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.
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.
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
AUC12 or 24 (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.
Effects of food on oral absorption:
Ingestion of ritonavir with food results in higher ritonavir exposure than ingestion in the fasted state.
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.
Metabolism:
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. F |
