Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: antivirals for systemic use, protease inhibitors ATC code: J05AE03 
Ritonavir dosed as a pharmacokinetic enhancer

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, see section 4.5 and refer to the prescribing information of the particular co- administered PIs.

Ritonavir dosed as an antiretroviral agent

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 (see section 4.2).

Effects on the Electrocardiogram

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 (see section 4.4).

Resistance

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 

prescribing information of other protease inhibitors or official continuous updates should be consulted for specific information regarding protease mutations associated with reduced response to these agents.

Clinical pharmacodynamic data

The effects of ritonavir (alone or combined with other antiretroviral agents) on biological markers of disease activity such as CD4 cell count and viral RNA were evaluated in several studies involving HIV-1 infected patients. The following studies are the most important.

Adult Use

A controlled study completed in 1996 with ritonavir as add-on therapy in HIV-1 infected patients extensively pre-treated with nucleoside analogues and baseline CD4 cell counts ≤ 100 cells/μl showed a reduction in mortality and AIDS defining events. The mean average change from baseline over 16 weeks for HIV RNA levels was -0.79 log10 (maximum mean decrease: 1.29 log10) in the ritonavir group versus -0.01 log10 in the control group. The most frequently used nucleosides in this study were zidovudine, stavudine, didanosine and zalcitabine.

In a study completed in 1996 recruiting less advanced HIV-1 infected patients (CD4 200-500 cells/μl) without previous antiretroviral therapy, ritonavir in combination with zidovudine or alone reduced viral load in plasma and increased CD4 count. The mean average change from baseline over 48 weeks for HIV RNA levels was -0.88 log10 in the ritonavir group versus -0.66 log10 in the ritonavir + zidovudine group versus - 0.42 log10 in the zidovudine group.

The continuation of ritonavir therapy should be evaluated by viral load because of the possibility of the emergence of resistance as described under section 4.1.

Paediatric Use

In an open label trial completed in 1998 in HIV infected, clinically stable children there was a significant difference (p = 0.03) in the detectable RNA levels in favour of a triple regimen (ritonavir, zidovudine and lamivudine) following 48 weeks treatment.

In a study completed in 2003, 50 HIV-1 infected, protease inhibitor and lamivudine naïve children age 4 weeks to 2 years received ritonavir 350 or 450 mg/m2 every 12 hours co-administered with zidovudine 160 mg/m2 every 8 hours and lamivudine 4 mg/kg every 12 hours. In intent to treat analyses, 72% and 36% of patients achieved reduction in plasma HIV-1 RNA of ≤ 400 copies/ml at Week 16 and 104, respectively.
Response was similar in both dosing regimens and across patient age.
In a study completed in 2000, 76 HIV-1 infected children aged 6 months to 12 years who were protease inhibitor naive and naive to lamivudine and/or stavudine received ritonavir 350 or 450 mg/m2 every 12 hours co-administered with lamivudine and stavudine. In intent to treat analyses, 50% and 57% of patients in the 350 and 450 mg/m2 dose groups, respectively, achieved reduction in plasma HIV-1 RNA to ≤ 400 copies/ml at Week 48.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
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      100 mg twice      200 mg once      200 mg twice    600 mg twice daily daily           daily1             daily            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 AUC12 or 24         6.6 ± 2.4           6.2            20.0 ± 5.6     21.92 ± 6.48        77.5 ± 31.5 (µg•h/ml) 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.

Effects of food on oral absorption

Food slightly decreases the bioavailability of the Norvir tablet. Administration of a single 100 mg dose of Norvir 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.

Distribution

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 μg /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.

Biotransformation

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 (see section 4.5).


Elimination
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.

Special populations

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.

Patients with impaired liver function

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.

Patients with impaired renal function

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.

Paediatric patients

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.