It is estimated that the fraction of dose absorbed for ritonavir is greater than 60-80%. Ritonavir is 98 to 99% bound to plasma proteins, with affinity for both albumin and a 1 -acid glycoprotein. The apparent volume of distribution of ritonavir in humans is approximately 20 to 40L.

Studies in human microsomes have shown that 3 major oxidative metabolites - M1, M2 and M11, are formed primarily by cytochrome P450 3A4. CYP2D6 was also found to produce the metabolite M2. About 86% of the dose is recovered in the faeces and 11% in the urine over a 148-hour period.

The pharmacokinetics of ritonavir were only moderately affected in patients with HIV with mild or moderate hepatic insufficiency. A trend of decreasing elimination rate constant with decreasing hepatic function was observed. As less than 3.5% of the dose is renally eliminated, renal impairment is expected to have no effect on the clearance of ritonavir.

Studies suggest that the nitrogen atom within the unsubstituted 5-thiazolyl group of ritonavir binds directly to the CYP heme iron. Several structural features combine to confer high CYP-inhibitory potency upon ritonavir, including direct heme interaction via an unhindered electron-rich atom, extensive hydrophobic interactions with the CYP-active site, and stability toward CYP-mediated oxidative chemistry. 3

All PIs are primarily (>50%) metabolized by CYP3A4 isoenzymes. PIs are also CYP3A inhibitors, with the following value order of potency: ritonavir >> indinavir = nelfinavir = amprenavir > saquinavir. 1

The actual effects observed with PI-boosting through P450 inhibition (with or without P-gp inhibition) vary among agents. Two effects are predominantly seen:

• C max, C min and t 1/2 boosting

• t 1/2 and C min boosting

For drugs that have high first-pass metabolism, such as saquinavir and lopinavir, the effects of low-dose ritonavir (e.g. 100 mg bid) are to boost all the key parameters - C max , C min and AUC - and to prolong the t 1/2 . Fortunately, very high plasma C max of these agents seems well tolerated. In addition, the high C max , together with P-gp inhibition, may lead to the intracellular C min being substantially above the plasma C min .

For drugs with reasonable bioavailability but short half-lives, such as indinavir and amprenavir, the effects of ritonavir are predominantly on the t 1/2 , C min and AUC. This is fortunate because an increased C max with indinavir may be associated with increased risk of crystalluria and nephrolithiasis. 4

The boosting effects of ritonavir on saquinavir, indinavir and nelfinavir respectively are summarized in Table 2. 5

Ritonavir is commonly used to boost levels of indinavir and saquinavir. Lopinavir is a protease inhibitor that is available as a co-formulation with low-dose ritonavir.

When combining ritonavir and another protease inhibitor, two strategies can be chosen. In one the ritonavir dose is kept as low as possible (e.g., 100 or 200 mg bid) to avoid ritonavir-specific side effects, accepting the fact that the plasma ritonavir levels will be too low to exert antiretroviral activity, and so the antiretroviral activity depends solely on the other protease inhibitor. Another strategy is to administer ritonavir in higher doses (e.g., 400 mg bid) so the drug itself inhibits HIV replication in addition to inhibition by the other protease inhibitor. However, since the toxicity of ritonavir is dose-dependent, 100 mg of ritonavir is increasingly being preferred.

Rifampin is a potent CYP3A inducer which affects the metabolism of ritonavir. The AUC and C min are decreased at therapeutic doses by 35 and 50% respectively.
Co-administration of ritonavir (at 600 mg b.i.d.) and rifampin may be associated with hepatic transaminase elevations. Thus, concomitant use of ritonavir and rifampicin is not recommended. 1

Since ritonavir is a potent CYP3A4 inhibitor, concurrent administration of ritonavir with another PI may increase trough levels, increase exposure, lead to dose reductions, and make twice daily dosing of PI combinations feasible. These are important issues for long-term viral suppression and adherence to HAART. Thus, ritonavir boosting overcomes many of the intrinsic unfavourable pharmacokinetic features of protease inhibitors.

This study9 evaluated the virologic efficacy and safety of quadruple therapy with 2 NRTIs and ritonavir 400 mg bid plus indinavir 400 mg bid in antiretroviral-naïve patients. Ninety patients with median baseline viral loads of 220,000 copies/ml and median CD4 counts of 189 cells/ m l were started on a twice-daily regimen of either zidovudine/lamivudine (49%), stavudine/lamivudine (38%) or stavudine/didanosine (13%) in combination with ritonavir and indinavir.

The proportion of patients with HIV RNA levels of < 500 copies/ml and
< 80 copies/ml increased steadily during follow-up, and are depicted in Figure 1. The CD4 count increased steadily from the mean baseline value of 214 ± 166 cells/ m l to 384 ± 250 cells/ m l at week 24. Figure 2 shows the mean increase in CD4 counts during the study.

Eleven patients (12.2%) stopped randomized treatment. Seven patients (7.7%) stopped treatment due to adverse events. The most frequent adverse events observed were diarrhoea, nausea and perioral paraesthesias during the first days of initial ritonavir administration. The majority of patients also showed elevations of triglycerides and cholesterol throughout the study period. Cholesterol levels rose from a mean baseline level of
179 mg/dl to 234 mg/dl at week 12 and 239 mg/dl at week 24. In parallel, triglycerides rose from 132 mg/dl at week 0 to 244 mg/dl at week 12 and 263 mg/dl at week 24. Over the 24-week follow-up no episode of renal toxicity was observed throughout the study population.

This study concluded that the twice daily regimen of ritonavir 400 mg/indinavir 400 mg plus double nucleoside therapy in antiretroviral-naïve patients has good antiviral efficacy even in the presence of high baseline viral loads.

Discussion

The fact that no episode of kidney stones was reported in this study suggests that the lower peak levels of indinavir in this twice daily combination, versus the indinavir peak levels obtained under the three times daily indinavir treatment, correlate with the decline in renal complications. In parallel, none of the study subjects developed an increase in serum creatinine > 1.4 mg/dl within the 24-week follow-up, which is in contrast with the creatinine elevations observed under the three times a day indinavir treatment.

The HIV NAT 005 study compared the virological and immunological efficacy and safety of indinavir 800 mg tid and indinavir/ritonavir 800 mg/100 mg bid, in combination with zidovudine 300 mg bid and lamivudine 150 mg bid. 106 patients were enrolled, of whom 104 started treatment. Median overall duration of therapy prior to study entry was 29 months. All patients had been exposed to zidovudine in combination with either didanosine or zalcitabine as dual therapy. 39% of patients had been treated with zidovudine monotherapy.

Median CD4 count at entry was 168, and median HIV RNA was 4.0 log.

At week 112 no significant differences were found in decrease in viral load or increase in CD4 counts (Table 1), or percentage of patients with viral load less than 50 copies/ml (59% tid, 64% bid, p=0.86).

The study concluded that there were no statistically significant differences in virological or immunological response between the tid and bid arms. Patients in both arms responded well despite past nucleoside exposure. However, there was a trend towards more drug interruptions, dose reductions and adverse events in the bid arm. Clinical nephrolithiasis and nephrotoxicity were observed in both arms, with a trend towards more events in the bid arm. Lipid levels in the bid arm were significantly raised compared to tid dosing.

Discussion

A recent study12 has evaluated the pharmacokinetics, efficacy and tolerability of a low-dose indinavir/ritonavir 400/100 mg bid in patients who were previously receiving a standard indinavir regimen (800 mg tid) and had plasma HIV RNA less than 200 copies/ml. Twenty patients were enrolled.

In this study, no nephrotoxicity and no lipid abnormalities were observed during the 48-week study period. The 2.5-fold reduction in peak indinavir concentrations may explain the good clinical and biological tolerability of IDV/RTV 400/100 mg bid. This regimen increased the IDV C min by 2.5-fold compared to the standard 800 mg tid regimen (p<0.001). This study also suggests that this dosage regimen offers a larger "safety margin" in case of missed doses, due to higher C min levels. This regimen also has cost advantages.

This study was a prospective, randomized, open-label comparative trial in treatment-naïve patients. It enrolled 69 patients with a median baseline viral load of 4.92 log10 copies/ml and median baseline CD4 count of 180 cells/ m l. Patients received zidovudine/lamivudine or stavudine/ didanosine plus nevirapine, efavirenz or ritonavir-boosted indinavir. An interim analysis was performed at 9 months (Table 3).

There was no statistically significant difference in virologic efficacy between nevirapine versus efavirenz, and NNRTIs versus indinavir/ritonavir. The median increase in CD4 count was significantly greater with stavudine/didanosine compared to zidovudine/lamivudine (p=0.006), without differences between nevirapine, efavirenz and indinavir/ ritonavir.