Ritonavir (Page 6 of 9)

11 DESCRIPTION

Ritonavir is an inhibitor of HIV protease with activity against the Human Immunodeficiency Virus (HIV).
Ritonavir, USP is chemically designated as 2, 4, 7, 12-Tetraazatridecan-13-oic acid,10-hydroxy-2-methyl-5-(1-methylethyl)-1-[2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11- bis(phenylmethyl)-5-thiazolymethyl ester [5S-(5R*,8R*,10R*,11R*)]. Its molecular formula is C ₃₇ H ₄₈ N ₆ O ₅ S ₂ , and its molecular weight is 720.94. Ritonavir has the following structural formula:

Ritonavir, USP is a white to off-white powder. It is freely soluble in methanol, methylene chloride, very slightly soluble in acetonitrile and practically insoluble in water.
Ritonavir tablets, USP are available for oral administration in a strength of 100 mg ritonavir with the following inactive ingredients: colloidal silicon dioxide, copovidone, dibasic calcium phosphate anhydrous, sodium stearyl fumarate and sorbitan monolaurate. The tablets are coated with Opadry White which contains colloidal anhydrous silica, hydroxypropyl cellulose, hypromellose, polyethylene glycol, polysorbate 80, talc, and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Ritonavir is an antiretroviral drug [see Microbiology ( 12.4)].

12.2 Pharmacodynamics

Cardiac Electrophysiology
QTcF interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg once-daily) controlled crossover study in 45 healthy adults, with 10 measurements over 12 hours on Day 3. The maximum mean (95% upper confidence bound) time-matched difference in QTcF from placebo after baseline correction was 5.5 (7.6) milliseconds (msec) for 400 mg twice-daily ritonavir. Ritonavir 400 mg twice daily resulted in Day 3 ritonavir exposure that was approximately 1.5 fold higher than observed with ritonavir 600 mg twice-daily dose at steady state. PR interval prolongation was also noted in subjects receiving ritonavir in the same study on Day 3. The maximum mean (95% confidence interval) difference from placebo in the PR interval after baseline correction was 22 (25) msec for 400 mg twice-daily ritonavir [see Warnings and Precautions ( 5.6)].

12.3 Pharmacokinetics

The pharmacokinetics of ritonavir have been studied in healthy volunteers and HIV-infected patients (CD ₄ greater than or equal to 50 cells per µL). See Table 5 for ritonavir pharmacokinetic characteristics.
Absorption
The absolute bioavailability of ritonavir has not been determined. After a 600 mg dose of oral solution, peak concentrations of ritonavir were achieved approximately 2 hours and 4 hours after dosing under fasting and non-fasting (514 KCal; 9% fat, 12% protein, and 79% carbohydrate) conditions, respectively.
Ritonavir tablets are not bioequivalent to ritonavir capsules. Under moderate fat conditions (857 kcal; 31% fat, 13% protein, 56% carbohydrates), when a single 100 mg ritonavir dose was administered as a tablet compared with a capsule, AUC( _{0 to ∞} ) met equivalence criteria but mean C _max was increased by 26% (92.8% confidence intervals: ↑15 to ↑39%).
No information is available comparing ritonavir tablets to ritonavir capsules under fasting conditions.
Effect of Food on Oral Absorption
The bioavailability of ritonavir tablet and oral solution is decreased under fed conditions as compared to fasted conditions.
Following the administration of a 100 mg tablet dose of ritonavir, C _max and AUC _inf of ritonavir were decreased by 21 to 23% under moderate fat (857 Kcal, 30% from fat) or high fat conditions (917 Kcal, 60% calories from fat) relative to fasting conditions.
Following the administration of a 600 mg dose ritonavir oral solution, C _max and AUC _inf of ritonavir were decreased by 23% and 7%, respectively, under nonfasting conditions (514 Kcal, 10% from fat) relative to fasting conditions. Dilution of the oral solution, within one hour of administration, with 240 mL of chocolate milk, Advera® or Ensure® did not significantly affect the extent and rate of ritonavir absorption.
Metabolism
Nearly all of the plasma radioactivity after a single oral 600 mg dose of 14C-ritonavir oral solution (n = 5) was attributed to unchanged ritonavir. Five ritonavir metabolites have been identified in human urine and feces. The isopropylthiazole oxidation metabolite (M-2) is the major metabolite and has antiviral activity similar to that of parent drug; however, the concentrations of this metabolite in plasma are low. In vitro studies utilizing human liver microsomes have demonstrated that cytochrome P450 3A (CYP3A) is the major isoform involved in ritonavir metabolism, although CYP2D6 also contributes to the formation of M–2.
Elimination
In a study of five subjects receiving a 600 mg dose of 14C-ritonavir oral solution, 11.3 ± 2.8% of the dose was excreted into the urine, with 3.5 ± 1.8% of the dose excreted as unchanged parent drug. In that study, 86.4 ± 2.9% of the dose was excreted in the feces with 33.8 ± 10.8% of the dose excreted as unchanged parent drug. Upon multiple dosing, ritonavir accumulation is less than predicted from a single dose possibly due to a time and dose-related increase in clearance. Table 5. Ritonavir Pharmacokinetic Characteristics

Parameter	N	Values (Mean ± SD)
Vβ/F‡	91	0.41 ± 0.25 L/kg
t½		3 — 5 h
CL/F SS†	10	8.8 ± 3.2 L/h
CL/F‡	91	4.6 ± 1.6 L/h
CLR	62	< 0.1 L/h
RBC/Plasma Ratio		0.14
Percent Bound*		98 to 99%
† SS = steady state; patients taking ritonavir 600 mg q12h. ‡ Single ritonavir 600 mg dose. * Primarily bound to human serum albumin and alpha-1 acid glycoprotein over the ritonavir concentration range of 0.01 to 30 mcg/mL.

Special Populations
Gender, Race and Age
No age-related pharmacokinetic differences have been observed in adult patients (18 to 63 years). Ritonavir pharmacokinetics have not been studied in older patients.
A study of ritonavir pharmacokinetics in healthy males and females showed no statistically significant differences in the pharmacokinetics of ritonavir. Pharmacokinetic differences due to race have not been identified.
Pediatric Patients
Steady-state pharmacokinetics were evaluated in 37 HIV-infected patients ages 2 to 14 years receiving doses ranging from 250 mg per m ² twice-daily to 400 mg per m ² twice-daily in PACTG Study 310, and in 41 HIV-infected patients ages 1 month to 2 years at doses of 350 and 450 mg per m ² twice-daily in PACTG Study 345. Across dose groups, ritonavir steady-state oral clearance (CL/F/m ²) was approximately 1.5 to 1.7 times faster in pediatric patients than in adult subjects. Ritonavir concentrations obtained after 350 to 400 mg per m ² twice-daily in pediatric patients greater than 2 years were comparable to those obtained in adults receiving 600 mg (approximately 330 mg per m ²) twice-daily. The following observations were seen regarding ritonavir concentrations after administration with 350 or 450 mg per m ² twice-daily in children less than 2 years of age. Higher ritonavir exposures were not evident with 450 mg per m2 twice-daily compared to the 350 mg per m2 twice-daily. Ritonavir trough concentrations were somewhat lower than those obtained in adults receiving 600 mg twice-daily. The area under the ritonavir plasma concentration time curve and trough concentrations obtained after administration with 350 or 450 mg per m ² twice-daily in children less than 2 years were approximately 16% and 60% lower, respectively, than that obtained in adults receiving 600 mg twice daily.
Renal Impairment
Ritonavir pharmacokinetics have not been studied in patients with renal impairment, however, since renal clearance is negligible, a decrease in total body clearance is not expected in patients with renal impairment.
Hepatic Impairment
Dose-normalized steady-state ritonavir concentrations in subjects with mild hepatic impairment (400 mg twice-daily, n = 6) were similar to those in control subjects dosed with 500 mg twice-daily. Dose-normalized steady-state ritonavir exposures in subjects with moderate hepatic impairment (400 mg twice-daily, n= 6) were about 40% lower than those in subjects with normal hepatic function (500 mg twice-daily, n = 6). Protein binding of ritonavir was not statistically significantly affected by mild or moderately impaired hepatic function. No dose adjustment is recommended in patients with mild or moderate hepatic impairment. However, health care providers should be aware of the potential for lower ritonavir concentrations in patients with moderate hepatic impairment and should monitor patient response carefully. Ritonavir has not been studied in patients with severe hepatic impairment.
Pregnancy
Based on evaluation of the published literature, ritonavir exposures are reduced during pregnancy relative to postpartum.
Drug Interactions
[see also Contraindications ( 4), Warnings and Precautions ( 5.1), and Drug Interactions ( 7)] Table 6 and Table 7 summarize the effects on AUC and C _max , with 95% confidence intervals (95% CI), of co-administration of ritonavir with a variety of drugs. For information about clinical recommendations see Table 4 in Drug Interactions ( 7).

Table 6. Drug Interactions — Pharmacokinetic Parameters for Ritonavir in the Presence of the Co-administered Drug

Co-administered Drug	Dose of Co- administered Drug (mg)	Dose of Ritonavir (mg)	N	AUC % (95% CI)	Cmax (95% CI)	Cmin (95% CI)
Clarithromycin	500 q12h, 4 d	200 q8h, 4 d	22	↑ 12% (2, 23%)	↑ 15% (2, 28%)	↑ 14% (-3, 36%)
Didanosine	200 q12h, 4 d	600 q12h, 4 d	12	↔	↔	↔
Fluconazole	400 single dose, day 1; 200 daily, 4 d	200 q6h, 4 d	8	↑ 12% (5, 20%)	↑ 15% (7, 22%)	↑ 14% (0, 26%)
Fluoxetine	30 q12h, 8 d	600 single dose, 1 d	16	↑ 19% (7, 34%)	↔	ND
Ketoconazole	200 daily, 7 d	500 q12h, 10 d	12	↑ 18% (-3, 52%)	↑ 10% (-11, 36%)	ND
Rifampin	600 or 300 daily, 10 d	500 q12h, 20 d	7, 9*	↓ 35% (7, 55%)	↓ 25% (-5, 46%)	↓ 49% (-14, 91%)
Voriconazole	400 q12h, 1 d; then 200 q12h, 8 d	400 q12h, 9 d		↔	↔	ND
Zidovudine	200 q8h, 4 d	300 q6h, 4 d	10	↔	↔	↔
ND=not determined

Table 7. Drug Interactions — Pharmacokinetic Parameters for Co-administered Drug in the Presence of Ritonavir

Co-administered Drug	Dose of Co- administered Drug (mg)	Dose of Ritonavir (mg)	N	AUC % (95% CI)	Cmax (95% CI)	Cmin (95% CI)
Alprazolam	1, single dose	500 q12h,10 d	12	↓ 12% (-5, 30%)	↓ 16 % (5, 27%)	ND
Avanafil	50, single dose	600 q12h	146	↑ 13-fold	↑ 2.4-fold	ND
Clarithromycin 14-OH clarithromycin metabolite	500 q12h, 4 d	200 q8h, 4 d	22	↑ 77% (56, 103%) ↓ 100%	↑ 31% (15, 51%) ↓ 99%	↑ 2.8-fold (2.4, 3.3X) ↓ 100%
Desipramine 2-OH desipramine metabolite	100, single dose	500 q12h, 12 d	14	↑ 145% (103, 211%) ↓ 15% (3, 26 %)	↑ 22% (12, 35%) ↓ 67% (62, 72%)	ND ND
Didanosine	200 q12h, 4 d	600 q12h, 4 d	12	↓ 13% (0, 23%)	↓ 16% (5, 26%)	↔
Ethinyl estradiol	50 mcg single dose	500 q12h, 16 d	23	↓ 40% (31, 49%)	↓ 32% (24, 39%)	ND
Fluticasone propionate aqueous nasal spray	200 mcg qd, 7 d	100 mg q12h, 7 d	18	↑ approximately 350-fold5	↑ approximately 25-fold5
Indinavir1 Day 14 Day 15	400 q12h, 15 d	400 q12h, 15 d	10	↑ 6% (-14, 29%) ↓ 7% (-22, 28%)	↓ 51% (40, 61%) ↓ 62% (52, 70%)	↑ 4-fold (2.8, 6.8X) ↑ 4-fold (2.5, 6.5X)
Ketoconazole	200 daily, 7 d	500 q12h, 10 d	12	↑ 3.4-fold (2.8, 4.3X)	↑ 55% (40, 72%)	ND
Meperidine Normeperidine metabolite	50 oral single dose	500 q12h, 10 d	8 6	↓ 62% (59, 65%) ↑ 47% (-24, 345%)	↓ 59% (42, 72%) ↑ 87% (42, 147%)	ND ND
Methadone2	5, single dose	500 q 12h, 15 d	11	↓ 36% (16, 52%)	↓ 38% (28, 46%)	ND
Raltegravir	400, single dose	100 q12h, 16 d	10	↓ 16% (-30, 1%)	↓ 24% (-45, 4%)	↓ 1% (-30, 40%)
Rivaroxaban	10, single dose (days 0 and 7)	600 q12h (days 2 to 7)	12	↑ 150% (130-170%)7	↑ 60% (40-70%)7	ND
Rifabutin 25- O -desacetyl rifabutin metabolite	150 daily, 16 d	500 q12h, 10 d	5, 11*	↑ 4-fold (2.8, 6.1X) ↑ 38-fold (28, 56X)	↑ 2.5-fold (1.9, 3.4X) ↑ 16-fold (13, 20X)	↑ 6-fold (3.5, 18.3X) ↑ 181- fold (ND)
Sildenafil	100, single dose	500 twice daily, 8 d	28	↑ 11-fold	↑ 4-fold	ND
Simeprevir	200 mg qd, 7 d	100 mg bid, 15 d	12	↑ 618% (463%-815%)8	↑370% (284%- 476%)8	↑1335% (929%-1901%)8
Sulfamethoxazole3	800, single dose	500 q12h, 12 d	15	↓ 20% (16, 23%)	↔	ND
Tadalafil	20 mg, single dose	200 mg q12h		↑ 124%	↔	ND
Theophylline	3 mg/kg q8h, 15 d	500 q12h, 10 d	13, 11*	↓ 43% (42, 45%)	↓ 32% (29, 34%)	↓57% (55, 59%)
Trazodone	50 mg, single dose	200 mg q12h, 4 doses	10	↑ 2.4-fold	↑ 34%
Trimethoprim3	160, single dose	500 q12h, 12 d	15	↑ 20% (3, 43%)	↔	ND
Vardenafil	5 mg	600 q12h		↑ 49-fold	↑ 13-fold	ND
Voriconazole	400 q12h, 1 d; then 200 q12h, 8 d	400 q12h, 9 d		↓ 82%	↓ 66%
	400 q12h, 1 d; then 200 q12h, 8 d	100 q12h, 9 d		↓ 39%	↓ 24%
Warfarin S-Warfarin R-Warfarin	5, single dose	400 q12h, 12d	12	↑ 9% (-17, 44%)4 ↓ 33% (-38, -27%)4	↓ 9% (-16, -2%)4 ↔	ND ND
Zidovudine	200 q8h, 4 d	300 q6h, 4 d	9	↓ 25% (15, 34%)	↓ 27% (4, 45%)	ND
ND=not determined 1 Ritonavir 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 q8h regimen under fasting conditions. 2 Effects were assessed on a dose-normalized comparison to a methadone 20 mg single dose. 3 Sulfamethoxazole and trimethoprim taken as single combination tablet. 4 90% CI presented for R- and S-warfarin AUC and Cmax ratios. 5 This significant increase in plasma fluticasone propionate exposure resulted in a significant decrease (86%) in plasma cortisol AUC. 6 For the reference arm: N=14 for Cmax and AUC (0 to inf), and for the test arm: N=13 for Cmax and N=4 for AUC (0 to inf). 7 90% CI presented for rivaroxaban 8 90% CI presented for simeprevir (change in exposure presented as percentage increase) ↑ Indicates increase, ↓ indicates decrease, ↔ indicates no change. * Parallel group design; entries are subjects receiving combination and control regimens, respectively.