"The U.S. Food and Drug Administration today approved Tivicay (dolutegravir), a new drug to treat HIV-1 infection.
Tivicay is an integrase strand transfer inhibitor that interferes with one of the enzymes necessary for HIV to multiply. "...
Mechanism Of Action
Ritonavir is an antiviral drug [see Microbiology].
The pharmacokinetics of ritonavir have been studied in healthy volunteers and HIV-1 infected patients (CD4 greater than or equal to 50 cells per μL). See Table 5 for ritonavir pharmacokinetic characteristics.
The absolute bioavailability of ritonavir has not been determined.
Effect of Food on Oral Absorption
After a single 600 mg dose under non-fasting conditions, in two separate studies, the soft gelatin capsule (n = 57) formulation yielded a mean ± SD area under the plasma concentration-time curve (AUC) of 121.7 ± 53.8. Relative to fasting conditions, the extent of absorption of ritonavir from the soft gelatin capsule formulation was 13% higher when administered with a meal (615 KCal; 14.5% fat, 9% protein, and 76% carbohydrate).
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.
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|
|Percent Bound*||98 to 99%|
|† SS = steady state; patients taking ritonavir 600 mg
‡ 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 μg/mL.
Effects on Electrocardiogram
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].
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.
Steady-state pharmacokinetics were evaluated in 37 HIV-1 infected patients ages 2 to 14 years receiving doses ranging from 250 mg per m² twice-daily to 400 mg per m² twice-daily in PACTG Study 310, and in 41 HIV-1 infected patients ages 1 month to 2 years at doses of 350 and 450 mg per m² twice-daily in PACTG Study 345. Across dose groups, ritonavir steady-state oral clearance (CL per F per m²) 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 m² twice-daily in pediatric patients greater than 2 years were comparable to those obtained in adults receiving 600 mg (approximately 330 mg per m²) twice-daily. The following observations were seen regarding ritonavir concentrations after administration with 350 or 450 mg per m² 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 m² 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.
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.
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.
Table 6 and Table 7 summarize the effects on AUC and Cmax, 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.
Table 6: Drug Interactions -Pharmacokinetic Parameters
for Ritonavir in the Presence of the Coadministered Drug
|Co-administered Drug||Dose of Co-administered Drug (mg)||Dose of NORVIR (mg)||n||AUC % (95% CI)||Cmax (95% CI)||Cmin (95% CI)|
|Clarithromycin||500 q12h, 4 d||200 q8h, 4 d||22||↑ 12%
|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%
|Fluoxetine||30 q12h, 8 d||600 single dose, 1 d||16||↑ 19%
|Ketoconazole||200 daily, 7 d||500 q12h, 10 d||12||↑ 18%
|Rifampin||600 or 300 daily, 10 d||500 q12h, 20 d||7, 9*||↓ 35%
|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||↔||↔||↔|
Table 7: Drug Interactions -Pharmacokinetic Parameters
for Co-administered Drug in the Presence of NORVIR
|Co-administered Drug||Dose of Coadministered Drug (mg)||Dose of NORVIR (mg)||n||AUC %
|Alprazolam||1, single dose||500 q12h, 10 d||12||↓ 12%
|Avanafil||50, single dose||600 q12h||146||↑ 13-fold||↑ 2.4-fold||ND|
|Clarithromycin||500 q12h, 4 d||200 q8h, 4 d||22||↑ 77%
|14-OH clarithromycin metabolite||↓ 100%||↓ 99%||↓ 100%|
|Desipramine||100, single dose||500 q12h, 12 d||14||↑ 145%
|2-OH desipramine metabolite||↓ 15%
|Didanosine||200 q12h, 4 d||600 q12h, 4 d||12||↓ 13%
|Ethinyl estradiol||50μg single dose||500 q12h, 16 d||23||↓ 40%
|Fluticasone propionate aqueous nasal spray||200 mcg qd, 7 d||100 mg q12h, 7 d||18||↑ approximately 350-fold5||↑ approximately 25-fold5|
|Day 14||400 q12h, 15 d||400 q12h, 15 d||10||↑ 6%
|Day 15||↓ 7%
|Ketoconazole||200 daily, 7 d||500 q12h, 10 d||12||↑ 3.4-fold
|Meperidine2||50 oral single dose||500 q12h, 10 d||8||↓ 62%
|Normeperidine metabolite||6||↑ 47%
|Methadone2||5, single dose||500 q12h, 15 d||11||↓ 36%
|Raltegravir||400, single dose||100 q12h, 16 d||10||↓ 16%
|Rivaroxaban||10, single dose
(days 0 and 7)
(days 2 to 7)
|Rifabutin 25-O-desacetyl rifabutin metabolite||150 daily, 16 d||500 q12h, 10 d||5, 11*||↑ 4-fold
|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%
|Sulfamethoxazole3||800, single dose||500 q12h, 12 d||15||↓ 20%
|Tadalafil||20 mg, single dose||200 mg q12h||↑ 124%||↔||ND|
|Theophylline||3 mg/kg q8h, 15 d||500 q12h, 10 d||13, 11*||↓ 43%
|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%
|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%
|Zidovudine||200 q8h, 4 d||300 q6h, 4 d||9||↓ 25%
|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-inf), and for the test arm: N=13 for Cmax and N=4 for AUC(0-inf).
7 90% CI presented for rivaroxaban
8 90% CI presented for simeprevir
(change in exposure presented as percentage increase)
↔Indicates no change.
* Parallel group design; entries are subjects receiving combination and control regimens, respectively.
Mechanism of Action
Ritonavir is a peptidomimetic inhibitor of the HIV-1 protease. Inhibition of HIV protease renders the enzyme incapable of processing the gag-pol polyprotein precursor which leads to production of non-infectious immature HIV-1 particles.
Antiviral Activity in Cell Culture
The activity of ritonavir was assessed in acutely infected lymphoblastoid cell lines and in peripheral blood lymphocytes. The concentration of drug that inhibits 50% (EC50) value of viral replication ranged from 3.8 to 153 nM depending upon the HIV-1 isolate and the cells employed. The average EC50 for low passage clinical isolates was 22 nM (n = 13). In MT4 cells, ritonavir demonstrated additive effects against HIV-1 in combination with either didanosine (ddI) or zidovudine (ZDV). Studies which measured cytotoxicity of ritonavir on several cell lines showed that greater than 20 μM was required to inhibit cellular growth by 50% resulting in a cell culture therapeutic index of at least 1,000.
HIV-1 isolates with reduced susceptibility to ritonavir have been selected in cell culture. Genotypic analysis of these isolates showed mutations in the HIV-1 protease gene encoding at amino acid substitutions I84V, V82F, A71V, and M46I. Phenotypic (n = 18) and genotypic (n = 48) changes in HIV-1 isolates from selected patients treated with ritonavir were monitored in phase I/II trials over a period of 3 to 32 weeks. Substitutions associated with the HIV-1 viral protease in isolates obtained from 43 patients appeared to occur in a stepwise and ordered fashion; in sequence, these substitutions were position V82A/F/T/S, I54V, A71V/T, and I36L, followed by combinations of substitutions at an additional 5 specific amino acid positions (M46I/L, K20R, I84V, L33F and L90M). Of 18 patients for whom both phenotypic and genotypic analysis were performed on free virus isolated from plasma, 12 showed reduced susceptibility to ritonavir in cell culture. All 18 patients possessed one or more substitutions in the viral protease gene. The V82A/F substitution appeared to be necessary but not sufficient to confer phenotypic resistance. Phenotypic resistance was defined as a greater than or equal to 5fold decrease in viral sensitivity in cell culture from baseline.
Cross-Resistance to Other Antiretrovirals
Among protease inhibitors variable cross-resistance has been recognized. Serial HIV-1 isolates obtained from six patients during ritonavir therapy showed a decrease in ritonavir susceptibility in cell culture but did not demonstrate a concordant decrease in susceptibility to saquinavir in cell culture when compared to matched baseline isolates. However, isolates from two of these patients demonstrated decreased susceptibility to indinavir in cell culture (8-fold). Isolates from 5 patients were also tested for cross-resistance to amprenavir and nelfinavir; isolates from 3 patients had a decrease in susceptibility to nelfinavir (6-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-1 isolate tested in cell culture retained full susceptibility to ritonavir.
The activity of NORVIR as monotherapy or in combination with nucleoside reverse transcriptase inhibitors has been evaluated in 1446 patients enrolled in two double-blind, randomized trials.
Advanced Patients With Prior Antiretroviral Therapy
Study 247 was a randomized, double-blind trial (with open-label follow-up) conducted in HIV-1 infected patients with at least nine months of prior antiretroviral therapy and baseline CD4 cell counts less than or equal to 100 cells per μL. 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 per μL. After the clinical benefit of NORVIR therapy was demonstrated, all patients were eligible to switch to open-label NORVIR for the duration of the follow-up period. Median duration of double-blind therapy with NORVIR and placebo was 6 months. The median duration of follow-up through the end of the open-label phase was 13.5 months for patients randomized to NORVIR and 14 months for patients randomized to placebo.
The cumulative incidence of clinical disease progression or death during the double-blind phase of Study 247 was 26% (140/543) for patients initially randomized to NORVIR compared to 42% (229/547) for patients initially randomized to placebo. This difference in rates was statistically significant.
Cumulative mortality through the end of the open-label follow-up phase for patients enrolled in Study 247 was 18% (99/543) for patients initially randomized to NORVIR compared to 26% (142/547) for patients initially randomized to placebo. This difference in rates was statistically significant. However, since the analysis at the end of the open-label phase includes patients in the placebo arm who were switched from placebo to NORVIR therapy, the survival benefit of NORVIR cannot be precisely estimated.
During the double-blind phase of Study 247, CD4 cell counts increases from baseline for patients randomized to NORVIR at Week 2 and Week 4 were observed. From Week 4 and through Week 24, mean CD4 cell counts for patients randomized to NORVIR appeared to plateau. In contrast, there was no apparent change in mean CD4 cell counts for patients randomized to placebo at any visit between baseline and Week 24 of the double-blind phase of Study 247.
Patients Without Prior Antiretroviral Therapy
In Study 245, 356 antiretroviral-naive HIV-1 infected patients (mean baseline CD4 = 364 cells/μL) were randomized to receive either NORVIR 600 mg twice-daily, zidovudine 200 mg three-times-daily, or a combination of these drugs.
During the double-blind phase of study 245, greater mean CD4 cell count increases were observed from baseline to Week 12 in the NORVIR-containing arms compared to the zidovudine arms. Mean CD4 cell count changes subsequently appeared to plateau through Week 24 in the NORVIR arm, whereas mean CD4 cell counts gradually diminished through Week 24 in the zidovudine and NORVIR plus zidovudine arms.
Greater mean reductions in plasma HIV-1 RNA levels were observed from baseline to Week 2 for the NORVIR-containing arms compared to the zidovudine arm. After Week 2 and through Week 24, mean plasma HIV-1 RNA levels either remained stable in the NORVIR and zidovudine arms or gradually rebounded toward baseline in the NORVIR plus zidovudine arm.
1. Sewester CS. Calculations. In: Drug Facts and Comparisons. St. Louis, MO: J.B. Lippincott Co; January, 1997:xix.
Last reviewed on RxList: 3/25/2015
This monograph has been modified to include the generic and brand name in many instances.
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