Chemical formula: C₃₇H₄₈N₆O₅S₂ Molecular mass: 720.944 g/mol PubChem compound: 392622
Pharmacokinetic enhancement by ritonavir is based on ritonavir’s activity as a potent inhibitor of CYP3A-mediated metabolism. The degree of enhancement is related to the metabolic pathway of the co-administered protease inhibitor and the impact of the co-administered protease inhibitor on the metabolism of ritonavir. Maximal inhibition of metabolism of the co-administered protease inhibitor is generally achieved with ritonavir doses of 100 mg daily to 200 mg twice daily, and is dependent on the co-administered protease inhibitor. For additional information on the effect of ritonavir on co-administered protease inhibitor metabolism, refer to the Summary of Product Characteristics of the particular co-administered PIs.
Ritonavir is an orally active peptidomimetic inhibitor of the HIV-1 and HIV-2 aspartyl proteases. Inhibition of HIV protease renders the enzyme incapable of processing the gag-pol polyprotein precursor which leads to the production of HIV particles with immature morphology that are unable to initiate new rounds of infection. Ritonavir has selective affinity for the HIV protease and has little inhibitory activity against human aspartyl proteases.
Ritonavir was the first protease inhibitor (approved in 1996) for which efficacy was proven in a study with clinical endpoints. However, due to ritonavir’s metabolic inhibitory properties its use as a pharmacokinetic enhancer of other protease inhibitors is the prevalent use of ritonavir in clinical practice.
QTcF interval was evaluated in a randomised, 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) difference in QTcF from placebo was 5.5 (7.6) for 400 mg twice daily ritonavir. The Day 3 ritonavir exposure was approximately 1.5 fold higher than that observed with the 600 mg twice daily dose at steady state. No subject experienced an increase in QTcF of ≥60 msec from baseline or a QTcF interval exceeding the potentially clinically relevant threshold of 500 msec.
Modest prolongation of the PR interval was also noted in subjects receiving ritonavir in the same study on Day 3. The mean changes from baseline in PR interval ranged from 11.0 to 24.0 msec in the 12 hour interval post dose. Maximum PR interval was 252 msec and no second or third degree heart block was observed.
Ritonavir-resistant isolates of HIV-1 have been selected in vitro and isolated from patients treated with therapeutic doses of ritonavir.
Reduction in the antiretroviral activity of ritonavir is primarily associated with the protease mutations V82A/F/T/S and I84V. Accumulation of other mutations in the protease gene (including at positions 20, 33, 36, 46, 54, 71, and 90) can also contribute to ritonavir resistance. In general, as mutations associated with ritonavir resistance accumulate, susceptibility to select other PIs may decrease due to cross-resistance. The Summary of Product Characteristics of other protease inhibitors or official continuous updates should be consulted for specific information regarding protease mutations associated with reduced response to these agents.
There is no parenteral formulation of ritonavir, therefore the extent of absorption and absolute bioavailability have not been determined. The pharmacokinetics of ritonavir during multiple dose regimens were studied in non-fasting HIV-infected adult volunteers. Upon multiple dosing, ritonavir accumulation is slightly less than predicted from a single dose due to a time and dose-related increase in apparent clearance (Cl/F). Trough concentrations of ritonavir decrease over time, possibly due to enzyme induction, but appeared to stabilise by the end of 2 weeks. The time to maximum concentration (Tmax) remained constant at approximately 4 hours with increasing dose. Renal clearance averaged less than 0.1 l/h and was relatively constant throughout the dosage range.
The pharmacokinetic parameters observed with various dosing schemes of ritonavir alone are shown in the table below. Plasma concentrations of ritonavir after administration of a single 100 mg dose tablet are similar to the 100 mg soft gelatin capsule under fed conditions.
Ritonavir Dosing Regimen:
| 100 mg once daily | 100 mg twice daily1 | 200 mg once daily | 200 mg twice daily | 600 mg twice daily | |
|---|---|---|---|---|---|
| Cmax (µg/ml) | 0.84 ± 0.39 | 0.89 | 3.4 ± 1.3 | 4.5 ± 1.3 | 11.2 ± 3.6 |
| Ctrough (µg/ml) | 0.08 ± 0.04 | 0.22 | 0.16 ± 0.10 | 0.6 ± 0.2 | 3.7 ± 2.6 |
| AUC12or24 (µg∙h/ml) | 6.6 ± 2.4 | 6.2 | 20.0 ± 5.6 | 21.92 ± 6.48 | 77.5 ± 31.5 |
| t½ (h) | ~5 | ~5 | ~4 | ~8 | ~3 to 5 |
| Cl/F (L/h) | 17.2 ± 6.6 | 16.1 | 10.8 ± 3.1 | 10.0 ± 3.2 | 8.8 ± 3.2 |
1 Values expressed as geometric means.
Note: ritonavir was dosed after a meal for all listed regimens.
Food slightly decreases the bioavailability of the ritonavir tablet. Administration of a single 100 mg dose of ritonavir tablet with a moderate fat meal (857 kcal, 31% calories from fat) or a high fat meal (907 kcal, 52% calories from fat) was associated with a mean decrease of 20-23% in ritonavir AUC and Cmax.
The apparent volume of distribution (VB/F) of ritonavir is approximately 20–40 l after a single 600 mg dose. The protein binding of ritonavir in human plasma is approximately 98–99% and is constant over the concentration range of 1.0–100 g/ml. Ritonavir binds to both human alpha 1-acid glycoprotein (AAG) and human serum albumin (HSA) with comparable affinities.
Tissue distribution studies with 14C-labelled ritonavir in rats showed the liver, adrenals, pancreas, kidneys and thyroid to have the highest concentrations of ritonavir. Tissue to plasma ratios of approximately 1 measured in rat lymph nodes suggests that ritonavir distributes into lymphatic tissues. Ritonavir penetrates minimally into the brain.
Ritonavir was noted to be extensively metabolised by the hepatic cytochrome P450 system, primarily by the CYP3A isozyme family and to a lesser extent by the CYP2D6 isoform. Animal studies as well as in vitro experiments with human hepatic microsomes indicated that ritonavir primarily underwent oxidative metabolism. Four ritonavir metabolites have been identified in man. The isopropylthiazole oxidation metabolite (M-2) is the major metabolite and has antiviral activity similar to that of parent compound. However, the AUC of the M-2 metabolite was approximately 3% of the AUC of parent compound.
Low doses of ritonavir have shown profound effects on the pharmacokinetics of other protease inhibitors (and other products metabolised by CYP3A4) and other protease inhibitors may influence the pharmacokinetics of ritonavir.
Human studies with radiolabelled ritonavir demonstrated that the elimination of ritonavir was primarily via the hepatobiliary system; approximately 86% of radiolabel was recovered from stool, part of which is expected to be unabsorbed ritonavir. In these studies renal elimination was not found to be a major route of elimination of ritonavir. This was consistent with the observations in animal studies.
No clinically significant differences in AUC or Cmax were noted between males and females. Ritonavir pharmacokinetic parameters were not statistically significantly associated with body weight or lean body mass. Ritonavir plasma exposures in patients 50–70 years of age when dosed 100 mg in combination with lopinavir or at higher doses in the absence of other protease inhibitors is similar to that observed in younger adults.
After multiple dosing of ritonavir to healthy volunteers (500 mg twice daily) and subjects with mild to moderate hepatic impairment (Child Pugh Class A and B, 400 mg twice daily) exposure to ritonavir after dose normalisation was not significantly different between the two groups.
Ritonavir pharmacokinetic parameters have not been studied in patients with renal impairment. However, since the renal clearance of ritonavir is negligible, no changes in the total body clearance are expected in patients with renal impairment.
Ritonavir steady-state pharmacokinetic parameters were evaluated in HIV infected children above 2 years of age receiving doses ranging from 250 mg/m² twice daily to 400 mg/m² twice daily. Ritonavir concentrations obtained after 350 to 400 mg/m² twice daily in paediatric patients were comparable to those obtained in adults receiving 600 mg (approximately 330 mg/m²) twice daily. Across dose groups, ritonavir oral clearance (CL/F/m²) was approximately 1.5 to 1.7 times faster in paediatric patients above 2 years of age than in adult subjects.
Ritonavir steady-state pharmacokinetic parameters were evaluated in HIV infected children less than 2 years of age receiving doses ranging from 350 to 450 mg/m² twice daily. Ritonavir concentrations in this study were highly variable and somewhat lower than those obtained in adults receiving 600 mg (approximately 330 mg/m²) twice daily. Across dose groups, ritonavir oral clearance (CL/F/m²) declined with age with median values of 9.0 L/h/m² in children less than 3 months of age, 7.8 L/h/m² in children between 3 and 6 months of age and 4.4 L/h/m² in children between 6 and 24 months of age.
Repeated dose toxicity studies in animals identified major target organs as the liver, retina, thyroid gland and kidney. Hepatic changes involved hepatocellular, biliary and phagocytic elements and were accompanied by increases in hepatic enzymes. Hyperplasia of the retinal pigment epithelium (RPE) and retinal degeneration have been seen in all of the rodent studies conducted with ritonavir, but have not been seen in dogs. Ultrastructural evidence suggests that these retinal changes may be secondary to phospholipidosis. However, clinical trials revealed no evidence of medicinal product-induced ocular changes in humans. All thyroid changes were reversible upon discontinuation of ritonavir. Clinical investigation in humans has revealed no clinically significant alteration in thyroid function tests. Renal changes including tubular degeneration, chronic inflammation and proteinurea were noted in rats and are felt to be attributable to species-specific spontaneous disease. Furthermore, no clinically significant renal abnormalities were noted in clinical trials.
Developmental toxicity observed in rats (embryolethality, decreased foetal body weight and ossification delays and visceral changes, including delayed testicular descent) occurred mainly at a maternally toxic dosage. Developmental toxicity in rabbits (embryolethality, decreased litter size and decreased foetal weights) occurred at a maternally toxic dosage.
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.
Long term carcinogenicity studies of ritonavir in mice and rats revealed tumourigenic potential specific for these species, but are regarded as of no relevance for humans.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
