18.3 to 25.7 mcg·h/mL which was approximately one-seventh of the expected human exposure of 150 mcg•h/mL. However, histopathological changes in liver were only observed in a single female dog at the highest dosage (125 mg/kg/day) at a plasma drug exposure of 482 mcg•h/mL.

Special Studies

A three month dietary study was conducted in mice at dosages of 0, 200, 400, 600, and 1000 mg/kg/day to select dosages for the two-year carcinogenicity study. The group mean AUC values in males were 57.1, 130.7, 219.1 and 381.4 mcg•h/mL and in females were 112.0, 209.1, 320.4 and 396.7 mcg•h/mL at the corresponding dosages of 200, 400, 600 and 1000 mg/kg/day.

No drug-related deaths were observed, but hunched posturing, alopecia and urine-stained or matted hair were noted at dosages of 600 mg/kg/day and above. Mean body weights of mice at 600 mg/kg/day and above were significantly decreased from controls. Differences from controls in clinical chemistry parameters included increased AST, ALT, cholesterol, and triglycerides in drug-treated mice. Increases in ALP, GGT, and total protein were noted in mice receiving 400 mg/kg/day and above. Mean liver weights were increased in all drug-treated mice. Pathology in the liver consisted of hepatocytomegaly, hepatocyte necrosis, and histiocytic microgranulomas in all drug-treated mice, vacuolation and increased mitosis in hepatocytes of mice receiving 400 mg/kg/day and higher doses. Treatment-related pathology of the eye consisted of hypertrophy of RPE in mice at 400 mg/kg/day or higher.

A three-month dietary study was conducted in rats at dosages of 0, 50, 100, 160, and 200 mg/kg/day and 0, 30, 75, 125, and 175 mg/kg/day for males and females, respectively to select dosages for the two-year carcinogenicity study. The group mean AUC values toward the end of the treatment period were 6.23, 21.72, 57.32 and 93.18 mcg·h/mL for males and 1.62, 23.41, 67.05 and 105.35 mcg•h/mL for females at corresponding nominal dosages of 50, 100, 160 and 200 mg/kg/day for males and 30, 75, 125 and 175 mg/kg/day for females. There were no drug-related deaths in the study. Emaciation, rough coat and hunched posture were noted in the high dosage rats.

Group mean body weights and food consumption for rats at the two higher dosage groups were lower than the controls. The mean ALT and AST activities for the drug-treated rats at all dosage levels were increased over the controls. Significantly increased GGT activities were noted in rats at the two higher dosage groups. Mean serum cholesterol values for rats at the three top dosage levels were higher than the controls. The mean serum thyroxine (T4) values for the drug-treated rats were lower than the controls, while the mean TSH values for female rats at the two top dosages were greater than the controls. The mean liver weights for rats at the top three dosage levels were increased over the controls. Histopathologic evaluation revealed the liver, eye and thyroid were major target organs. The hepatic and retinal changes seen in this dietary study were similar to those noted in the three-month oral gavage study in rats. The liver changes were noted at all dosage levels, while the ocular alterations were limited to rats at the two top dosage levels. Thyroid follicular epithelial cell hypertrophy occurred in rats at the three top dosage levels.

Ritonavir was evaluated for the potential to produce delayed contact hypersensitivity in guinea pigs. The Maximization Method was used in this study and the data generated indicated that ritonavir did not induce delayed contact hypersensitivity in guinea pigs.

Mutagenicity and Carcinogenicity

Carcinogenicity studies with ritonavir have been conducted in mice and rats. In male mice, at dosage levels of 50, 100, or 200 mg/kg/day, there was a dose dependent increase in the incidence of both adenomas and combined adenomas and carcinomas in the liver. Based on the drug exposure (AUC) measurements, the exposure at the high dosage was approximately 0.3-fold for males that of exposure in humans with the recommended therapeutic dose (600 mg twice daily). There were no carcinogenic effects seen in females at the dosages tested. The exposure at the high dosage was approximately 0.6-fold for the females that of the exposure in humans. In rats dosed at levels of 7, 15, or 30 mg/kg/day there were no carcinogenic effects. In this study the exposure at the high dose was approximately 5% that of the exposure in humans with the 600 mg twice daily regimen. Based on the exposures achieved in the animal studies, the significance of the observed effects is not known.

Ritonavir was not found to be mutagenic or clastogenic in a battery of in vitro and in vivo assays including the Ames bacterial reverse mutation assay using S. Typhimurium and E. coli, the mouse lymphoma assay, the mouse micronucleus test and chromosomal aberration assays in human lymphocytes.

Reproduction and Teratology

Fertility and General Reproductive Performance

Rats

Ritonavir was administered orally by gavage to female rats at dosages of 0, 20, 40, and 75 mg/kg/day beginning at 14 days prior to mating with males that were treated at dosages of 0, 20, 40, and 125 mg/kg/day beginning at 28 days prior to mating. The treatment in female rats was continued through mating until gestation Day 9. The group mean plasma AUC values for males near the end of the premating period were 8.2, 19.7 and 61.0 mcg•h/mL, respectively, for the 20, 40, and 125 mg/kg/day treatment groups. The corresponding values for females were 14.6, 33.1 and 90.5 mcg•h/mL, respectively, for the 20, 40 and 75 mg/kg/day treatment groups. There were no treatment-related deaths in the study. Maternal toxicity consisted of adverse clinical signs and decreases in mean body weights and food intake in the mid and high dosage groups.

There were no treatment-related effects on the estrous cycle or male and female reproductive indices. Maternal survival and pregnancy status of the ritonavir-treated groups were also comparable to the controls. No treatment-related effects were seen in the number of corpora lutea, implantation sites, viable and nonviable embryos. There were no increases in the incidence of preimplantation and postimplantation losses. The no-toxic-effect level for systemic toxicity in F0 generation rats was 20 mg/kg/day. However, there were no adverse effects on male or female reproduction or early embryonic development up to the highest dosage (125/75 mg/kg/day) tested.

Developmental Toxicity

Rats

Ritonavir was administered orally to mated female rats at dosages of 0, 15, 35, and 75 mg/kg/day from Gestation Day 6 to 17. Three high dosage rats were euthanized in moribund condition during the study. The group mean plasma AUC values on Gestation Day 16 were 17.3, 34.3 and 45.2 mcg•h/mL at dosages of 15, 35 and 75 mg/kg/day, respectively. Decreased activity, emaciation, dehydration, rough coat and/or matted coat, hunched posture, tremors, and noisy respiration were observed in rats at the high dosage level. Marked decreases in body weights and food consumption were evident in the high dosage group. Reduction in food consumption accompanied by a reduction in body weight gain was also noted for the mid dosage group during Gestation Days 6 to 9. No effects were found in the number of corpora lutes or implantation sites. Developmental toxicity in the high dosage group was characterized by increased postimplantation loss, decreased fetal body weights, and an increased incidence of ossification delays and developmental variations (enlarged fontanelles, cryptorchidism and wavy ribs). Developmental toxicity at the 35 mg/kg/day dosage level was characterized by a slight increase in cryptorchidism. No treatment-related malformations were observed in this study.

Developmental toxicity occurred only at maternally toxic dosages. The no-effect level for maternal and developmental toxicity was 15 mg/kg/day corresponding to a systemic exposure of 17.3 mcg•h/mL.

Rabbits

Ritonavir was administered to mated female rabbits by oral gavage at dosages of 0, 25, 50, and 110 mg/kg/day from Gestation Day 6 to 19. The group mean plasma AUC values on Gestation Day 20 were 1.30 and 28.55 mcg•h/mL at dosages of 25 and 50 mg/kg/day, respectively. Plasma AUC values were not calculated for the 110 mg/kg/day group because plasma samples were obtained from the three surviving rabbits at only two time points. Four deaths in rabbits given 110 mg/kg/day were considered to be possibly drug-related. There was an increased incidence of decreased defecation and soft stool in all drug-treated groups. The observation of no stool was noted in mid and high dosage groups; rales and mucoid stool occurred only at the high dosage. Marked decreases in body weights, body weight gain and food consumption were noted in the high dosage group. Developmental toxicity was evident at the high dosage level with four whole litter resorptions and in surviving litters a significant increase in postimplantation losses, decreased litter size and decreased uterine and fetal weights. There were no drug-related fetal malformations in this study.

The no-observable-effect level was 50 mg/kg/day with respect to maternal and developmental toxicity.

Peri-/Postnatal Toxicity

Rats

Mated female rats were administered ritonavir orally at dosages of 0, 15, 35, or 60 mg/kg/day beginning on Gestation Day (GD) 6. Treatment continued throughout gestation, parturition and lactation; the final dosage was given on Postpartum Day (PD) 20. Plasma drug levels were not determined in this study. No deaths or treatment-related clinical signs were observed among the F0 dams. Dams in the 60 mg/kg/day group gained less weight and consumed less food during GD 6 to 9. Gestation length, litter size at birth, and F1 pup growth and survival were unaffected. No effects on the time of appearance of developmental landmarks or learning as measured by a passive avoidance test were evident. The ontogeny of various reflexes were unaffected. The reproductive competence of the F1 generation was unaffected. Therefore, the no-observed-effect level for developmental toxicity was considered to be 60 mg/kg/day, the highest dosage tested.